FSHD - Word Gene Mutation

A number sign (#) is used with this entry because facioscapulohumeral muscular
dystrophy-1 (FSHD1) is associated with contraction of the D4Z4 macrosatellite repeat

(see 606009) in the subtelomeric region of chromosome 4q35.
In unaffected individuals, the D4Z4 array consists of 11 to 150 repeat units
(corresponding to EcoRI fragments of 41 to 350 kb), whereas FSHD patients have
contraction of the repeat units from 1 to 10 (corresponding to EcoRI fragments of 10 to
35 kb). Borderline fragment sizes (35 to 40 kb) must be interpreted with caution
(summary by Mostacciuolo et al., 2009).
The genetics of FSHD is, however, complex, and detection of a D4Z4-reduced allele may
not be sufficient for diagnosis (see DIAGNOSIS below and Scionti et al., 2012).
▼ Description
Facioscapulohumeral muscular dystrophy is the third most common hereditary disease
of muscle after Duchenne (DMD; 310200) and myotonic (160900) dystrophy. It is a
highly variable disorder with weakness appearing from infancy to late life but typically
in the second decade. In general, the disease initially involves the face and the scapulae
followed by the foot dorsiflexors and the hip girdles. Typical features are striking
asymmetry of muscle involvement from side to side and sparing of bulbar extraocular
and respiratory muscles (Tawil et al., 1998).
Richards et al. (2012) provided a detailed review of FSHD.
See also FSHD2 (158901), which is phenotypically indistinguishable from FSHD1 but not
associated with contraction of the D4Z4 microsatellite repeat. Evidence suggests,
however, that epigenetic changes in this region are associated with both FSHD1 and
FSHD2 (Zeng et al., 2009).
▼ Clinical Features
Justin-Besancon et al. (1964) added 3 affected generations to the 4 described
by Landouzy and Dejerine (1885) and gave autopsy findings in 1 of the original patients
who died at age 86 years. Some cases show congenital absence of part or all of certain
muscles such as a pectoral muscle. The relationship of the congenital defect of muscle to
the dystrophy is unclear. Tyler and Stephens (1950)and Tyler (1953) reported 17 families.
In 1 kindred 150 members were affected over 6 generations. A girl, whose face alone was
affected at age 9 when examined by Landouzy and Dejerine (1885), did not develop
weakness of the arms until age 60 and of the legs until age 70, and survived to age 85
years. In her family, affected members were distributed through 8 generations.
Meyerson et al. (1984) reported sensorineural hearing loss in 2 sibs with FSH muscular
dystrophy which affected other members of the family in typical manner. The studies
of Brouwer et al. (1991)suggest that a 'change of hearing function is part of the disease
and may lead to severe hearing loss in some patients.' Deafness and abnormalities of
retinal vessels (see later) are probably integral parts of the disorder.
Sayli et al. (1984) found at least 53 affected persons in a Turkish kindred originating in
the village of Cullar. Initial signs and symptoms seemed to appear early in infancy in
many. The disorder progressed slowly without interfering significantly with survival
and reproduction. Symptoms first involved the face, upper arms, and shoulder muscles.
Creatine kinase levels were 1.5 to 2 times normal. Many of the affected persons were
identified on examination; only 13 reported complaints and their mean age was 40.1
years. After the kindred reported by Tyler and Stephens (1950), this is the most
extensively affected family studied to date. Awerbuch et al. (1990) found that the Beevor
sign was present in 27 of 30 patients with FSHD but absent in all 40 patients with other
neuromuscular disorders. They concluded that it is a common finding in FSHD patients
even before functional weakness of abdominal wall muscles is apparent. Because of
weakness of the lower rectus abdominis muscles, the umbilicus moves upward when
the subject in the supine position raises his or her head, producing the Beevor sign. (This
sign was originally proposed by English neurologist Charles E. Beevor as an indication
of the level of involvement in spinal cord lesions.) Bodensteiner and Schochet
(1986) suggested the supraspinatus muscle as the site of choice for biopsy in this
disorder. Reardon et al. (1991) pointed out the difficulties in some cases in
distinguishing FSHD from the Becker type of muscular dystrophy (300376). Calf
hypertrophy, although rare, has been reported in FSHD. Jardine et al. (1993) reexamined
the 3 affected members in the family reported by Reardon et al. (1991) and demonstrated
that they had a rearrangement in the region of the FSHD gene as indicated by studies
with probe p13E-11.
Shen and Madsen (1991) described symptomatic atrial tachycardia, for which an
antitachycardic pacing device was implanted, in a 44-year-old woman. Her severe
scapular and shoulder weakness led to recurrent dislodgment of the atrial pacemaker
lead.
According to Bailey et al. (1986), infantile facioscapulohumeral muscular dystrophy was
recognized by Duchenne (1862) and differentiated from pseudohypertrophic muscular
dystrophy over 20 years before the description of the usual form of facioscapulohumeral
muscular dystrophy by Landouzy and Dejerine (1885). Whereas FSHD is generally a
benign, slowly progressive myopathy that begins in late childhood or adolescence and
leads to disability only late in its course, occasional families contain individuals with a
severe infantile form of the disorder who have 1 asymptomatic or minimally affected
parent. Bailey et al. (1986) reported a family in which the severe infantile presentation
predominated. They suggested 'that the gene coding for this disorder may be different
from that responsible for conventional facioscapulohumeral muscular dystrophy.' The
genes for the 2 forms of the disease may, of course, be allelic.
In 56 of 75 persons with clinical or genetic evidence of FSH muscular
dystrophy, Fitzsimons et al. (1987) found peripheral retinal capillary abnormalities
including telangiectasia, closure, leakage, and microaneurysm formation. They were
prompted to do this study by the occasional reports of exudative retinal detachment and
deafness with this disorder. The study included 1 FSH family in which the proband was
treated for exudative retinopathy and 13 other members had retinal telangiectasia. There
were 8 cases, including 3 parents of apparently 'sporadic' FSH cases, in which
fluorescein angiography 'confirmed the abnormal genotype, even though clinical
examination of skeletal muscle revealed no clear abnormality.' Fitzsimons et al.
(1987) concluded that retinal capillary abnormalities are an integral part of FSH
muscular dystrophy and raised the question as to whether analogous capillary
abnormalities may be implicated in the pathogenesis of the muscle disease. Padberg et
al. (1992) came to similar conclusions on the basis of studies using fluorescein retinal
angiography in 32 patients from 19 families. In 16 of the 32, representing 11 families,
retinal capillary changes were found consisting of telangiectasia, microaneurysms,
vessel occlusions, and small exudates and hemorrhages in the macular as well as in the
peripheral retina. In addition, tone audiometry was performed, with the finding that 20
sibs from 14 families had some degree of high-tone deafness. Similar findings were
observed in 8 sporadic cases: 4 had retinal vasculopathy and 5 had high-tone deafness.
Combined with linkage data, these observations demonstrated that retinal vasculopathy
and high-tone sensorineural deafness are part of the clinical picture of FSHD and are no
grounds for assuming genetic heterogeneity.
Small (1968) described 4 sibs with facioscapulohumeral dystrophy and bilateral retinal
exudative telangiectasia, labeled Coats disease (see 300216). Neurosensory deafness and
mental retardation were present in all 4. Taylor et al. (1982) and Voit et al.
(1986) described the same association. Yasukohchi et al. (1988) described a brother and
sister with facioscapulohumeral dystrophy. The brother, aged 13 years, also had
sensorineural hearing loss, marked tortuosity of retinal arterioles, early onset and
progression of severe restrictive pulmonary dysfunction, and cor pulmonale. The 8-year-
old sister had only muscle manifestations. Bilateral sensorineural hearing loss in the
high frequency range was described in the above patients. In some, the hearing loss was
clearly progressive and with time tended to involve lower frequencies (Voit et al., 1986).
As noted from the cases cited, autosomal dominant inheritance was not always clear;
recessive inheritance was possible and might point to this being an entity separate from
FSHD. Brouwer et al. (1991) performed screening audiometry in 56 patients with
autosomal dominant FSHD and in 72 healthy family members, and found that the
difference in hearing levels between 4,000 Hz and 6,000 Hz was significantly greater in
FSHD patients than in their unaffected relatives. This led them to conclude that a change
in hearing function is part of the disease and may lead to severe hearing loss in some
patients. Gieron et al. (1985) described a mother and 3 children with FSHD,
sensorineural hearing loss, and marked tortuosity of retinal vessels. The deafness, which
varied from mild to moderate, was bilateral and early in onset. Audiologic studies
indicated the cochlea as the site of the abnormality. Matsuzaka et al. (1986) reported a
sporadic case of this constellation of manifestations plus mental retardation and
suggested that these cases constitute a nosologically specific form of FSHD.
Shields et al. (2007) noted that retinal telangiectasia compatible with Coats disease
(300216) can be an extramuscular manifestation of FSHD but that most affected patients
have asymptomatic retinal telangiectasia found at ocular screening after diagnosis of
FSHD. They described a young child who had advanced eye findings of unilateral
neovascular glaucoma from bilateral retinal telangiectasia 3 years before FSHD became
apparent.
Miura et al. (1998) reported 2 sporadic cases of early-onset scapulohumeral muscular
dystrophy with mental retardation and epilepsy in unrelated, severely affected females.
In both cases, Southern blot analysis of the EcoRI-digested genomic DNA, using 2
probes, detected 10-kb EcoRI fragments, the shortest reported to that time. Patient 1
showed infantile spasms at the age of 4 months and localization-related epilepsy at the
age of 2.5 years. Muscular atrophy in the face, shoulder girdle, and upper arms was
observed from the age of 4 years. In patient 2, lack of facial expression was noticed since
the age of 1 year, and at 4 years she was noted to have loss of upward gaze bilaterally.
She developed localization-related epilepsy at the age of 9 years. From the age of 10
years, weakness of the lower limbs progressed and she became wheelchair-bound at the
age of 14 years. She had moderate sensorineural hearing loss, a loss of upward gaze
bilaterally, and tongue atrophy. Their IQs were 33 and 45, respectively. Miura et al.
(1998) suggested that mental retardation and epilepsy may be part of the clinical
spectrum of FSHD, especially in very early-onset patients with large deletions.
Among 151 Japanese patients with FSHD, Yamanaka et al. (2001) reported 7 patients
with tongue atrophy with abnormal tongue MRI findings (disorganized architecture)
and typical myogenic patterns of electromyography. All patients were classified as
having early-onset FSHD with large gene deletions within the 4q35 gene region.
Krasnianski et al. (2003) described atypical features in 6 of 41 patients with FSHD and
