title: 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.
authors.affiliation: Department of Genome Analysis, Institute of Molecular Biotechnology, Jena, Germany, Institute of Human Genetics, Medical School Hannover, D-30625 Hannover, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Sandoval
authors.forename: M
authors.initials: M
authors.lastname: Platzer
authors.forename: A
authors.initials: A
authors.lastname: Rosenthal
authors.forename: T
authors.initials: T
authors.lastname: Dörk
authors.forename: R
authors.initials: R
authors.lastname: Bendix
authors.forename: B
authors.initials: B
authors.lastname: Skawran
authors.forename: M
authors.initials: M
authors.lastname: Stuhrmann
authors.forename: R D
authors.initials: RD
authors.lastname: Wegner
authors.forename: K
authors.initials: K
authors.lastname: Sperling
authors.forename: S
authors.initials: S
authors.lastname: Banin
authors.forename: Y
authors.initials: Y
authors.lastname: Shiloh
authors.forename: A
authors.initials: A
authors.lastname: Baumer
authors.forename: U
authors.initials: U
authors.lastname: Bernthaler
authors.forename: H
authors.initials: H
authors.lastname: Sennefelder
authors.forename: M
authors.initials: M
authors.lastname: Brohm
authors.forename: B H
authors.initials: BH
authors.lastname: Weber
authors.forename: D
authors.initials: D
authors.lastname: Schindler
mesh_terms: D001260:Ataxia Telangiectasia / Q000235:genetics* / Q000378:metabolism; D064007:Ataxia Telangiectasia Mutated Proteins; D001483:Base Sequence; D018797:Cell Cycle Proteins; D002460:Cell Line; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000235:genetics; D004268:DNA-Binding Proteins; D005260:Female; D014644:Genetic Variation; D005858:Germany; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D017346:Protein Serine-Threonine Kinases; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D012326:RNA Splicing / Q000235:genetics; D017384:Sequence Deletion; D025521:Tumor Suppressor Proteins
chemical_list: D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D017931:DNA Primers; D004268:DNA-Binding Proteins; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human