Variant Ataxia Telangiectasia: Clinical and Molecular Findings and Evaluation of Radiosensitive Phenotypes in a Patient and Relatives
| Autor: | Julie Depuydt, A. Malcolm R. Taylor, Kim De Leeneer, Marc D’Hooghe, Peter Schietecatte, Veerle Vandersickel, Kathleen Claes, Bruce Poppe, Anne Vral, Annelot Baert |
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| Rok vydání: | 2013 |
| Předmět: |
Adult
G2 Phase Male Heterozygote Ataxia Mutation Missense Breast Neoplasms Ataxia Telangiectasia Mutated Proteins Biology Compound heterozygosity Radiation Tolerance S Phase Ataxia Telangiectasia Cellular and Molecular Neuroscience Neoplastic Syndromes Hereditary Caffeine medicine Humans Missense mutation Rhabdomyosarcoma Embryonal Lymphocytes Allele Kinase activity Child Neurologic Examination Micronucleus Tests Recombinational DNA Repair Heterozygote advantage Exons Sequence Analysis DNA medicine.disease Molecular biology Pedigree Phenotype Amino Acid Substitution Neurology Ataxia-telangiectasia Micronucleus test Molecular Medicine Female RNA Splice Sites medicine.symptom |
| Zdroj: | NeuroMolecular Medicine. 15:447-457 |
| ISSN: | 1559-1174 1535-1084 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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