the 4q35 deletion. Three patients from 1 family showed the typical phenotype with the
additional feature of chronic progressive external ophthalmoplegia. Three patients, 2
from 1 family, showed sparing of the facial muscles, and 2 of these patients had severe,
diffuse myalgia. There was no correlation between the atypical features and the DNA
fragment size due to the deletion.
Wohlgemuth et al. (2006) found that 10 of 87 individuals with FSHD had signs of
weakness in the jaw, lips, or tongue. Oropharyngeal evaluation in 8 of these patients
detected mild to moderate swallowing abnormalities in 7 patients and tongue atrophy in
6.
See 182970 for a form of spinal muscular atrophy simulating FSH muscular dystrophy.
Pathologic Features
In a 20-year-old woman who had inherited FSHD from her father and who also had an
affected brother, Slipetz et al. (1991) found that muscle biopsy showed fiber atrophy
with patchy staining for oxidative enzymes; that electron microscopy of liver showed
many enlarged mitochondria with paracrystalline inclusions; and that skin fibroblasts
showed decreased oxidation of the respiratory substrates alanine and succinate,
suggesting deficiency of complex III of the electron-transport chain. Cytochrome c
oxidase activity (complex IV) was normal. Biochemical analysis of liver supported the
fibroblast data, since succinate oxidase activity (electron-transport activity through
complexes II-IV) was reduced and complex IV activity was normal. Cytochrome b, a
component of complex III, was undetectable in liver, although typical peaks were found
for other cytochromes. Southern blot analysis of fibroblast mtDNA showed no major
deletions or rearrangements.
Using confocal microscopy, Reed et al. (2006) found that some of the structures at the
sarcolemma in FSHD skeletal muscle biopsies were misaligned with respect to the
underlying contractile apparatus. Electron microscopy showed a significant increase in
the distance between the sarcolemma and the nearest myofibrils, from less than 100 nm
in controls to 550 nm in FSHD. Reed et al. (2006) concluded that the pathophysiology of
FSHD includes novel changes in the organization of the sarcolemma and the
subsarcolemmal membrane cytoskeleton.
▼ Mapping
Padberg et al. (1984) found possible linkage to Gm (147100) (maximum lod score = 1.428
at theta = 0.2). Padberg et al. (1988) followed up on this observation by testing linkage
with D14S1 (107750). They excluded linkage, thus suggesting that the FSH muscular
dystrophy locus is not situated on the distal part of the long arm of chromosome
14. Sarfarazi et al. (1989) presented exclusion data, resulting from an international
collaboration, showing that more than 85% of the human genome has been excluded as
a likely location for the FSHD gene. Chromosomes 3, 5, 10, 11, 15, and 19 remained
largely unexcluded. Lucotte et al. (1989) excluded 3 chromosomal regions, including
proximal 19q. Lunt et al. (1989) presented linkage data for 22 different DNA markers in
24 families with FSHD. They achieved a maximum lod score of 1.87 at a theta of 0.15
with anonymous marker D18S3, which has been localized to 18p11.3. In a clinically
homogeneous group of families, Jacobsen et al. (1990)excluded chromosomes 1, 2, 5, 7,
10, and 16 as the site of the FMD mutation. They estimated that 23% of the human
genome was excluded.
In a study of 10 Dutch families, Wijmenga et al. (1990) found linkage of FSH muscular
dystrophy to a microsatellite marker Mfd22 (D4S171) on chromosome 4; maximum lod
score = 6.34 at theta = 0.13. Only 1 family was uninformative for this marker. No
evidence of heterogeneity was found. From the map location of the marker, it appeared
that the FSHD gene was located near the distal end of 4q. Siddique et al. (1989) studied 2
multigeneration families with the neurogenic form of facioscapulohumeral disease
considered to be a form of spinal muscular atrophy. Possible linkage to MNS on 4q was
found.
In a linkage study of FSHD families, Upadhyaya et al. (1991) found 3 recombinants in a
total of 140 meioses for linkage with a hypervariable DNA probe on 4q (pH30, locus
D4S139), giving a maximum lod score of 36.77 at a recombination fraction of
0.02. Wijmenga et al. (1991) found a VNTR locus, D4S139, to be much more closely
linked to FSHD than to D4S171. This marker was mapped to 4q35-qter by in situ
hybridization. One small family yielded a negative lod score for D4S139, but otherwise
there was no evidence of genetic heterogeneity. In 9 informative families, they found a
maximum lod score of 17.28 at theta = 0.027.
Mathews et al. (1991) defined the location of FSHD as 4q35. They used a probe derived
from the breakpoint of an X;4 translocation with a breakpoint at 4q35. The patient had
facial weakness at age 4 years. A peak lod score of 8.23 at theta = 0.00 was found with a
4q35 probe, D4S139. Reporting for a consortium, Sarfarazi et al. (1992) defined the
relationship of the FSHD locus to markers in the 4q35 region in 65 families containing a
total of 504 affected persons. No evidence of heterogeneity was found in the initial
study; however, after completion of the analysis, 1 large family that might show
heterogeneity was identified. In view of this and the fact that all of the linked markers
were on the centromeric side of the FSHD locus, Sarfarazi et al. (1992) recommended
that these markers not yet be used in clinical applications. Upadhyaya et al. (1992) found
that FSHD was situated telomeric to all 4 DNA markers that they used in a series of 23
families. However, Wijmenga et al. (1992) found at least one recombination event which
suggested that 1 of the 4 markers, D4S139, might lie distal to FSHD. In a study of 4
families with FSHD, Mathews et al. (1992) found close linkage to three 4q35 probes,
D4S163, D4S139, and D4S171. Two of their families included males with a rapidly
progressive muscle disease that had been diagnosed, on the basis of clinical features, as
Duchenne muscular dystrophy. One of these males was available for linkage study and
shared the haplotype of his FSHD-affected cousin and aunt.
Mills et al. (1992) generated a fine-structured genetic map of the distal long arm of
chromosome 4 by a combination of classical RFLPs and PCR-based polymorphisms
including CA repeats and single-strand conformation polymorphisms (SSCP). Gilbert et
al. (1992) and Weiffenbach et al. (1992)demonstrated that both D4S139 and D4S163 are
closely linked to FSHD, with D4S139 being the closest proximal marker to FSHD. No
telomeric marker to FSHD had been demonstrated.
Gilbert et al. (1993) found evidence for heterogeneity in FSHD. In linkage studies, 5 of 7
families gave a posterior probability of more than 95% of being of the linked type, while
2 families appeared unlinked to that region of distal 4q. Affected members of the 2
unlinked families met the clinical criteria for the diagnosis of FSHD, including facial
weakness, clavicular flattening, scapula winging, proximal muscle weakness, and
myopathic changes on muscle biopsy without inflammatory or mitochondrial
pathology. See 158901.
▼ Molecular Genetics
All patients with a confirmed diagnosis of FSHD and for whom detailed molecular
studies have been performed carry a chromosomal rearrangement within the
subtelomeric region of 4q (4q35). This subtelomeric region is composed mainly of a
polymorphic repeat structure consisting of 3.3-kb repeated elements, designated D4Z4
(see 606009). The number of repeat units varies from 10 to more than 100 in the
population, and, in FSHD patients, an allele of 1 to 10 residual units is observed because
of the deletion of an integral number of these units (Wijmenga et al., 1992; Hewitt et al.,
1994).
D4Z4 Macrosatellite Repeat
For a full discussion of the D4Z4 macrosatellite repeat, see 606009.
Lemmers et al. (2004) summarized the relationship of the D4Z4 repeat to FSHD. The
polymorphic D4Z4 repeat is highly recombinogenic, since somatic mosaicism for
rearrangement of D4Z4 is found in as much as 3% of the general population (van
Overveld et al., 2000). The D4Z4 repeat consists of identical units defined by the
restriction enzyme KpnI, each 3.3 kb, ordered in a head-to-tail fashion, and varying
between 11 and 100 units on 'healthy' chromosomes (van Deutekom et al., 1993).
Patients with FSHD carry a repeat of 1 to 10 units on one of their chromosomes 4
(Wijmenga et al., 1992). A rough and inverse correlation has been observed between the
severity and age at onset of the disease and the residual repeat unit number.
In a review of genetic disorders associated with aberrant chromatin structure, Bickmore
and van der Maarel (2003) noted that FSHD represents a potential example of gene
activation through loss of repression complexes.
A review of the D4Z4 repeat-mediated pathogenesis of FSHD was provided by van der
Maarel and Frants (2005). They pointed out that in contrast to most monogenic
disorders, in which the genetic lesion typically affects the structure or function of a
specific disease gene, evidence suggested that FSHD is caused by a complex epigenetic
mechanism involving the contraction of a subtelomeric macrosatellite repeat. It is likely
not the structure but rather the (spatiotemporal-restricted) transcriptional control of one
or more disease genes that is perturbed in FSHD as a result of repeat-contraction-
mediated chromatin alterations. Their review focused on the cause and consequence of
the repeat-array contraction. Van der Maarel and Frants (2005) designated FSHD a
macrosatellite repeat-contraction disease.
Van Overveld et al. (2003) showed that contraction of the D4Z4 repeat array causes
marked hypomethylation of the contracted D4Z4 allele in individuals with FSHD1.
Individuals with FSHD clinically identical to other cases but with an unaltered D4Z4
(FSHD2; 158901) also have hypomethylation of D4Z4. These results strongly suggested
that hypomethylation of D4Z4 is a key event in the cascade of epigenetic events causing
FSHD1.
Using chromatin immunoprecipitation (ChIP) in HeLa cells, Zeng et al. (2009) found
SUV39H1 (300254)-mediated trimethylation of histone H3 (see 602810) at lysine-9
(H3K9), as well as trimethylation at H3 at lysine-27 (H3K27), both at D4Z4, representing
transcriptionally repressive heterochromatin. There was also H3K4 dimethylation and
H3 acetylation at proximal D4Z4 repeat regions, marking transcriptionally permissive
euchromatin. The methylation signal at H3K9, at both the 4q and the 10q locus, was
significantly decreased in cell lines derived from patients with FSHD1 (myoblasts and
fibroblasts) and FSHD2 (fibroblasts) compared to controls. Contraction of D4Z4 at 1
allele showed a dominant effect on methylation of H3K9 at the other allele, as well as at
the 10q locus, suggesting a spreading effect of histone modification. DNA
hypomethylation was not observed in FSHD cells, and the decrease in H3K9
methylation was not observed in cells from patients with other forms of muscular
dystrophy. Immunoprecipitation studies showed that loss of methylation at H3K9
interrupted binding of CBX3 (604477) and the cohesin complex (see, e.g., SCC1, 606462)
at this region. Zeng et al. (2009) hypothesized that loss of H3K9 methylation, and thus
loss of CBX3 and cohesion, results in the disruption of chromatin regulation, thereby
causing abnormal derepression of distant target genes that leads to the dystrophic
phenotype specific to muscle tissue.
DUX4 Expression
Dmitriev et al. (2008) noted that the DUX4 gene (606009) found within the D4Z4 repeat
was initially considered to be nonfunctional because it lacked introns and
polyadenylation signals. Furthermore, expression of DUX4 could not be detected
