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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Variant ataxia telangiectasia: Clinical and molecular findings and evaluation of radiosensitive phenotypes in a patient and relatives
NeuroMolecular Medicine, Volume 15, No. 3, Year 2013
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Description
Variant ataxia telangiectasia (A-T) may be an underdiagnosed entity. We correlate data from radiosensitivity and kinase assays with clinical and molecular data from a patient with variant A-T and relatives. The coding region of ATM was sequenced. To evaluate the functional effect of the mutations, we performed kinase assays and developed a novel S-G2 micronucleus test. Our patient presented with mild dystonia, moderately dysarthric speech, increased serum α-fetoprotein but no ataxia nor telangiectasias, no nystagmus or oculomotor dyspraxia. She has a severe IgA deficiency, but does not have recurrent infections. She is compound heterozygote for ATM c.8122G>A (p.Asp2708Asn) and c.8851-1G>T, leading to in frame loss of 63 nucleotides at the cDNA level. A trace amount of ATM protein is translated from both alleles. Residual kinase activity is derived only from the p.Asp2708Asn allele. The conventional G0 micronucleus test, based on irradiation of resting lymphocytes, revealed a radiosensitive phenotype for the patient, but not for the heterozygous relatives. As ATM is involved in homologous recombination and G2/M cell cycle checkpoint, we optimized an S-G2 micronucleus assay, allowing to evaluate micronuclei in lymphocytes irradiated in the S and G2 phases. This test showed increased radiosensitivity for both the patient and the heterozygous carriers. Intriguingly, heterozygous carriers of c.8851-1G>T (mutation associated with absence of kinase activity) showed a stronger radiosensitive phenotype with this assay than heterozygous carriers of p.Asp2708Asn (mutation associated with residual kinase activity). The modified S-G2 micronucleus assay provided phenotypic insight into complement the diagnosis of this atypical A-T patient. © 2013 Springer Science+Business Media New York.
Authors & Co-Authors
Claes, Kathleen B.M.
Belgium, Ghent
Universitair Ziekenhuis Gent
Depuydt, Julie
Belgium, Ghent
Universiteit Gent
Taylor, A. M.R.
United Kingdom, Birmingham
University of Birmingham
Last, James I.
United Kingdom, Birmingham
University of Birmingham
Baert, Annelot
Belgium, Ghent
Universitair Ziekenhuis Gent
Belgium, Ghent
Universiteit Gent
Schietecatte, Peter
Belgium, Ghent
Universitair Ziekenhuis Gent
Vandersickel, Veerle
South Africa, Somerset West
Ithemba Laboratory for Accelerator-based Sciences
Poppe, Bruce
Belgium, Ghent
Universitair Ziekenhuis Gent
de Leeneer, Kim
Belgium, Ghent
Universitair Ziekenhuis Gent
D'Hooghe, Marc
Belgium, Brugge
General Hospital St. Jan
Vral, Anne M.
Belgium, Ghent
Universiteit Gent
Statistics
Citations: 31
Authors: 11
Affiliations: 5
Identifiers
Doi:
10.1007/s12017-013-8231-4
ISSN:
15351084
e-ISSN:
15591174
Research Areas
Cancer
Genetics And Genomics
Health System And Policy