Ataxia telangiectasia: more variation at clinical and cellular levels

Ataxia telangiectasia (A‐T) is a rare recessively inherited disorder resulting in a progressive neurological decline. It is caused by biallelic mutation of the ATM gene that encodes a 370 kDa serine/threonine protein kinase responsible for phosphorylating many target proteins. ATM is activated by au...

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Bibliographic Details
Published in:Clinical genetics 2015-03, Vol.87 (3), p.199-208
Main Authors: Taylor, A.M.R., Lam, Z., Last, J.I., Byrd, P.J.
Format: Article
Language:English
Subjects:
Age of Onset
Ataxia
Ataxia Telangiectasia - complications
Ataxia Telangiectasia - diagnosis
Ataxia Telangiectasia - epidemiology
Ataxia Telangiectasia - genetics
Ataxia Telangiectasia - metabolism
Ataxia Telangiectasia Mutated Proteins - deficiency
Ataxia Telangiectasia Mutated Proteins - genetics
ATM
Deoxyribonucleic acid
Disease Progression
DNA
DNA-Binding Proteins - genetics
Enzyme Activation
Genetic Heterogeneity
Humans
kinase activity
Kinases
MRE11 Homologue Protein
Mutation
Neoplasms - etiology
Phenotype
Signal Transduction
telangiectasia
Ubiquitin-Protein Ligases - genetics
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Summary:Ataxia telangiectasia (A‐T) is a rare recessively inherited disorder resulting in a progressive neurological decline. It is caused by biallelic mutation of the ATM gene that encodes a 370 kDa serine/threonine protein kinase responsible for phosphorylating many target proteins. ATM is activated by auto(trans)phosphorylation in response to DNA double strand breaks and leads to the activation of cell cycle checkpoints and either DNA repair or apoptosis as part of the cellular response to DNA damage. The allelic heterogeneity in A‐T is striking. While the majority of mutations are truncating, leading to instability and loss of the ATM protein from the allele, a significant proportion of patients carry one of a small number of mutations that are either missense or leaky splice site mutations resulting in retention of some ATM with activity. The allelic heterogeneity in ATM, therefore, results in an equally striking clinical heterogeneity. There is also locus heterogeneity because mutation of the MRE11 gene can cause an obvious A‐T like disorder both clinically and also at the cellular level and mutation of the RNF168 gene results in a much milder clinical phenotype, neurologically, with the major clinical feature being an immunological defect.
ISSN:0009-9163
1399-0004
DOI:10.1111/cge.12453