despite the efforts of several groups using various methods including screening of
cDNA libraries, RT-PCR, microarray, and Pol II ChIP. Subsequently, work by Dixit et al.
(2007) and Clapp et al. (2007) confirmed expression of DUX4 in human and mouse,
respectively, and showed conservation of the DUX4 ORF for more than 100 million
years.
Bosnakovski et al. (2008) conditionally expressed cDNAs for FSHD candidate genes
within the D4Z4 repeat, DUX4, FRG1 (601278), FRG2 (609032), and ANT1
(SLC25A4; 103220), in mouse C2C12 myoblasts at both high and low expression levels
and found that only DUX4 was overtly toxic, as indicated by cellular ATP content,
morphologic changes, and apoptosis. DUX4 showed variable toxicity when expressed in
mouse fibroblasts or embryoid bodies. DUX4 localized to C2C12 cell nuclei within 2
hours of induction. Microarray analysis revealed altered expression in a broad range of
genes, with greatest changes in those involved in growth and development and signal
transduction. Expression of Myod was also downregulated at an early time point.
Oxidative stress and heat shock genes were downregulated at later time points,
suggesting that they may be secondary targets. The DUX4 homeodomains are most
similar to those of PAX3 (606597) and PAX7 (167410), and overexpression of these genes
rescued viability and proliferation in DUX4-expressing C2C12 cells. Bosnakovski et al.
(2008) concluded that DUX4 may cause FSHD by interfering with normal PAX3 or PAX7
function in muscle satellite cells.
Lemmers et al. (2010) showed that FSHD patients carry specific single-nucleotide
polymorphisms in the chromosomal region distal to the last D4Z4 repeat. This FSHD-
predisposing configuration creates a canonic polyadenylation signal for transcripts
derived from DUX4, a double homeobox gene that straddles the last repeat unit and the
adjacent sequence. Transfection studies revealed that DUX4 transcripts are efficiently
polyadenylated and are more stable when expressed from permissive chromosomes.
This particular chromosomal setting containing the pathogenic sequences was named
4APAS (4A polyadenylation signal; Scionti et al., 2012). Lemmers et al. (2010) concluded
that their findings suggested that FSHD arises through a toxic gain of function
attributable to the stabilized distal DUX4 transcript.
By RT-PCR, Snider et al. (2010) found that full-length DUX4 (DUX4-fl) was aberrantly
expressed in 5 of 10 FSHD muscle biopsy specimens, but not in normal muscle
specimens. PCR analysis of myoblast cultures of varying pool size, and
immunohistochemical analysis of cultured myoblasts revealed that only about 0.1% of
FSHD muscle nuclei expressed a relatively abundant amount of DUX4-fl mRNA and
protein. DUX4-fl was also aberrantly expressed in differentiated FSHD embryoid bodies.
A short variant of DUX4 (DUX4-s) was expressed in both FSHD and control tissues and
cells. Aberrant DUX4-fl was often associated with apoptotic changes, and in all cases
was associated with the FSHD permissive 4qA haplotype (see below). Snider et al.
(2010) concluded that repressive chromatin associated with D4Z4 in differentiated cells
may facilitate usage of the noncanonical splice donor site to generate DUX4-s, and the
more permissive chromatin in FSHD may favor polymerase progression through to the
consensus splice donor and generate DUX4-fl.
Wallace et al. (2011) showed that apoptotic changes observed in DUX4-expressing
HEK293 cells were eliminated by inactivating mutation of the first DNA-binding
homeobox domain of DUX4. The development of lesions in DUX4-injected mouse
muscle was also abrogated by mutation of the DUX4 homeobox domain. Pharmacologic
inhibition of p53 (TP53; 191170) mitigated DUX4 toxicity in HEK293 cells, and muscle
from p53-null mice were resistant to DUX4-induced damage. Wallace et al.
(2011) concluded that DUX4-induced myopathy is dependent on p53-induced
apoptosis.
4qA and 4qB Polymorphic Segment
Human 4qter and 10qter share a high degree of similarity, including the D4Z4 repeat
array; however, contractions affecting the 10qter repeat are nonpathogenic. Van Geel et
al. (2002) detected a polymorphic segment of 10 kb directly distal to D4Z4, which they
called alleles 4qA and 4qB. Lemmers et al. (2002) reported that although the 2 alleles are
equally common in the general population, FSHD is associated solely with the 4qA
allele. They suggested that this was the first example of an intrinsically benign
subtelomeric polymorphism predisposing to the development of human disease.
Lemmers et al. (2004) concluded that contractions of D4Z4 on 4qB subtelomeres do not
cause FSHD. The 2 allelic variants of 4q, 4qA and 4qB, exist in the region distal to D4Z4.
Although both variants are almost equally present in the population, FSHD is associated
exclusively with the 4qA allele. Lemmers et al. (2004) identified 3 families with FSHD in
which each proband carried 2 FSHD-sized alleles and was heterozygous for the 4qA/4qB
polymorphism. Segregation analysis demonstrated that FSHD-sized 4qB alleles are not
associated with disease, since these were present in unaffected family members. Thus, in
addition to a contraction of D4Z4, additional cis-acting elements on 4qA may be
required for the development of FSHD. Alternatively, 4qB subtelomeres may contain
elements that prevent FSHD pathogenesis.
Lemmers et al. (2007) hypothesized that allele-specific sequence differences among 4qA,
4qB, and 10q alleles underlie the 4qA specificity of FSHD. By examining sequence
variations in the FSHD locus, they demonstrated that the subtelomeric domain of
chromosome 4q can be subdivided into 9 distinct haplotypes, of which 3 carry the distal
4qA variation. They showed that repeat contractions in 2 of the 9 haplotypes, 1 of which
is a 4qA haplotype, are not associated with FSHD. Lemmers et al. (2007) showed that
each of these haplotypes has its unique sequence signature, and proposed that specific
SNPs in the disease haplotype are essential for the development of FSHD.
Thomas et al. (2007) measured the frequency of 4qA-defined and 4qB-defined
subtelomeric sequences in 164 unrelated patients with FSHD from the UK and Turkey,
all known to have large D4Z4 deletions. An almost complete association (162 of 164
patients) was found between large D4Z4 repeat array deletions located on 4qA-defined
4qter subtelomeres and disease expression. DNA samples from 50 controls displayed
equivalent frequencies for 4qA and 4qB markers, as did the normal chromosome 4 in all
65 patients studied. The 4qA and 4qB probes failed to hybridize in 2 patients, confirming
the presence of an additional rare type of 4qter subtelomeric sequence in humans.
Wang et al. (2011) provided evidence that the 4qB-associated D4Z4 contraction is not
pathogenic in Chinese individuals. Molecular reexamination of 3 unrelated Chinese
patients originally diagnosed with FSHD on the basis of a D4Z4 contraction showed that
all were nonpathogenic 4qB variants. All 3 patients were found to have different
disorders with similar phenotypes, including LGMD2A (253600), LGMD2E (604286),
and DM1 (160900), respectively. A fourth Chinese patient originally diagnosed with
FSHD was found to have a pathogenic 18-kb D4Z4 4qA contraction that she inherited
from her symptomatic mother. Her 2 daughters carried a paternally inherited 24-kb
nonpathogenic contraction that was found to be a mixture of 4q and 10q. The daughters
were thus considered unaffected, whereas previously they had been misdiagnosed as
asymptomatic cases. Wang et al. (2011) concluded that the D4Z4 repeat length analysis
alone is insufficient for the diagnosis of FSHD, and should be accompanied by 4qA/4qB
variant determination.
Expression of Other Genes within the FSHD Candidate Region
Van Deutekom et al. (1996) identified a novel gene, which they referred to as FRG1
(601278), that mapped 100 kb centromeric of the repeated units on chromosome 4q35
that are deleted in FSHD. They identified a polymorphism in exon 1 of this gene and
used RT-PCR to amplify reverse transcribed mRNA from lymphocytes and muscle
biopsies of patients and controls. These studies indicated that both alleles were
transcribed and gave no evidence of 'position effect' variegation leading to repression of
allelic transcription.
Gabellini et al. (2002) found that in FSHD muscle, genes located upstream of D4Z4 on
4q35, including FRG1, FRG2 (609032), and ANT1 (103220), are inappropriately
overexpressed. They showed that an element within D4Z4 specifically binds a
multiprotein complex consisting of transcriptional repressor YY1 (600013), HMGB2
(163906), and nucleolin (NCL; 164035). This multiprotein complex binds D4Z4 in vitro
and in vivo and mediates transcriptional repression of 4q35 genes. Gabellini et al.
(2002) proposed that deletion of D4Z4 leads to the inappropriate transcriptional
derepression of 4q35 genes, resulting in disease. In normal individuals, the presence of a
threshold number of D4Z4 repeats leads to repression of 4q35 genes by virtue of the
DNA-bound multiprotein complex that actively suppresses gene expression. In FSHD
patients, deletion of an integral number of D4Z4 repeats reduces the number of bound
repressor complexes and consequently decreases or abolishes transcriptional repression
of 4q35 genes.
By oligonucleotide microarrays, Winokur et al. (2003) compared FSHD expression
profiles with those from normal muscle and DMD and LGMD2D (608099). Several genes
whose expression was altered in an FSHD-specific and highly significant manner are
involved in myogenic differentiation, suggesting a partial block in the normal
differentiation program. Many of the transcripts affected in FSHD were direct targets of
the transcription factor MYOD1 (159970). Additional misexpressed genes confirmed a
diminished capacity to buffer oxidative stress, as demonstrated in FSHD myoblasts. This
enhanced vulnerability of proliferative stage myoblasts to reactive oxygen species was
also disease-specific, further implicating a defect in FSHD muscle satellite cells. None of
the genes localizing to the FSHD region at 4q35 were found to exhibit a significantly
altered pattern of expression in FSHD muscle. Winokur et al. (2003) hypothesized that
disruptions in FSHD myogenesis and oxidative capacity may not arise from a position
effect mechanism, as has been previously suggested, but rather from a global effect on
gene regulation.
Jiang et al. (2003) found that H4 acetylation levels of a nonrepeated region adjacent to
the 4q35 and 10q26 D4Z4 arrays in normal and FSHD lymphoid cells were like those in
unexpressed euchromatin, rather than like constitutive heterochromatin. The control
and FSHD cells also displayed similar H4 hyperacetylation (like that of expressed genes)
at the 5-prime regions of 4q35 candidate genes FRG1 (601278) and ANT1. There was no
position-dependent increase in transcript levels from these genes in FSHD skeletal
muscle samples compared with controls. Jiang et al. (2003) proposed a model for FSHD
in which differential long-distance cis looping depends upon the presence of a 4q35
D4Z4 array with less than a threshold number of copies of the 3.3-kb repeat.
Perini and Tupler (2006) suggested that FSHD might be considered a useful model for
the study of position effect in humans. D4Z4 deletion might result in stochastic variation
in gene expression in muscle cells and explain the asymmetric involvement of muscles,
the great variability of clinical expression between and within families, and the apparent
threshold effect whereby there is a requirement for the deletion of a certain number of
copies of D4Z4 to develop FSHD.
