Ataxia telangiectasia pathophysiology: Difference between revisions
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Pathophysiology
The responsible gene in AT, ataxia-telangiectasia mutated (ATM), was discovered in 1995 by Savitsky et al.,[1] a team led by Yosef Shiloh of Tel Aviv University in Israel. Researchers linked the hyper-sensitivity of AT patients to ionizing radiation (IR) and predisposition to cancer, to "chromosomal instability, abnormalities in genetic recombination, and defective signaling to programmed cell death and several cell cycle checkpoints activated by DNA damage".[2] Earlier observations predicted that the gene altered in AT played a role in DNA damage recognition. These predictions were confirmed when a single gene on chromosome 11 (11q 22-23) was discovered.[1][3] Since its discovery, the protein product of the ATM gene has been shown to be a part of eukaryotic cell cycle control, DNA repair, and DNA recombination (Lavin, 2004). Specifically, the AT gene serves as a tumor suppressor gene by contributing to a network of genes that link double stranded breaks in DNA to cell cycle arrest and apoptosis (programmed cell death). Patients with ATM have a defective AT gene, which leaves them susceptible to contracting cancer. For example, female ATM patients have a two-fold higher chance of ever having breast cancer, which often occur before the age of 50. ATM patients must try avoiding x-rays at all costs since the radiation induces double-stranded breaks.
Genetics
AT is an autosomal recessive disorder caused by mutations in the ATM gene located on chromosome 11q22-23. [4] It was characterised in June of 1995 and is made up of 66 exons spread across 150kb of genomic DNA. It encodes a 13kb mature transcript with an open reading frame of 9168 nucleotides. The ATM protein is about 370kDa and is ubiquitously expressed and is localised to the cell nucleus. The ATM protein is a large serine-threonine kinase thought to play a role in regulating cell cycle checkpoints, repair of double stranded DNA and meiosis (similar to the BRCA genes). ATM is also known to play a role in regulating p53, BRCA1 and CHEK2. Part of ATM’s role in DNA repair is known to be that of telomere repair as telomeres degrade more rapidly in people affected with AT.
Mutations in the ATM gene are thought to come in two types:
- Null mutations are those which cause complete loss of function of the protein and are therefore inherited in a recessive manner and cause AT.
- ‘Missense’ mutations which produce stable, full sized protein with reduced function e.g. substitutions, short in-frame insertions and deletions etc. These mutations act by dominantly interfering with the normal copy of the protein.
The majority of AT sufferers, 65-70%, have truncating mutations, with exon skipping mutations being particularly common. This results in very low or undetectable levels of ATM protein. Missense mutations are the most common type of mutation found in carriers with breast cancer. Individuals with two missense mutations are believed to have a milder form of AT, which may account for cases of attenuated AT. Therefore it is thought that "subtle constitutional alterations of ATM may impart an increased risk of developing breast cancer and therefore act as a low penetrance, high prevalence gene in the general population" (Maillet et al 2002).
Oculo-cutaneous telangiectasia combined with ataxia are the defining features of the condition. However, some patients with AT, even those with two null mutations who produce no ATM protein at all, may never present with oculo-cutaneous telangiectasia.
References
- ↑ 1.0 1.1 Savitsky K, Bar-Shira A, Gilad S; et al. (1995). "A single ataxia telangiectasia gene with a product similar to PI-3 kinase". Science. 268 (5218): 1749–53. doi:10.1126/science.7792600. PMID 7792600.
- ↑ Canman CE, Lim DS (1998). "The role of ATM in DNA damage responses and cancer". Oncogene. 17 (25): 3301–8. doi:10.1038/sj.onc.1202577. PMID 9916992.
- ↑ Gatti RA, Bick M, Tam CF; et al. (1982). "Ataxia-Telangiectasia: a multiparameter analysis of eight families". Clin. Immunol. Immunopathol. 23 (2): 501–16. doi:10.1016/0090-1229(82)90134-9. PMID 6213343.
- ↑ Online Mendelian Inheritance in Man (OMIM) 209800