Fragile X Syndrome

Instructor:
Muhammad Imran Shabbir, PhD
Lecture
www.fragilex.org.uk/ page6.htm
Signs and Symptoms
Mild to Moderate Mental
Retardation
Long, narrow face
Large, protuberant ears
Macroorchidism (enlarged
testicles)
behavioral characteristics
such as stereotypic
movements (e.g. hand-
flapping), and social anxiety.
Hypotonia (low muscle tone)
Sign and Symptoms (Detailed)
Background
X-linked disease
Mutation is located at Xq27.3
FMR1 Gene
Polymorphic (CCG)
n
repeat in
the 5 untranslated reagion of
exon 1
Hypermethylation of a CpG
island upstream of the
mutation

Molecular Basis
In 1991, scientists discovered the gene (called FMR1) that causes Fragile X. In
individuals with Fragile X Syndrome, a defect in FMR1 (a full mutation) shuts the
gene down. Like a defective factory, the FMR1 gene cannot manufacture the
protein that it normally makes.

Some indiviuals are carriers: they have a small defect in the FMR1 gene (called a
premutation) but do not show symptoms of Fragile X.

Fragile X is inherited. Carrier men (transmitting males) pass the premutation to all
their daughters but none of their sons. Each child of a carrier woman has a 50%
chance of inheriting the gene. The fragile X premutation can be passed silently
down through generations in a family before a child is affected by the syndrome. A
DNA blood test identifies both carriers and affected individuals. While the exact
prevelance of Fragile X is unknown, recent studies indicate the statistics below:

1 in 2000 boys and 1 in 4000 girls are estimated to be affected
Molecular Basis
Named for its association with a chromosomal fragile site observed
in many patients (FRAXA chromosomal locus Xq27.3), fragile X
syndrome (FXS) is the most common cause of inherited mental
retardation (MR).
FXS results from loss or severe reduction of the protein FMRP,
encoded by the FMR1 (fragile X mental retardation) gene.
All patients with FXS have mutations in FMR1, as no mutations
leading to FXS have been identified in other genes.
Both males and females may be affected with FXS, but females are
typically less severely affected. Thus, FXS is considered to be X-
linked dominant with reduced penetrance in females.
The molecular genetics of FMR1 are complex. A repeated
trinucleotide sequence, composed primarily of CGG repeats, is
located in the untranslated portion of exon 1, ending 69 base pairs
upstream of the translational start.


Molecular Basis
Nearly all mutations (>99%) resulting in FXS occur as instability of the
trinucleotide repeat,leading to dramatic expansion of the repeat segment
(>200 to a few thousand repeats) accompanied by aberrant
hypermethylation of CpG dinucleotides within the gene (full mutations).
Relatively rare deletions and point mutations in FMR1 account for the
remaining mutations found in patients with FXS.

The mechanism of repeat instability in FMR1 is believed to be DNA
polymerase slippage during DNA replication.
AGG repeats, spaced at about 10 repeat intervals within the CGG repeat
segment, may mitigate potential repeat instability through disruption of
higher-order molecular structures formed during DNA replication.
These secondary structures contribute to polymerase slippage, and alleles
that lack interrupting AGG repeats are at higher risk for expansion.
Anticipation
Stuttering Alleles
Some genetically inherited
diseases have more severe
symptoms each succeeding
generation due to segments of
the defective genes being
doubled in their transmission
to children (as illustrated
below). These are referred to
as stuttering alleles or unstable
alleles. Examples of this
phenomenon are Huntington's
disease, fragile-X syndrome,
and the myotonic form
of muscular dystrophy.
Unstable allele doubling each generation
FMR1Tripple Repeat Expansion