Osborne et al. (2007) detected no change in expression of the FRG1, FRG2, or ANT1
genes in muscle biopsies from 19 FSHD patients compared to controls. Further studies
of the 8-Mb region proximal to the D4Z4 array showed no significant changes in gene
expression, no evidence of a position effect, and no evidence of unequal allele-specific
expression. However, microarray analysis of global gene expression in FSHD muscle
identified 11 upregulated genes with a role in vascular smooth muscle or endothelial
cells, suggesting a possible link between muscular dystrophy and vasculopathy in
FSHD.
Davidovic et al. (2008) found that myoblasts isolated from patients with FSHD showed
an abnormal pattern of expression of isoforms of the FXR1P (600819) gene compared to
controls. FXR1P encodes an RNA-binding protein involved in the metabolism of muscle-
specific-mRNAs during myogenesis. The altered pattern of FXR1P expression was due
to a specific reduced stability of muscle-specific FXR1 mRNA variants. The findings
suggested that the molecular basis of FSHD not only involves splicing alterations, but
may also involve a deregulation of mRNA stability.
Using RNA-DNA FISH, Masny et al. (2010) found no change in gene transcription of 16
genes in cis in the 4q35 region in nuclei of differentiated myotubes derived from patients
with FSHD compared to differentiated myotubes from controls. In particular, there was
no change in expression in the FRG1, FRG2, or ANT1 genes, which had previously been
implicated.
Dmitriev et al. (2011) showed that KLF15 (606465) bound an enhancer element within
the D4Z4 repeat unit. Binding of KLF15 to 2 sites within the D4Z4 enhancer drove
expression of FRG2 and DUX4C (DUX4L9; 615581), which are located over 40 kb
centromeric to the D4Z4 repeat array. KLF15 expression was upregulated following
differentiation of normal human myoblasts and following expression of MYOD, and it
was upregulated in FSHD myoblasts, myotubes, and muscle biopsies. FSHD cells also
showed upregulated expression of MYOD and the KLF15 target gene PPARG (601487),
in addition to DUX4C and FRG2. Dmitriev et al. (2011) concluded that MYOD-
dependent KLF15 expression is involved in partial activation of the differentiation
program in FSHD myoblasts.
Associations Pending Confirmation
For discussion of a possible association between FSHD and variation in the FAT1 gene,
see 600976.
▼ Genotype/Phenotype Correlations
As indicated earlier, FSHD is associated with a short (less than 35 kb) EcoRI/BlnI
fragment resulting from deletion of an integral number of units of a 3.3-kb repeat
located at 4q35. Vitelli et al. (1999)determined fragment sizes separated by pulsed field
gel electrophoresis in a patient with an apparently sporadic case of FSHD and in his
healthy family members. A 38-kb fragment was detected in the proband, in his older
brother, and in their father. This finding prompted a clinical reevaluation of the father
and brother. A subclinical phenotype restricted to abdominal muscle weakness was
detected, and serum creatine kinase values were found to be elevated in both. Thus,
whereas in healthy individuals the size of the 4q35 polymorphic fragment varies from 48
to 300 kb, and most patients with FSHD show fragments less than 35 kb, fragment sizes
between 35 and 48 kb must be interpreted with caution. An inverse correlation between
fragment size and severity was described by Lunt et al. (1995) and Tawil et al. (1996). In
familial cases, although the size of the inherited fragment remains constant, FSHD seems
to become more severe with each generation (anticipation), according to the findings
of Griggs et al. (1993), Lunt et al. (1995), Nakagawa et al. (1996), and Tawil et al. (1996).
Wohlgemuth et al. (2003) reported 2 unrelated families with FSHD in which the
probands were compound heterozygous for 2 FSHD-sized alleles: a severely affected
woman had chromosome 4-type arrays of 17 and 24 kb, and in the other family, a man
had arrays of 33 and 36 kb. All of these alleles resided on 4qA. In the first family, 1
unaffected member had the 24-kb allele and 1 affected member had the 17-kb allele; in
the second family, 3 unaffected children of the proband carried either the 33-kb allele or
the 36-kb allele. Wohlgemuth et al. (2003) noted that the findings showed that having 2
disease alleles is not lethal, and proposed that the phenotype in both probands reflected
a dosage effect.
In 21 FSHD1 patients who had 1 translocated chromosome 10-type array on
chromosome 4, referred to as 'monosomic,' van Overveld et al. (2005) found D4Z4
hypomethylation compared to monosomic controls. Further analysis delineated 2 classes
of clinical severity: patients with repeat sizes of 10 to 20 kb were severely affected and
showed pronounced hypomethylation, whereas patients with repeat sizes of 20 to 31 kb
showed variation in clinical severity and in hypomethylation. However, the authors
could not establish a linear relationship between methylation and disease severity.
Sacconi et al. (2013) found that the SMCHD1 gene (614982), mutation in which causes
FSHD2, is a modifier of disease severity in families affected by FSHD1. Three unrelated
families with intrafamilial clinical variability of the disorder were studied. In 1 family, a
mildly affected man with FSHD1 carried a 9-unit D4Z4 repeat on a 4A allele with no
SMCHD1 mutations, whereas his mildly affected wife carried a SMCHD1 mutation
(T527M; 614982.0006) on a normal-sized 4A allele, consistent with FSHD2. Their more
severely affected son and grandson each carried the 9-unit D4Z4 repeat on a 4A allele as
well as the T527M SMCHD1 mutation, consistent with having both FSHD1 and FSHD2.
In a second family, a man with a severe early-onset phenotype had both a 9-unit D4Z4
repeat on a 4A permissive allele and a mutation in the SMCHD1 gene. Each of his
children, who had milder symptoms, inherited 1 of the genetic defects. In a third family,
a man with a severe phenotype was also found to carry a 9-unit D4Z4 repeat on a 4A
permissive allele with a SMCHD1 mutation. No information from his parents was
available. Transduction of SMCHD1 shRNA into FSHD1 myotubes caused increased
levels of DUX4 mRNA as well as transcriptional activation of known DUX4 target genes.
These findings were consistent with further chromatin relaxation of the contracted
FSHD1 repeat upon knockdown of SMCHD1. Sacconi et al. (2013) concluded that
FSHD1 and FSHD2 share a common pathophysiologic pathway converging on
transcriptional derepression of DUX4 in skeletal muscle.
▼ Inheritance
Morton and Chung (1959) estimated the frequency to be about 2 per million living
persons, with a frequency of about 4 persons destined to develop the trait in each
million births. Fertility is little reduced and the mutation rate is not more than 5 per 10
million gametes. Lunt et al. (1989) estimated that the penetrance of the FSHD gene is less
than 5% for ages 0 to 4 years, 21% for ages 5 to 9, 58% for ages 10 to 14, 86% for ages 15
to 19, and 95% for age 20 years and over.
Lunt and Harper (1991) studied the families of 41 probands. They found 6 isolated cases
that might represent new mutation. Although penetrance reaches 95% by age 20, one-
third of heterozygotes over age 40 are mildly affected; 19% over age 40 require
wheelchairs. Most patients develop significant lower limb weakness--a fact that is not
reflected in the term 'facioscapulohumeral.' Distribution of weakness, severity, age of
onset, and serum creatine kinase levels varied among subjects, but provided no clinical
evidence for genetic heterogeneity in a comparison of the 11 largest families. Genetic
homogeneity, including subjects previously diagnosed with FSH-type spinal muscular
atrophy, is strongly supported by the genetic linkage data. They estimated the minimum
prevalence in Wales of 2 per 100,000. In this study only 2 of 113 affected persons from
the 11 largest families showed no detectable facial weakness; one of these was an
obligate carrier, aged 42 years, with complete nonpenetrance. Lunt and Harper
(1991) concluded that there is a dominantly inherited scapulohumeral or
scapuloperoneal syndrome genetically distinct from FSHD that does not have facial
weakness as a feature.
Using the EcoRI polymorphism demonstrated by Wijmenga et al. (1992), Weiffenbach et
al. (1993)found 12 recombinants in 5 families, giving a recombination fraction of 0.05
between this marker and the disease. Two families with apparent germline mosaicism
were also identified. In these instances, 2 offspring were affected but both parents were
clinically normal.
In a study of 34 Brazilian FSHD families, Zatz et al. (1995) concluded that at least one-
third of cases may represent new mutations. Somatic mosaicism, furthermore, may not
be rare. Biologic fitness was reduced to the 0.6 to 0.82 range, with no difference in sexes.
The age at onset of clinical signs, as well as the age at ascertainment, in patients from
multigenerational families suggested that anticipation occurs for FSHD.
Zatz et al. (1998) extended their study to 52 families, including 172 patients (104 males
and 68 females). Among 273 individuals, 131 (67 males and 64 females) were shown to
carry an EcoRI fragment smaller than 35 kb. Of these 131, 114 were examined. The
excess of affected males was explained by a greater proportion of asymptomatic females
and significantly greater number of affected sons than daughters of asymptomatic
mothers. The penetrance by age 30 was 95% for males but only 69% for females. New
mutations occurred more frequently in females than in males among somatic/germinal
mosaic cases. Severely affected cases were more commonly the result of new mutations
or mutations transmitted through maternal lines, including through mosaic
mothers. Zatz et al. (1998) noted the implications of these results for prenatal and
prognostic counseling depending on the gender of the affected patient.
Tupler et al. (1998) reported monozygotic male twins with FSHD carrying an identical
de novo p13E-11 EcoRI fragment of paternal origin. This had arisen in paternal
gametogenesis or postzygotically in the paternal chromosome 4 before twinning. A
mutated fragment was subsequently transmitted to one of the affected male children.
The twins showed great difference in clinical expression with one being almost
asymptomatic and the other severely affected. Medical history was the same with the
exception of an antirabies vaccination performed at the age of 5 in the more severely
affected twin. Tupler et al. (1998) hypothesized that the vaccination might have
triggered an inflammatory immune reaction contributory to the more severe phenotype.
Van der Maarel et al. (2000) surveyed 35 de novo FSHD families and found somatic
mosaicism in 40% of cases, in either the patient or an asymptomatic parent. Mosaic
males were typically affected; mosaic females were more often the unaffected parent of a
nonmosaic de novo patient. A genotypic-severity score, composed of the residual repeat
size and the degree of somatic mosaicism, yielded a consistent relationship with severity
and age at onset of disease. Mosaic females had a higher proportion of somatic
mosaicism than did mosaic males. The somatic mosaicism suggested a mainly mitotic
origin.
Almost half of de novo FSHD cases originate from a mitotic change leading to somatic
mosaicism for the FSHD allele. Lemmers et al. (2004) found that 9 of 37 (24%) patients
with presumed de novo FSHD were somatic mosaic, with contraction of D4Z4 identified
in 40 to 90% cells. In 7 cases (19%), 1 of the minimally affected or asymptomatic parents
was a mosaic 'carrier,' with 10 to 50% affected cells. The authors concluded that although
