Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
, 58 (10), 1009-15

Molecular Pathology of Ataxia Telangiectasia

Affiliations
Review

Molecular Pathology of Ataxia Telangiectasia

A M R Taylor et al. J Clin Pathol.

Abstract

Ataxia telangiectasia (A-T) is one of a group of autosomal recessive cerebellar ataxias. Presentation is usually by the age of 2 years and ataxia of both upper and lower limbs develops, such that by early teenage most patients require a wheelchair for mobility. Speech and eye movement are also affected. Other important features are t(7;14) translocations, immunodeficiency, a high serum alpha fetoprotein concentration, growth retardation, telangiectasia-most noticeably on the bulbar conjunctiva-and a very high risk of developing a lymphoid tumour. Patients also show an increased sensitivity to ionising radiation. The classic form of A-T results from the presence of two truncating ATM mutations, leading to total loss of the ATM protein, a protein kinase. Importantly, A-T shows clinical heterogeneity, including milder forms where neurological progression may be slower or of later onset. In these cases there is a correlation between the preservation of neurological function, decreased radiosensitivity, and the degree of retained ATM protein kinase activity. Considerable scope remains for understanding the progress of the disorder in relation to the types of ATM mutation present.

Figures

Figure 1
Figure 1
An aid to the confirmation of ataxia telangiectasia (A-T) or ataxia oculomotor apraxia 1 (AOA1) by screening for the loss of a DNA damage response protein. Lymphoblastoid cell lines were derived from blood samples of 11 consecutive patients and screened for ATM, hRad50, Nbs1, hMre11, and aprataxin by western blotting. Actin was used as the loading control. The western blot shows that cell extracts from two of the patients are abnormal; patient 7 has no aprataxin and patient 9 has a very much reduced amount of ATM protein. After this initial screen, mutations for APTX1 and ATM, respectively, were identified.
Figure 2
Figure 2
Cells from patients with ataxia telangiectasia (A-T) and a milder clinical presentation retain some ATM kinase activity. An in vitro assay of γ ray induced ATM activity shows that cells derived from patients with A-T and either one or both ATM alleles carrying the 5762ins137 mutation retain some ATM kinase activity. Cells homozygous (lanes 6 and 8) for the mutation show approximately three times the induced activity of heterozygous cells (lanes 10 and 12). The induced ATM kinase activity in a normal cell extract is shown in lane 2 and absence of activity in extracts of cells from a patient with classic A-T in lane 4. ATM was immunoprecipitated from 2 mg of protein of the cell extract in each lane, except for the normal control, where only 1 mg was used. The ATM was then used to phosphorylate a p531–72 substrate (bottom panel). The relative amounts of ATM used in the kinase assay are shown in the top panel. Taken from Sutton et al.

Similar articles

See all similar articles

Cited by 55 PubMed Central articles

See all "Cited by" articles

Publication types

MeSH terms

Substances

Feedback