Characterization of ATM gene mutations in 66 ataxia telangiectasia families
Abstract
Ataxia telangiectasia (AT) is an autosomal recessive disease characterized by neurological and immunological symptoms, radiosensitivity and cancer predisposition. The gene mutated in AT, designated the ATM gene, encodes a large protein kinase with a PI-3 kinase-related domain. In this study, we investigated the mutational spectrum of the ATM gene in a cohort of AT patients living in Germany. We amplified and sequenced all 66 exons and the flanking untranslated regions from genomic DNA of 66 unrelated AT patients. We identified 46 different ATM mutations and 26 sequence polymorphisms and variants scattered throughout the gene. A total of 34 mutations have not been described in other populations. Seven mutations occurred in more than one family, but none of these accounted for more than five alleles in our patient group. The majority of the mutations were truncating, confirming that the absence of full-length ATM protein is the most common molecular basis of AT. Transcript analyses demonstrated single exon skipping as the consequence of most splice site substitutions, but a more complex pattern was observed for two mutations. Immunoblot studies of cell lines carrying ATM missense substitutions or in-frame deletions detected residual ATM protein in four cases. One of these mutations, a valine deletion proximal to the kinase domain, resulted in ATM protein levels >20% of normal in an AT lymphoblastoid cell line. In summary, our results survey and characterize a plethora of variations in the ATM gene identified by exon scanning sequencing and indicate a high diversity of mutations giving rise to AT in a non-isolated population.
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Four cases in the complex rearrangement subgroup had germline pathogenic variants in ATM, CHEK2, or TP53, all with somatic LOH.
“Four cases within this group harboured germline pathogenic variants in ATM [23], CHEK2 [24] or TP53 [25], all with somatic LOH.”
From Whole-genome sequencing reveals clinically relevant insights into the aetiology of familial breast cancers (2019) · cites this paper as [23]
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- Authors
- Sandoval, N.
- Affiliations
- Medizinische Hochschule Hannover (DE)
- Corresponding author
- Sandoval, N
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 1999-01-01
- Volume
- 8
- Issue
- 1
- Pages
- 69-79
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2115322319
- Cited by
- 226
- References
- 61
- Citations by year
- 2026: 5 · 2025: 2 · 2024: 8 · 2023: 6 · 2022: 6 · 2021: 12 · 2020: 11 · 2019: 13 · 2018: 6 · 2017: 10 · 2016: 6 · 2015: 8 · 2014: 11 · 2013: 3 · 2012: 7
- FWCI
- 5.14
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- University of Regensburg Publication Server (University of Regensburg) (submittedVersion)
- HighWire Press Open Archive (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Keywords
- ataxia telangiectasia, ATM gene, ATM mutations, mutation spectrum, truncating mutations, splice site mutation, exon skipping, missense mutations, in-frame deletion, sequence variation, German patients
- MeSH terms
- Ataxia Telangiectasia, Base Sequence, Cell Line, DNA Mutational Analysis, DNA-Binding Proteins, Female, Germany, Humans, Male, Molecular Sequence Data, Mutation, Polymorphism, Genetic, Proteins, RNA Splicing, Genetic Variation, Cohort Studies, Polymerase Chain Reaction, Protein Serine-Threonine Kinases, Sequence Deletion, DNA Primers, Cell Cycle Proteins, Phosphatidylinositol 3-Kinases, Tumor Suppressor Proteins, Ataxia Telangiectasia Mutated Proteins
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