mosaic patients have a lower recurrence risk of having affected offspring than
nonmosaic patients, the offspring of a mildly affected patient may have a more severe
phenotype than expected based on the phenotype of the parent. Pulsed-field gel
electrophoresis (PFGE) was more sensitive in detecting the D4Z4 contraction than linear
gel electrophoresis.
Scionti et al. (2012) examined 11 nonconsanguineous Italian families in which 15
individuals were compound heterozygous for 2 D4Z4-reduced alleles. Most had the
typical FSHD phenotype, although 1 man was asymptomatic at age 55 years. The
phenotype was more severe in compound heterozygotes compared to carriers of 1
reduced allele, but the differences were not statistically significant. Analysis of relatives
showed significantly reduced penetrance in those with a single reduced allele (25%)
compared to those who were compound heterozygous for 2 reduced alleles (50%). In 4
families, the only FSHD-affected subject was the compound heterozygote for the D4Z4-
reduced allele, and 52.6% of individuals with a single D4Z4-reduced 4A161PAS
haplotype were nonpenetrant carriers. Analysis of surrounding polymorphisms did not
support the predictive value of any specific 4q35 haplotype, and the population
frequency of the 4A161PAS haplotype associated with a D4Z4-reduced allele was
calculated to be as high as 1.2%. Overall, the findings challenged the notion that FSHD is
a fully penetrant autosomal dominant disorder uniquely associated with the 4A161PAS
haplotype, with repercussions for genetic counseling.
▼ Diagnosis
Upadhyaya et al. (1990) reported markers useful in the presymptomatic and prenatal
diagnosis of FSHD. Their findings confirmed the chromosome 4 location and suggested
homogeneity.
Van der Maarel et al. (1999) described the limitations of molecular diagnostic techniques
then available. They reported a Southern blot-based method, a BglII-BlnI dosage test
that identified translocations between the repeat arrays on chromosomes 4 and 10 and
deletion of p13E-11. The test also identified complex combinations of these events. Van
der Maarel et al. (1999) suggested that this test would increase the sensitivity and
specificity of FSHD diagnosis. They also noted that this study delimited the FSHD
candidate region by mapping the 4;10 translocation breakpoint proximal to the
polymorphic BlnI site in the first repeat unit.
Homologous polymorphic repeat arrays on chromosomes 4 and 10 have made definitive
diagnosis of FSHD difficult. Lemmers et al. (2001) found that the restriction enzyme
Xap1 complements Bln1, as the former uniquely digests repeat units derived from
chromosome 4 and the latter uniquely digests those derived from chromosome 10. A
triple analysis with EcoRI, EcoRI/Bln1, and Xap1 allowed unequivocal characterization
of each of the alleles. Analysis of 2 patients with symptoms of possible FSHD showed 1
to be a carrier of a partial deletion of chromosome 4, and thus to have the disease,
whereas the other patient had a normal-sized allele on chromosome 4 and thus did not
have the disease.
Some FSHD patients have proximally extended D4Z4 deletions that include the
D4F104S1 region. Such extended deletions can lead to problems of interpretation of the
diagnostic test. Lemmers et al. (2003) described use of a telomeric probe, 4qA, that
identifies large genomic deletions involving both D4Z4 and D4F104S1 using
conventional gel electrophoresis. These extended deletions can be found in patients with
a normal spectrum of the disease. Use of the assay should improve the accuracy and
reliability of molecular diagnostic testing for FSHD.
Almost half of new FSHD-related mutations, i.e., contractions of the polymorphic D4Z4
repeat on 4qter, occur postfertilization, resulting in somatic mosaicism for D4Z4. On
detailed D4Z4 analysis of 11 mosaic individuals with FSHD, Lemmers et al. (2004) found
a mosaic mixture of a contracted FSHD-sized allele and the unchanged ancestral allele in
8 cases, which is suggestive of a mitotic gene conversion without crossover. However, in
the other 3 cases, the D4Z4 rearrangement resulted in 2 different-sized D4Z4 repeats,
indicative of a gene conversion with crossover. In all 11 cases, DNA markers proximal
and distal to D4Z4 showed no allelic exchanges, suggesting that all rearrangements were
intrachromosomal. Lemmers et al. (2004) proposed that D4Z4 rearrangements occur via
a synthesis-dependent strand annealing model that relatively frequently allows for
crossovers. Furthermore, the distribution of different cell populations in mosaic patients
with FSHD suggested that mosaicism results from D4Z4 rearrangements occurring
during the first few zygotic cell divisions after fertilization.
In an asymptomatic female FSHD carrier, Tonini et al. (2006) detected mosaicism for a
pathogenic D4Z4 contraction in peripheral blood cells and muscle tissue: the normal
allele and the pathogenic 12-kb allele were present in 75% and 25% of both types of cells,
respectively. The 12-kb allele was identified in virtually 100% of peripheral blood cells
from the carrier's affected daughter, confirming the diagnosis and inheritance. The
finding of comparable mosaicism in peripheral blood cells and muscle from an
asymptomatic mother suggested that a mitotic contraction of D4Z4 is an early
embryonic event and indicated that the degree of mosaicism in peripheral blood cells is
representative of that in muscle.
Deak et al. (2007) reported an FSHD family in which 11 affected members had a
contracted D4Z4 allele and a large 78-kb proximal deletion. The family was initially
designated as having non-chromosome-4 linked FSHD (158901) because commercial
diagnostic testing of the proband failed to detect the deletion allele. The probe used,
p13E-11, was unable to recognize proximally extended deletion alleles. Updated
molecular analysis using a triple digest method revealed 10 D4Z4 repeat units, which
the authors considered borderline. The extended deletion included the p13E-11 and B31
binding sites, the inverted repeat D4S463, and the FRG2 and TUBB4Q genes. The
phenotype was typical for FSHD. Deak et al. (2007) noted that this was the largest
proximal deletion reported to date and emphasized the complexity of molecular
diagnosis of FSHD.
Sacconi et al. (2012) performed molecular analysis of 16 patients with a clinical
phenotype resembling FSHD. Affected individuals had 3 or more of the following
features: (1) evidence of autosomal dominant inheritance and/or weakness in (2) facial
muscles, (3) shoulder girdle muscles, (4) anterior foreleg muscles, and (5) asymmetric
muscle involvement. All had a myopathic pattern on EMG. One patient carried a
complex rearrangement in the FSHD locus that masked the D4Z4 contraction associated
with FSHD1, and 1 patient was somatic mosaic for the D4Z4 contraction. The pathogenic
chromosome in the first patient (also reported by Lemmers et al., 2010) was the result of
a meiotic exchange between chromosomes 10q and 4q, creating a contracted hybrid
D4Z4 repeat array on a permissive background; it was associated with a mild
phenotype. The second patient, who was somatic mosaic for a contracted D4Z4 repeat
on a 4A161 allele, also had a mild phenotype. Of the remaining patients, 6 were
diagnosed as having FSHD2, 4 had a CAPN3 (114240) mutation consistent with
LGMD2A (253600); 2 had a VCP (601023) mutation, consistent with VCP-related
myopathy (167320); and 2 had no identifiable genetic defect.
As a follow-up to the study of Scionti et al. (2012), Scionti et al. (2012) analyzed D4Z4-
related DNA elements in 801 controls, including 560 Italian and 241 Brazilian healthy
individuals. Three percent of these individuals carried alleles with a reduced number (4
to 8) of D4Z4 repeats on chromosome 4q, and 1.3% carried the reduction on the
supposedly pathogenic 4A161PAS haplotype. In addition, only 127 (50.1%) of 253
unrelated patients with FSHD carried alleles with 1 to 8 D4Z4 repeats associated with
4A161PAS; the remaining FSHD probands carried different haplotypes or alleles with a
greater number of D4Z4 repeats. The study demonstrated that the current genetic
signature of FSHD (4A161PAS) is a common polymorphism and that only half of FSHD
probands carry this molecular signature. The findings indicated that the genetic basis of
FSHD needs to be revisited because of the important implications for genetic counseling
and prenatal diagnosis of at-risk families.
▼ Population Genetics
In a population-based study in northeastern Italy, Mostacciuolo et al. (2009) identified 40
patients with a clinical diagnosis of FSHD. Thirty (76%) patients from 13 families had a
family history of the disorder, whereas 10 had sporadic disease. Of the 40 patients, 33
(82.5%) had a contraction at chromosome 4q35 ranging from 14 to 35 kb, whereas 4
patients from 1 family had a borderline 38-kb fragment, and 3 had a fragment greater
than 40 kb. The 4 patients with the 38-kb fragment had onset of slowly progressive mild
proximal muscle weakness between age 15 and 35 years without facial weakness. In
contrast, 2 related patients with the fragment greater than 40 kb had a typical FSHD
phenotype with facial involvement and profound weakness in the lower and upper
region muscles, but the fragment was also found in an unaffected family member, thus
excluding it as disease-causing. One asymptomatic 43-year-old man with a 20-kb
fragment was identified, yielding an overall penetrance of 97%. Mostacciuolo et al.
(2009) estimated the prevalence of genetically confirmed FSHD in this population to be
44 in 1,000,000.
▼ History
Wijmenga et al. (1992) demonstrated rearrangements in the cosmid clone p13E-11 in
patients with FSHD. This cosmid clone had been isolated in a search for homeobox
genes and was mapped to chromosome 4q35 just distal to D4S139. In normal individuals
the clone detected a polymorphic EcoRI fragment usually larger than 28 kb. A shorter
EcoRI fragment was found in 5 out of 6 new FSHD cases. In 10 Dutch families analyzed,
a specific shorter fragment between 14 and 28 kb cosegregated with FSHD. FSHD is
associated with contraction of a tandem repeat rather than an expansion such as occurs
in the fragile X syndrome (300624) and in myotonic dystrophy.
Fischbeck and Garbern (1992) reviewed the possibility that a previously uncharacterized
homeobox gene or genes might be involved in the disorder; a graded, rostro-caudal
expression of the gene(s) would explain the regional muscle degeneration. Previously
known homeobox mutations cause congenital malformations; if FSHD is the result of a
homeobox gene rearrangement, this would be the first example of a developmental
control gene producing a phenotype with onset later in life.
Tawil et al. (1993) reported monozygotic twins discordant for the FSHD phenotype and
with no family history of FSHD. Using a new marker, D4S809, which is close to or
within the FSHD gene, Tawil et al. (1993) demonstrated a unique 4q35 DNA
rearrangement in the affected twin. The most likely explanation for the discordance was
occurrence of a de novo postzygotic mutation on 4q35 during or after the twinning
process. Most studied sporadic cases demonstrate similar 4q35 rearrangements not
present in their parents (Wijmenga et al., 1992; Weiffenbach et al., 1993). Using D4S809
probes that map near or within the FSHD gene, Griggs et al. (1993) investigated 8
sporadic patients with FSHD whose parents showed no signs of the disease. The probe
detected novel DNA fragments in 7 of the 8 sporadic individuals and not in the parents.
A novel DNA fragment was found in each of 2 sisters with FSHD whose parents were
