MORE ABOUT HRAS

COSTELLO SYNDROME 11p15.5

In this disease, the mutation causes changes in amino acid sequence, which are made up of
• HRSA is 3325 base pairs
single building blocks called amino acids 2. There are at least 15 mutations in HRAS
Costello syndrome is a rare condition long 6.
associated with Costello Syndrome and the most common mutation occurs when there is a
that alters many parts of the human
• It is between nucleotide replacement of the amino acid glycine with the amino acid serine, at position 12 of the
body. It is characterised by growth amino acid sequence, known as Gly12Ser (G12S)4. Other notable mutations include G12A
position 533 242 and
deficiency, failure to thrive, heart and G13C4.
535 5676.
problems, impaired intellectual capacity,
increased risk to cancer and distinctive • Contains 7 exons and 6 Mutations in Costello Syndrome results in the overproduction of H-ras in cells around body.
facial features such as a wide mouth1. introns6. The high level of H-ras induces cellular processes such as cell differentiation and cell cycle
progression, resulting in unwanted cell growth and division9. It can also lead to the deletion
Genes can be viewed as blueprints that • More than 80% of of negative regulators called GAP and GEF, which regulate the level of RAS in the cell. As a
provide specific instructions for protein Costello Syndrome is result of high cell growth, it predisposes individuals with Costello syndrome to a significantly
synthesis 2. The disease arises when from Gly12Ser5. higher risk of cancer8. In particular, a study in 2003 found that members of the Ras family
there are changes in the DNA sequence are associated with bladder cancer progression9.
(known as mutations) found within the • Only 200-300 people Active Inactive Active Inactive
GAP GAP
HRAS gene. This gene belongs to a family have Costello Syndrome RAS
PO4-2
RAS
PO4-2
RAS RAS RAS RAS
worldwide7. ++ ++
of genes called oncogenes. When + +

Effector

Effector
GTP
GTP GTP GTP
GTP GTP
oncogenes are dysfunctional, it has the GTP GDP GTP GDP
potential to cause the growth of tumour GEF GEF
(cancer) cells 1.
Normal individual Costello Syndrome
The HRAS gene is responsible for
producing the protein called H-ras, which The exact mechanisms that causes the symptoms found in Costello syndrome (aside from predisposition to cancer) remains
plays a regulatory role in a process called unclear but it is largely thought to be the result of elevated H-ras levels7. This is supported by Cardiofaciocutaneous syndrome
signal transduction3. It falls under a and Noonan syndrome, which share many overlapping symptoms with Costello syndrome. Each of these conditions involves a
mutation in a protein that has a functional role in a pathway called the RAS/MAPK pathway10, 11. The uncontrolled upregulation of
family of Ras proteins and all Ras
chemical signalling and increased activity of cellular processes is the common factor between these three syndromes10, 11.
proteins belong to a class of protein
called GTPases. Ras proteins provide Costello syndrome does not have a direct cure but the aspects of the clinical features may be treated individually. For example,
signals for cells to undergo important failure to thrive is considered to be the most complicated symptom but can be treated through gastrostomy feeding12. Other
cellular processes such as methods include lengthening of tendons via surgery, special education catered towards impaired intellectual capacity and drugs
differentiation1,3. to treat abnormal heartbeats12.
1. National Center for Biotechnology Information. (2008).PubChem Database; NCBI GeneID=3265,
https://pubchem.ncbi.nlm.nih.gov/target/gene/HRAS/human#section=Top.
2. Lodish H, Berk A, Zipursky SL, et al. (2000). Molecular Cell Biology 4th Edition. New York: W. H. Freeman.
3. Colicelli J (2004). Human RAS superfamily Proteins and Related GTPases. Science’s STKE. 140(250):RE13.
4. Estep A, Tidyman W, Teitell M, et al. (2005). HRAS mutations in Costello syndrome: Detection of constitutional activating mutations in codon 12 and 13 and
loss of wild-type allele in malignancy. American Journal of Medical Genetics. 140(1): 8-16.
5. Bertola D, Buscarilli M, Stabley D, et al. (2017). Phenotypic Spectrum of Costello Syndrome Individuals Harboring the Rare HRAS Mutation p.Gly13As.
America Journal of Medical Genetics. 173(5): 1309-1318.
6. National Center for Biotechnology Information. (2008). PubChem Database; NCBI GeneID=3265, https://www.ncbi.nlm.nih.gov/gene/3265.
7. Abe Y, Aoki Y, Kuriyama S et al. (2012) Prevalence and clinical features of Costello syndrome and cardio-facio-cutaneous syndrome in Japan: findings from a
nationwide epidemiological survey. American Journal of Medical Genetics. 158A(5): 1083-1094.
8. Geihl K. (2005). Oncogenic Ras in tumour progression and metastasis. Biological Chemistry. 386(3):193-205.
9. Oxford Gm, Theodorescu D. (2003). The role of Ras superfamily proteins in bladder cancer progression.. The Journal of Urology. 170(5):1987-93
10. Armour CM, Allanson JE. (2008). Further delineation of cardio-facio-cutaneous syndrome: clinical features of 38 individuals with proven mutations.. Journal
of Medical Genetics. 45(4):249-54.
11. C P Kratz, Franke L, Peters H et al. (2015). Cancer spectrum and frequency among children with Noonan, Costello, and cardio-facio-cutaneous syndromes.
British Journal of Cancer. 112(8):1392-1397.
12. Adam MP, Ardinger HH, Pagon RA, et al., editors (2012). Costello Syndrome GeneReviews. University of Washington.