clinically normal; the finding was taken as evidence of germline mosaicism. Use of the
D4S809 probe in genetic counseling is limited; however, because the probe may also
detect a locus unlinked to chromosome 4, because of possible genetic heterogeneity in
FSHD and because of the presence of recombinants in families with the inherited form.
Hence, closer markers or gene definition will be required.
Hewitt et al. (1994) and Winokur et al. (1993) postulated that FSHD may be due to a
position effect. Bengtsson et al. (1994) reported results indicating that the tandem array
of 3.2-kb repeats, disrupted in FSHD, lies immediately adjacent to the telomere of 4q and
that the gene responsible for FSHD is probably located proximal to the tandem repeat.
▼ Animal Model
Because of its mapping to a region of homology to human 4q, Mills et al.
(1995) suggested that 'myodystrophy' (myd), an autosomal recessive mutation in the
mouse, is a homolog of FSHD. The mouse disorder is characterized by progressive
weakness and dystrophic muscle histology and maps to the central portion of mouse
chromosome 8. This portion of mouse chromosome 8 contains the genes for
mitochondrial uncoupling protein (UCP; 113730) and kallikrein (KLKB1; 229000).
Contrary to the suggestion of Mills et al. (1995), Grewal et al. (2001) found that the gene
mutated in myd, Large, encodes a glycosyltransferase. The human homolog of this gene
maps to 22q; see 603590. In myd, Grewal et al. (2001) identified an intragenic deletion of
exons 4-7 that causes a frameshift in the resultant mRNA and a premature termination
codon before the first of the 2 catalytic domains. On immunoblots, a monoclonal
antibody to alpha-dystroglycan (128239), a component of the dystrophin (300377)-
associated glycoprotein complex, showed reduced binding in myd, which Grewal et al.
(2001) attributed to altered glycosylation of the protein. They speculated that abnormal
posttranslational modification of alpha-dystroglycan may contribute to the myd
phenotype.
To identify the gene responsible for facioscapulohumeral muscular dystrophy
pathogenesis, Gabellini et al. (2006) generated transgenic mice selectively
overexpressing in skeletal muscle the 4q35 genes FRG1 (601278), FRG2 (609032), or
ANT1 (103220). The authors found that FRG1 transgenic mice developed a muscular
dystrophy with features characteristic of the human disease; by contrast, FRG2 and
ANT1 transgenic mice seemed normal. FRG1 is a nuclear protein, and several lines of
evidence suggest it is involved in pre-mRNA splicing. Gabellini et al. (2006) found
changes in the alternative splicing pattern of the pre-mRNAs of TNNT3 (600692) and
myotubularin related-protein 1 (MTMR1; 300171) in muscle of FRG1 transgenic mice
and FSHD patients. Collectively, the results suggested that FSHD results from
inappropriate overexpression of FRG1 in skeletal muscle, which leads to abnormal
alternative splicing of specific pre-mRNAs.
▼ REFERENCES
1. Awerbuch, G. I., Nigro, M. A., Wishnow, R. Beevor's sign and
facioscapulohumeral dystrophy. Arch. Neurol. 47: 1208-1209, 1990.
[PubMed: 2146943, related citations] [Full Text]
2. Bailey, R. O., Marzulo, D. C., Hans, M. B. Infantile facioscapulohumeral
muscular dystrophy: new observations. Acta Neurol. Scand. 74: 51-58, 1986.
3. Bengtsson, U., Altherr, M. R., Wasmuth, J. J., Winokur, S. T. High resolution
fluorescence in situ hybridization to linearly extended DNA visually maps a
tandem repeat associated with facioscapulohumeral muscular dystrophy
immediately adjacent to the telomere of 4q. Hum. Molec. Genet. 3: 1801-1805,
1994. [PubMed: 7849703, related citations]
4. Bickmore, W. A., van der Maarel, S. M. Perturbations of chromatin structure in
human genetic disease: recent advances. Hum. Molec. Genet. 12: R207-R213,
2003. [PubMed: 12915455, related citations] [Full Text]
5. Bodensteiner, J. B., Schochet, S. S. Facioscapulohumeral muscular dystrophy: the
choice of a biopsy site. Muscle Nerve 9: 544-547, 1986. [PubMed: 3736585, related
citations] [Full Text]
6. Bosnakovski, D., Xu, Z., Gang, E. J., Galindo, C. L., Liu, M., Simsek, T., Garner, H.
R., Agha-Mohammadi, S., Tassin, A., Coppee, F., Belayew, A., Perlingeiro, R. R.,
Kyba, M. An isogenic myoblast expression screen identifies DUX4-mediated
FSHD-associated molecular pathologies. EMBO J. 27: 2766-2779, 2008.
[PubMed: 18833193, images, related citations] [Full Text]
7. Brouwer, O. F., Padberg, G. W., Ruys, C. J. M., Brand, R., de Laat, J. A. P. M.,
Grote, J. J.Hearing loss in facioscapulohumeral muscular dystrophy. Neurology
41: 1878-1881, 1991. [PubMed: 1745341, related citations]
8. Clapp, J., Mitchell, L. M., Bolland, D. J., Fantes, J., Corcoran, A. E., Scotting, P. J.,
Armour, J. A. L., Hewitt, J. E. Evolutionary conservation of a coding function for
D4Z4, the tandem DNA repeat mutated in facioscapulohumeral muscular
dystrophy. Am. J. Hum. Genet. 81: 264-279, 2007.
9. Davidovic, L., Sacconi, S., Bechara, E. G., Delplace, S., Allegra, M., Desnuelle, C.,
Bardoni, B.Alteration of expression of muscle specific isoforms of the fragile X
related protein 1 (FXR1P) in facioscapulohumeral muscular dystrophy
patients. J. Med. Genet. 45: 679-685, 2008. [PubMed: 18628314, related citations]
[Full Text]
10. Deak, K. L., Lemmers, R. J. L. F., Stajich, J. M., Klooster, R., Tawil, R., Frants, R. R.,
Speer, M. C., van der Maarel, S. M., Gilbert, J. R. Genotype-phenotype study in
an FSHD family with a proximal deletion encompassing p13E-11 and
D4Z4. Neurology 68: 578-582, 2007. [PubMed: 17229919, related citations] [Full
Text]
11. Dixit, M., Ansseau, E., Tassin, A., Winokur, S., Shi, R., Qian, H., Sauvage, S.,
Matteotti, C., van Acker, A. M., Leo, O., Figlewicz, D., Barro, M., Laoudj-
Chenivesse, D., Belayew, A., Coppee, F., Chen, Y.-W. DUX4, a candidate gene of
facioscapulohumeral muscular dystrophy, encodes a transcriptional activator of
PITX1. Proc. Nat. Acad. Sci. 104: 18157-18162, 2007.
12. Dmitriev, P., Lipinski, M., Vassetsky, Y. S. Pearls in the junk: dissecting the
molecular pathogenesis of facioscapulohumeral muscular
dystrophy. Neuromusc. Disord. 19: 17-20, 2008. [PubMed: 18974002, related
13. Dmitriev, P., Petrov, A., Ansseau, E., Stankevicins, L., Charron, S., Kim, E., Bos, T.
J., Robert, T., Turki, A., Coppee, F., Belayew, A., Lazar, V., Carnac, G., Laoudj, D.,
Lipinski, M., Vassetzky, Y. S. The Kruppel-like factor 15 as a molecular link
between myogenic factors and a chromosome 4q transcriptional enhancer
implicated in facioscapulohumeral dystrophy. J. Biol. Chem. 286: 44620-44631,
2011. [PubMed: 21937448, images, related citations] [Full Text]
14. Duchenne, G.-B. Album de photographies pathologiques complementaire de
liver initule de l'electrisation localisee. Paris: J.-B. Bailliere (pub.) 1862.
15. Fischbeck, K. H., Garbern, J. Y. Facioscapulohumeral muscular dystrophy defect
identified.Nature Genet. 2: 3-4, 1992. [PubMed: 1363882, related citations] [Full
Text]
16. Fitzsimons, R. B., Gurwin, E. B., Bird, A. C. Retinal vascular abnormalities in
facioscapulohumeral muscular dystrophy: a general association with genetic
and therapeutic implications. Brain 110: 631-648, 1987. [PubMed: 3580827, related
citations]
17. Gabellini, D., D'Antona, G., Moggio, M., Prelle, A., Zecca, C., Adami, R.,
Angeletti, B., Ciscato, P., Pellegrino, M. A., Bottinelli, R., Green, M. R., Tupler,
R. Facioscapulohumeral muscular dystrophy in mice overexpressing
FRG1. Nature 439: 973-977, 2006. [PubMed: 16341202, related citations] [Full Text]
18. Gabellini, D., Green, M. R., Tupler, R. Inappropriate gene activation in FSHD: a
repressor complex binds a chromosomal repeat deleted in dystrophic
muscle. Cell 110: 339-348, 2002. [PubMed: 12176321, related citations] [Full Text]
19. Gieron, M. A., Korthals, J. K., Kousseff, B. G. Facioscapulohumeral dystrophy
with cochlear hearing loss and tortuosity of retinal vessels. Am. J. Med. Genet.
22: 143-147, 1985. [PubMed: 4050849, related citations] [Full Text]
20. Gilbert, J. R., Stajich, J. M., Speer, M. C., Vance, J. M., Stewart, C. S., Yamaoka, L.
H., Samson, F., Fardeau, M., Potter, T. G., Roses, A. D., Pericak-Vance, M.
A. Linkage studies in facioscapulohumeral muscular dystrophy (FSHD). Am. J.
Hum. Genet. 51: 424-427, 1992. [PubMed: 1642241, related citations]
21. Gilbert, J. R., Stajich, J. M., Wall, S., Carter, S. C., Qiu, H., Vance, J. M., Stewart, C.
S., Speer, M. C., Pufky, J., Yamaoka, L. H., Rozear, M., Samson, F., Fardeau, M.,
Roses, A. D., Pericak-Vance, M. A. Evidence for heterogeneity in
facioscapulohumeral muscular dystrophy (FSHD). Am. J. Hum. Genet. 53: 401-
408, 1993. [PubMed: 8328457, related citations]
22. Grewal, P. K., Holzfeind, P. J., Bittner, R. E., Hewitt, J. E. Mutant
glycosyltransferase and altered glycosylation of alpha-dystroglycan in the
myodystrophy mouse. Nature Genet. 28: 151-154, 2001.
23. Griggs, R. C., Tawil, R., Storvick, D., Mendell, J. R., Altherr, M. R. Genetics of
facioscapulohumeral muscular dystrophy: new mutations in sporadic
cases. Neurology 43: 2369-2372, 1993. [PubMed: 8232958, related citations]
24. Hewitt, J. E., Lyle, R., Clark, L. N., Valleley, E. M., Wright, T. J., Wijmenga, C., van
Deutekom, J. C. T., Francis, F., Sharpe, P. T., Hofker, M., Frants, R. R., Williamson,
R. Analysis of the tandem repeat locus D4Z4 associated with
facioscapulohumeral muscular dystrophy. Hum. Molec. Genet. 3: 1287-1295,
25. Jacobsen, S. J., Diala, E. S., Dorsey, B. V., Rising, M. B., Graveline, R., Falls, K.,
Schultz, P., Hogan, C., Rediker, K., D'Amico, C., Weiffenbach, B. A clinically
homogeneous group of families with facioscapulohumeral (Landouzy-
Dejerine) muscular dystrophy: linkage analysis of six autosomes. Am. J. Hum.
Genet. 47: 376-388, 1990. [PubMed: 1975474, related citations]
26. Jardine, P., Jones, M., Tyfield, L., Upadhyaya, M., Lunt, P. De novo DNA
rearrangement in atypical facioscapulohumeral muscular dystrophy.
(Letter) Clin. Genet. 44: 167, 1993. [PubMed: 8275579, related citations] [Full Text]
27. Jiang, G., Yang, F., van Overveld, P. G. M., Vedanarayanan, V., van der Maarel, S.,
Ehrlich, M.Testing the position-effect variegation hypothesis for
facioscapulohumeral muscular dystrophy by analysis of histone modification
and gene expression in subtelomeric 4q. Hum. Molec. Genet. 12: 2909-2921, 2003.
28. Justin-Besancon, L., Pequignot, H., Contamin, F., Delavierre, P., Rolland,
P. Myopathie du type Landouzy-Dejerine. Rapport d'une observation
historique. Sem. Hop. Paris 40: 2990-2999, 1964. [PubMed: 14257214, related
citations]
29. Krasnianski, M., Eger, K., Neudecker, S., Jakubiczka, S., Zierz, S. Atypical
phenotypes in patients with facioscapulohumeral muscular dystrophy 4q35
deletion. Arch. Neurol. 60: 1421-1425, 2003. [PubMed: 14568813, related citations]
[Full Text]
30. Landouzy, L., Dejerine, J. De la myopathie atrophique progressive. Rev. Med.
Franc. 5: 81, 1885.
31. Lemmers, R. J. F. L., Wohlgemuth, M., Frants, R. R., Padberg, G. W., Morava, E.,
van der Maarel, S. M. Contractions of D4Z4 on 4qB subtelomeres do not cause
facioscapulohumeral muscular dystrophy. Am. J. Hum. Genet. 75: 1124-1130,
32. Lemmers, R. J. L. F., de Kievit, P., Sandkuijl, L., Padberg, G. W., van Ommen, G.-J.
B., Frants, R. R., van der Maarel, S. M. Facioscapulohumeral muscular dystrophy
is uniquely associated with one of the two variants of the 4q subtelomere.
(Letter) Nature Genet. 32: 235-236, 2002. [PubMed: 12355084, related citations]
[Full Text]
33. Lemmers, R. J. L. F., de Kievit, P., van Geel, M., van der Wielen, M. J. R., Bakker,
E., Padberg, G. W., Frants, R. R., van der Maarel, S. M. Complete allele
information in the diagnosis of facioscapulohumeral muscular dystrophy by
triple DNA analysis. Ann. Neurol. 50: 816-819, 2001. [PubMed: 11761483, related
34. Lemmers, R. J. L. F., Osborn, M., Haaf, T., Rogers, M., Frants, R. R., Padberg, G.
W., Cooper, D. N., van der Maarel, S. M., Upadhyaya, M. D4F104S1 deletion in
facioscapulohumeral muscular dystrophy: phenotype, size, and
detection. Neurology 61: 178-183, 2003. [PubMed: 12874395, related citations]
[Full Text]
35. Lemmers, R. J. L. F., van der Vliet, P. J., Klooster, R., Sacconi, S., Camano, P.,
Dauwerse, J. G., Snider, L., Straasheijm, K. R., van Ommen, G. J., Padberg, G. W.,
Miller, D. G., Tapscott, S. J., Tawil, R., Frants, R. R., van der Maarel, S. M. A
unifying genetic model for facioscapulohumeral muscular dystrophy. Science
329: 1650-1653, 2010. [PubMed: 20724583,images, related citations] [Full Text]
36. Lemmers, R. J. L. F., van der Wielen, M. J. R., Bakker, E., Padberg, G. W., Frants,
R. R., van der Maarel, S. M. Somatic mosaicism in FSHD often goes
undetected. Ann. Neurol. 55: 845-850, 2004. [PubMed: 15174019, related citations]
[Full Text]
37. Lemmers, R. J. L. F., van Overveld, P. G. M., Sandkuijl, L. A., Vrieling, H.,
Padberg, G. W., Frants, R. R., van der Maarel, S. M. Mechanism and timing of
mitotic rearrangements in the subtelomeric D4Z4 repeat involved in
facioscapulohumeral muscular dystrophy. Am. J. Hum. Genet. 75: 44-53, 2004.
38. Lemmers, R. J. L. F., Wohlgemuth, M., van der Gaag, K. J., van der Vliet, P. J., van
Teijlingen, C. M. M., de Knijff, P., Padberg, G. W., Frants, R. R., van der Maarel, S.
M. Specific sequence variations within the 4q35 region are associated with
39. Lucotte, G., Berriche, S., Fardeau, M. Linkage analysis of French families with
facioscapulohumeral muscular dystrophy. J. Med. Genet. 26: 485-486, 1989.
40. Lunt, P. W., Compston, D. A. S., Harper, P. S. Estimation of age dependent
penetrance in facioscapulohumeral muscular dystrophy by minimising
ascertainment bias. J. Med. Genet. 26: 755-760, 1989. [PubMed: 2614794, related
41. Lunt, P. W., Harper, P. S. Genetic counselling in facioscapulohumeral muscular
dystrophy. J. Med. Genet. 28: 655-664, 1991. [PubMed: 1941962, related citations]
[Full Text]
42. Lunt, P. W., Jardine, P. E., Koch, M. C., Maynard, J., Osborn, M., Williams, M.,
Harper, P. S., Upadhyaya, M. Correlation between fragment size at D4F104S1
and age at onset or at wheelchair use, with a possible generation effect,
accounts for much phenotypic variation in 4q35-facioscapulohumeral muscular
dystrophy (FSHD). Hum. Molec. Genet. 4: 951-958, 1995. Note: Erratum: Hum.
Molec. Genet. 4: 1243-1244, 1995. [PubMed: 7633457, related citations]
43. Lunt, P. W., Upadhyaya, M., Sarfarazi, M., Broadhead, W., Harper, P. S. Linkage
studies in facioscapulohumeral disease. (Abstract) Cytogenet. Cell Genet. 51:
1036, 1989.
44. Masny, P. S., Chan, O. Y. A., de Greef, J. C., Bengtsson, U., Ehrlich, M., Tawil, R.,
Lock, L. F., Hewitt, J. E., Stocksdale, J., Martin, J. H., van der Maarel, S. M.,
Winokur, S. T. Analysis of allele-specific RNA transcription in FSHD by RNA-
DNA FISH in single myonuclei. Europ. J. Hum. Genet. 18: 448-456, 2010.
45. Mathews, K. D., Mills, K. A., Bosch, E. P., Ionasescu, V. V., Wiles, K. R., Buetow,
K. H., Murray, J. C. Linkage localization of facioscapulohumeral muscular
dystrophy (FSHD) in 4q35. Am. J. Hum. Genet. 51: 428-431, 1992.
[PubMed: 1642242, related citations]
46. Mathews, K. D., Mills, K. A., Leysens, N. J., Xu, Y., Bodrug, S., Buetow, K. H.,
Murray, J. C.Characterization of the facioscapulohumeral dystrophy locus on
4q35. (Abstract) Am. J. Hum. Genet. 49 (suppl.): 350, 1991.
47. Matsuzaka, T., Sakuragawa, N., Terasawa, K., Kuwabara,
H. Facioscapulohumeral dystrophy associated with mental retardation, hearing
loss, and tortuosity of retinal arterioles. J. Child Neurol. 1: 218-223, 1986.
48. Meyerson, M. D., Lewis, E., Ill, K. Facioscapulohumeral muscular dystrophy and
accompanying hearing loss. Arch. Otolaryng. 110: 261-266, 1984.
49. Mills, K. A., Buetow, K. H., Xu, Y., Ritty, T. M., Mathews, K. D., Bodrug, S. E.,
Wijmenga, C., Balazs, I., Murray, J. C. Genetic and physical mapping on
chromosome 4 narrows the localization of the gene for facioscapulohumeral
muscular dystrophy (FSHD). Am. J. Hum. Genet. 51: 432-439, 1992.
50. Mills, K. A., Mathews, K. D., Scherpbier-Heddema, T., Schelper, R. L., Schmalzel,
R., Bailey, H. L., Nadeau, J. H., Buetow, K. H., Murray, J. C. Genetic mapping
near the myd locus on mouse chromosome 8. Mammalian Genome 6: 278-280,
51. Miura, K., Kumagai, T., Matsumoto, A., Iriyama, E., Watanabe, K., Goto, K.,
Arahata, K. Two cases of chromosome 4q35-linked early onset
facioscapulohumeral muscular dystrophy with mental retardation and
epilepsy. Neuropediatrics 29: 239-241, 1998. [PubMed: 9810558, related citations]
[Full Text]
52. Morton, N. E., Chung, C. S. Formal genetics of muscular dystrophy. Am. J. Hum.
53. Mostacciuolo, M. L., Pastorello, E., Vazza, G., Miorin, M., Angelini, C., Tomelleri,
G., Galluzzi, G., Trevisan, C. P. Facioscapulohumeral muscular dystrophy:
epidemiological and molecular study in a north-east Italian population
sample. Clin. Genet. 75: 550-555, 2009. [PubMed: 19320656, related citations] [Full
Text]
54. Nakagawa, M., Higuchi, I., Yoshidome, H., Isashiki, Y., Ohkubo, R., Kaseda, S.,
Iwaki, H., Fukunaga, H., Osame, M. Familial facioscapulohumeral muscular
dystrophy: phenotypic diversity and genetic abnormality. Acta Neurol. Scand.
55. Osborne, R. J., Welle, S., Venance, S. L., Thornton, C. A., Tawil, R. Expression
profile of FSHD supports a link between retinal vasculopathy and muscular
dystrophy. Neurology 68: 569-577, 2007. [PubMed: 17151338, related citations]
[Full Text]
56. Padberg, G., Eriksson, A. W., Volkers, W. S., Bernini, L., van Loghem, E., Meera
Khan, P., Nijenhuis, L. E., Pronk, J. C., Schreuder, G. M. T. Linkage studies in
autosomal dominant facioscapulohumeral muscular dystrophy. J. Neurol. Sci.
57. Padberg, G. W., Brouwer, O. F., de Keizer, R. J. W., Gruter, A. M., Wijmenga, C.,
Grote, J. J., Frants, R. R. Retinal vascular disease and sensorineural deafness are
part of facioscapulohumeral muscular dystrophy. (Abstract) Am. J. Hum. Genet.
51 (suppl.): A104, 1992.
58. Padberg, G. W., Klasen, E. C., Volkers, W. S., de Lange, G. G., Wintzen, A.
R. Linkage studies in facioscapulohumeral muscular dystrophy. Muscle Nerve
59. Perini, G., Tupler, R. Altered gene silencing and human diseases. Clin. Genet. 69:
1-7, 2006. [PubMed: 16451126, related citations] [Full Text]
60. Reardon, W., Temple, I. K., Harwood, G., Baraitser, M. Atypical facio-scapulo-
humeral muscular dystrophy--a counselling dilemma. Clin. Genet. 39: 172-177,
61. Reed, P., Porter, N. C., Strong, J., Pumplin, D. W., Corse, A. M., Luther, P. W.,
Flanigan, K. M., Bloch, R. J. Sarcolemmal reorganization in facioscapulohumeral
muscular dystrophy. Ann. Neurol. 59: 289-297, 2006. [PubMed: 16437580, related
62. Richards, M., Coppee, F., Thomas, N., Belayew, A., Upadhyaya,
M. Facioscapulohumeral muscular dystrophy (FSHD): an enigma
unravelled? Hum. Genet. 131: 325-340, 2012. [PubMed: 21984394, related
63. Sacconi, S., Camano, P., de Greef, J. C., Lemmers, R. J. L. F., Salviati, L., Boileau,
P., Lopez de Munain Arregui, A., van der Maarel, S. M., Desnuelle, C. Patients
with a phenotype consistent with facioscapulohumeral muscular dystrophy
display genetic and epigenetic heterogeneity.J. Med. Genet. 49: 41-46, 2012.
64. Sacconi, S., Lemmers, R. J. L. F., Balog, J., van der Vliet, P. J., Lahaut, P., van
Nieuwenhuizen, M. P., Straasheijm, K. R., Debipersad, R. D., Vos-Versteeg, M.,
Salviati, L., Casarin, A., Pegoraro, E., Tawil, R., Bakker, E., Tapscott, S. J.,
Desnuelle, C., van der Maarel, S. M. The FSHD2 gene SMCHD1 is a modifier of
disease severity in families affected by FSHD1. Am. J. Hum. Genet. 93: 744-751,
65. Sarfarazi, M., Upadhyaya, M., Padberg, G., Pericak-Vance, M., Siddique, T.,
Lucotte, G., Lunt, P.An exclusion map for facioscapulohumeral (Landouzy-
Dejerine) disease. J. Med. Genet. 26: 481-484, 1989. [PubMed: 2769720, related
66. Sarfarazi, M., Wijmenga, C., Upadhyaya, M., Weiffenbach, B., Hyser, C.,
Mathews, K., Murray, J., Gilbert, J., Pericak-Vance, M., Lunt, P., Frants, R. R.,
Jacobsen, S., Harper, P. S., Padberg, G. W. Regional mapping of
facioscapulohumeral muscular dystrophy gene on 4q35: combined analysis of
an international consortium. Am. J. Hum. Genet. 51: 396-403, 1992.
67. Sayli, B. S., Yaltkaya, K., Cin, S. Facioscapulohumeral muscular dystrophy
concentrated in the village Cullar, Nevsehir, Turkey. Hum. Genet. 67: 201-208,
68. Scionti, I., Fabbri, G., Fiorillo, C., Ricci, G., Greco, F., D'Amico, R., Termanini, A.,
Vercelli, L., Tomelleri, G., Cao, M., Santoro, L., Percesepe, A., Tupler,
R. Facioscapulohumeral muscular dystrophy: new insights from compound
heterozygotes and implication for prenatal genetic counselling. J. Med. Genet.
69. Scionti, I., Greco, F., Ricci, G., Govi, M., Arashiro, P., Vercelli, L., Berardinelli, A.,
Angelini, C., Antonini, G., Cao, M., Di Muzio, A., Moggio, M., and 12
others. Large-scale population analysis challenges the current criteria for the
molecular diagnosis of fascioscapulohumeral muscular dystrophy. Am. J. Hum.
Genet. 90: 628-635, 2012. [PubMed: 22482803, images, related citations] [Full Text]
70. Shen, E. N., Madsen, T. Facioscapulohumeral muscular dystrophy and recurrent
pacemaker lead dislodgment. Am. Heart J. 122: 1167-1169, 1991.
71. Shields, C. L., Zahler, J., Falk, N., Furuta, M., Eagle, R. C., Jr., Espinosa, L. E. B.,
Fischer, P. R., Shields, J. A. Neovascular glaucoma from advanced Coats disease
as the initial manifestation of facioscapulohumeral dystrophy in a 2-year-old
child. Arch. Ophthal. 125: 840-842, 2007. [PubMed: 17563001, related citations]
[Full Text]
72. Siddique, T., Roper, H., Pericak-Vance, M. A., Shaw, J., Warner, K. L., Hung, W.-
Y., Phillips, K. L., Lunt, P., Cumming, W. J. K., Roses, A. D. Linkage analysis in
the spinal muscular atrophy type of facioscapulohumeral disease. J. Med.
Genet. 26: 487-489, 1989. [PubMed: 2570155, related citations] [Full Text]
73. Slipetz, D. M., Aprille, J. R., Goodyer, P. R., Rozen, R. Deficiency of complex III
of the mitochondrial respiratory chain in a patient with facioscapulohumeral
disease. Am. J. Hum. Genet. 48: 502-510, 1991. [PubMed: 1847791, related
citations]
74. Small, R. G. Coats' disease and muscular dystrophy. Trans. Am. Acad. Ophthal.
Otolaryng. 72: 225-231, 1968. [PubMed: 5659903, related citations]
75. Snider, L., Geng, L. N., Lemmers, R. J. L. F., Kyba, M., Ware, C. B., Nelson, A. M.,
Tawil, R., Filippova, G. N., van der Maarel, S. M., Tapscott, S. J., Miller, D.
G. Facioscapulohumeral dystrophy: incomplete suppression of a
retrotransposed gene. PLoS Genet. 6: e1001181, 2010. Note: Electronic Article.
76. Tawil, R., Figlewicz, D. A., Griggs, R. C., Weiffenbach, B., FSH
Consortium.Facioscapulohumeral dystrophy: a distinct regional myopathy with
a novel molecular pathogenesis. Ann. Neurol. 43: 279-282, 1998.
77. Tawil, R., Forrester, J., Griggs, R. C., Mendell, J., Kissel, J., McDermott, M., King,
W., Weiffenbach, B., Figlewicz, D., FSH-DY Group. Evidence for anticipation and
association of deletion size with severity in facioscapulohumeral muscular
dystrophy. Ann. Neurol. 39: 744-748, 1996. [PubMed: 8651646, related citations]
[Full Text]
78. Tawil, R., Storvick, D., Feasby, T. E., Weiffenbach, B., Griggs, R. C. Extreme
variability of expression in monozygotic twins with FSH muscular
79. Tawil, R., Storvick, D., Weiffenbach, B., Altherr, M. R., Feasby, T. E., Griggs, R.
C. Chromosome 4q DNA rearrangement in monozygotic twins discordant for
facioscapulohumeral muscular dystrophy. Hum. Mutat. 2: 492-494, 1993.
80. Taylor, D. A., Carroll, J. E., Smith, M. E., Johnson, M. O., Johnston, G. P., Brooke,
M. H.Facioscapulohumeral dystrophy associated with hearing loss and Coats
syndrome. Ann. Neurol. 12: 395-398, 1982. [PubMed: 7149664, related citations]
[Full Text]
81. Thomas, N. S. T., Wiseman, K., Spurlock, G., MacDonald, M., Ustek, D.,
Upadhyaya, M. A large patient study confirming that facioscapulohumeral
muscular dystrophy (FSHD) disease expression is almost exclusively associated
with an FSHD locus located on a 4qA-defined 4qter subtelomere.(Letter) J. Med.
Genet. 44: 215-218, 2007. [PubMed: 16987949, images, related citations] [Full Text]
82. Tonini, M. M. O., Lemmers, R. J. L. F., Pavanello, R. C. M., Cerqueira, A. M. P.,
Frants, R. R., van der Maarel, S. M., Zatz, M. Equal proportions of affected cells
in muscle and blood of a mosaic carrier of facioscapulohumeral muscular
dystrophy. Hum. Genet. 119: 23-28, 2006. [PubMed: 16341710, related citations]
[Full Text]
83. Tupler, R., Barbierato, L., Memmi, M., Sewry, C. A., De Grandis, D., Maraschio,
P., Tiepolo, L., Ferlini, A. Identical de novo mutation at the D4F104S1 locus in
monozygotic male twins affected by facioscapulohumeral muscular dystrophy
(FSHD) with different clinical expression. J. Med. Genet. 35: 778-783, 1998.
84. Tyler, F. H., Stephens, F. E. Studies in disorders of muscle. II. Clinical
manifestations and inheritance of facioscapulohumeral dystrophy in a large
family. Ann. Intern. Med. 32: 640-660, 1950. [PubMed: 15411118, related citations]
[Full Text]
85. Tyler, F. H. The inheritance of neuromuscular disorders. Res. Publ. Assoc. Res.
Nerv. Ment. Dis. 33: 283-292, 1953.
86. Upadhyaya, M., Lunt, P., Sarfarazi, M., Broadhead, W., Farnham, J., Harper, P.
S. The mapping of chromosome 4q markers in relation to facioscapulohumeral
muscular dystrophy (FSHD).Am. J. Hum. Genet. 51: 404-410, 1992.
87. Upadhyaya, M., Lunt, P. W., Sarfarazi, M., Broadhead, W., Daniels, J., Owen, M.,
Harper, P. S.DNA marker applicable to presymptomatic and prenatal diagnosis
of facioscapulohumeral disease. (Letter) Lancet 336: 1320-1321, 1990.
88. Upadhyaya, M., Lunt, P. W., Sarfarazi, M., Broadhead, W., Daniels, J., Owen, M.,
Harper, P. S.A closely linked DNA marker for facioscapulohumeral disease on
chromosome 4q. J. Med. Genet. 28: 665-671, 1991. [PubMed: 1941963, related
89. van der Maarel, S. M., Deidda, G., Lemmers, R. J. L. F., Bakker, E., van der Wielen,
M. J. R., Sandkuijl, L., Hewitt, J. E., Padberg, G. W., Frants, R. R. A new dosage
test for subtelomeric 4;10 translocations improves conventional diagnosis of
facioscapulohumeral muscular dystrophy (FSHD). J. Med. Genet. 36: 823-828,
90. van der Maarel, S. M., Deidda, G., Lemmers, R. J. L. F., van Overveld, P. G. M.,
van der Wielen, M., Hewitt, J. E., Sandkuijl, L., Bakker, B., van Ommen, G.-J. B.,
Padberg, G. W., Frants, R. R. De novo facioscapulohumeral muscular dystrophy:
frequent somatic mosaicism, sex-dependent phenotype, and the role of mitotic
transchromosomal repeat interaction between chromosomes 4 and 10. Am. J.
Hum. Genet. 66: 26-35, 2000. [PubMed: 10631134, images, related citations] [Full
Text]
91. van der Maarel, S. M., Frants, R. R. The D4Z4 repeat-mediated pathogenesis of
92. van Deutekom, J. C. T., Lemmers, R. J. L. F., Grewal, P. K., van Geel, M., Romberg,
S., Dauwerse, H. G., Wright, T. J., Padberg, G. W., Hofker, M. H., Hewitt, J. E.,
Frants, R. R.Identification of the first gene (FRG1) from the FSHD region on
human chromosome 4q35.Hum. Molec. Genet. 5: 581-590, 1996.
93. van Deutekom, J. C. T., Wijmenga, C., van Tienhoven, E. A. E., Gruter, A.-M.,
Hewitt, J. E., Padberg, G. W., van Ommen, G.-J., Hofker, M. H., Frants, R.
R. FSHD associated DNA rearrangements are due to deletions of integral copies
of a 3.2 kb tandemly repeated unit.Hum. Molec. Genet. 2: 2037-2042, 1993.
94. van Geel, M., Dickson, M. C., Beck, A. F., Bolland, D. J., Frants, R. R., van der
Maarel, S. M., de Jong, P. J., Hewitt, J. E. Genomic analysis of human
chromosome 10q and 4q telomeres suggests a common origin. Genomics 79: 210-
217, 2002. [PubMed: 11829491, related citations] [Full Text]
95. van Overveld, P. G. M., Enthoven, L., Ricci, E., Rossi, M., Felicetti, L., Jeanpierre,
M., Winokur, S. T., Frants, R. R., Padberg, G. W., van der Maarel, S. M. Variable
hypomethylation of D4Z4 in facioscapulohumeral muscular dystrophy. Ann.
Neurol. 58: 569-576, 2005. [PubMed: 16178028, related citations] [Full Text]
96. van Overveld, P. G. M., Lemmers, R. J. F. L., Deidda, G., Sandkuijl, L., Padberg, G.
W., Frants, R. R., van der Maarel, S. M. Interchromosomal repeat array
interactions between chromosomes 4 and 10: a model for subtelomeric
plasticity. Hum. Molec. Genet. 9: 2879-2884, 2000. [PubMed: 11092764, related
citations]
97. van Overveld, P. G. M., Lemmers, R. J. F. L., Sandkuijl, L. A., Enthoven, L.,
Winokur, S. T., Bakels, F., Padberg, G. W., van Ommen, G.-J. B., Frants, R. R., van
der Maarel, S. M.Hypomethylation of D4Z4 in 4q-linked and non-4q-linked
facioscapulohumeral muscular dystrophy. Nature Genet. 35: 315-317, 2003.
98. Vitelli, F., Villanova, M., Malandrini, A., Bruttini, M., Piccini, M., Merlini, L.,
Guazzi, G., Renieri, A. Inheritance of a 38-kb fragment in apparently sporadic
facioscapulohumeral muscular dystrophy. Muscle Nerve 22: 1437-1441, 1999.
99. Voit, T., Lamprecht, A., Lenard, H. G., Goebel, H. H. Hearing loss in
facioscapulohumeral dystrophy. Europ. J. Pediat. 145: 280-285, 1986.
100. Wallace, L. M., Garwick, S. E., Mei, W., Belayew, A., Coppee, F., Ladner, K. J.,
Guttridge, D., Yang, J., Harper, S. Q. DUX4, a candidate gene for
facioscapulohumeral muscular dystrophy, causes p53-dependent myopathy in
vivo. Ann. Neurol. 69: 540-552, 2011. [PubMed: 21446026,images, related citations]
[Full Text]
101. Wang, Z.-Q., Wang, N., van der Maarel, S., Murong, S.-X., Wu, Z.-
Y. Distinguishing the 4qA and 4qB variants is essential for the diagnosis of
facioscapulohumeral muscular dystrophy in the Chinese population. Europ. J.
Hum. Genet. 19: 64-69, 2011. [PubMed: 20736973, images, related citations] [Full
Text]
102. Weiffenbach, B., Bagley, R., Falls, K., Hyser, C., Storvick, D., Jacobsen, S. J.,
Schultz, P., Mendell, J., van Dijk, K. W., Milner, E. C. B., Griggs, R. Linkage
analyses of five chromosome 4 markers localizes the facioscapulohumeral
muscular dystrophy (FSHD) gene to distal 4q35. Am. J. Hum. Genet. 51: 416-423,
103. Weiffenbach, B., Dubois, J., Storvick, D., Tawil, R., Jacobsen, S. J., Gilbert, J.,
Wijmenga, C., Mendell, J. R., Winokur, S., Altherr, M. R., Schultz, P., Olandt, S.,
Frants, R. R., Pericak-Vance, M., Griggs, R. C. Mapping the facioscapulohumeral
muscular dystrophy gene is complicated by chromosome 4q35 recombination
events. Nature Genet. 4: 165-169, 1993. [PubMed: 8102297, related citations] [Full
Text]
104. Wijmenga, C., Frants, R. R., Brouwer, O. F., Moerer, P., Weber, J. L., Padberg, G.
W. Location of facioscapulohumeral muscular dystrophy gene on chromosome
4. Lancet 336: 651-653, 1990. [PubMed: 1975852, related citations] [Full Text]
105. Wijmenga, C., Hewitt, J. E., Sandkuijl, L. A., Clark, L. N., Wright, T. J.,
Dauwerse, H. G., Gruter, A.-M., Hofker, M. H., Moerer, P., Williamson, R., van
Ommen, G.-J. B., Padberg, G. W., Frants, R. R. Chromosome 4q DNA
rearrangements associated with facioscapulohumeral muscular
dystrophy. Nature Genet. 2: 26-30, 1992. [PubMed: 1363881, related citations]
[Full Text]
106. Wijmenga, C., Padberg, G. W., Moerer, P., Wiegant, J., Liem, L., Brouwer, O. F.,
Milner, E. C. B., Weber, J. L., van Ommen, G. B., Sandkuyl, L. A., Frants, R.
R. Mapping of facioscapulohumeral muscular dystrophy gene to chromosome
4q35-qter by multipoint linkage analysis and in situ hybridization. Genomics 9:
570-575, 1991. [PubMed: 2037288, related citations]
107. Wijmenga, C., Sandkuijl, L. A., Moerer, P., van der Boorn, N., Bodrug, S. E.,
Ray, P. N., Brouwer, O. F., Murray, J. C., van Ommen, G. J. B., Padberg, G. W.,
Frants, R. R. Genetic linkage map of facioscapulohumeral muscular dystrophy
and five polymorphic loci on chromosome 4q35-qter. Am. J. Hum. Genet. 51:
411-415, 1992. [PubMed: 1642239, related citations]
108. Winokur, S. T., Chen, Y.-W., Masny, P. S., Martin, J. H., Ehmsen, J. T., Tapscott,
S. J., van der Maarel, S. M., Hayashi, Y., Flanigan, K. M. Expression profiling of
FSHD muscle supports a defect in specific stages of myogenic
differentiation. Hum. Molec. Genet. 12: 2895-2907, 2003.
109. Winokur, S. T., Schutte, B., Weiffenbach, B., Washington, S. S., McElligott, D.,
Chakravarti, A., Wasmuth, J. H., Altherr, M. R. A radiation hybrid map of 15 loci
on the distal long arm of chromosome 4, the region containing the gene
responsible for facioscapulohumeral muscular dystrophy (FSHD). Am. J. Hum.
110. Wohlgemuth, M., de Swart, B. J. M., Kalf, J. G., Joosten, F. B. M., Van der Vliet,
A. M., Padberg, G. W. Dysphagia in facioscapulohumeral muscular
[Full Text]
111. Wohlgemuth, M., Lemmers, R. J., van der Kooi, E. L., van der Wielen, M. J., van
Overveld, P. G., Dauwerse, H., Bakker, E., Frants, R. R., Padberg, G. W., van der
Maarel, S. M. Possible phenotypic dosage effect in patients compound
heterozygous for FSHD-sized 4q35 alleles.Neurology 61: 909-913, 2003.
112. Yamanaka, G., Goto, K., Matsumura, T., Funakoshi, M., Komori, T., Hayashi, Y.
K., Arahata, K.Tongue atrophy in facioscapulohumeral muscular
[Full Text]
113. Yasukohchi, S., Yagi, Y., Akabane, T., Terauchi, A., Tamagawa, K., Mizuno,
Y.Facioscapulohumeral dystrophy associated with sensorineural hearing loss,
tortuosity of retinal arterioles, and an early onset and rapid progression of
respiratory failure. Brain Dev. 10: 319-324, 1988. [PubMed: 3239698, related
114. Zatz, M., Marie, S. K., Cerqueira, A., Vainzof, M., Pavanello, R. C. M., Passos-
Bueno, M. R. The facioscapulohumeral muscular dystrophy (FSHD1) gene
affects males more severely and more frequently than females. Am. J. Med.
Genet. 77: 155-161, 1998. [PubMed: 9605290, related citations] [Full Text]
115. Zatz, M., Marie, S. K., Passos-Bueno, M. R., Vainof, M., Campiotto, S.,
Cerqueira, A., Wijmenga, C., Padberg, G., Frants, R. High proportion of new
mutations and possible anticipation in Brazilian facioscapulohumeral muscular
dystrophy families. Am. J. Hum. Genet. 56: 99-105, 1995.
116. Zeng, W., de Greef, J. C., Chen, Y.-Y., Chien, R., Kong, X., Gregson, H. C.,
Winokur, S. T., Pyle, A., Robertson, K. D., Schmiesing, J. A., Kimonis, V. E., Balog,
J., Frants, R. R., Ball, A. R., Jr., Lock, L. F., Donovan, P. J., van der Maarel, S. M.,
Yokomori, K. Specific loss of histone H3 lysine 9 trimethylation and HP1-
gamma/cohesin binding at D4Z4 repeats is associated with
facioscapulohumeral dystrophy (FSHD). PLoS Genet. 5: e1000559, 2009. Note:
Electronic Article. [PubMed: 19593370, images, related citations] [Full Text]
Contributors:
Cassandra L. Kniffin - updated : 11/4/2013
Creation Date:
Victor A. McKusick : 6/2/1986
Edit History:
carol : 11/17/2017

FSHD - Word Gene Mutation

Hochgeladen von

Dokumentinformationen

Originaltitel

Copyright

Verfügbare Formate

Dieses Dokument teilen

Dokument teilen oder einbetten

Freigabeoptionen

Stufen Sie dieses Dokument als nützlich ein?

Sind diese Inhalte unangemessen?

Copyright:

Verfügbare Formate

FSHD - Word Gene Mutation

Hochgeladen von

Copyright:

Verfügbare Formate

A number sign (#) is used with this entry because facioscapulohumeral muscular

dystrophy-1 (FSHD1) is associated with contraction of the D4Z4 macrosatellite repeat

Das könnte Ihnen auch gefallen