title: A double missense mutation in the ATM gene of a Dutch family with ataxia telangiectasia.
abstract: Ataxia telangiectasia (AT) is an autosomal recessive disorder characterized by cerebellar ataxia, telangiectasia, immunodeficiency, elevated alpha-fetoprotein levels, chromosomal instability, predisposition to cancer, and radiation sensitivity. We report the identification of a new, double missense mutation in the ataxia telangiectasia gene (ATM) of a Dutch family. This homozygous mutation consists of two consecutive base substitutions in exon 55: a T-->G transversion at position 7875 of the ATM cDNA and a G-->C transversion at position 7876. These transversions were confirmed by polymerase chain reaction/primer-induced restriction analysis with CelII. The double base substitution results in an amino acid change of an aspartic acid to a glutamic acid at codon 2625 and of an alanine to a proline at codon 2626 of the ATM protein. Both amino acids are conserved between the ATM protein and its functional homolog, the Atm gene product in the mouse. Furthermore, the Chou-Fasman and Robson predictions both demonstrate a change in the secondary structure of the ATM protein carrying the D2625E/A2626P mutation. These findings suggest that the double base substitution in the ATM gene is a disease-causing mutation.
authors.affiliation: Laboratory of Pediatrics and Neurology, University Hospital Nijmegen, The Netherlands.
authors.forename: M J
authors.initials: MJ
authors.lastname: van Belzen
authors.forename: J A
authors.initials: JA
authors.lastname: Hiel
authors.forename: C M
authors.initials: CM
authors.lastname: Weemaes
authors.forename: F J
authors.initials: FJ
authors.lastname: Gabreëls
authors.forename: B G
authors.initials: BG
authors.lastname: van Engelen
authors.forename: D F
authors.initials: DF
authors.lastname: Smeets
authors.forename: L P
authors.initials: LP
authors.lastname: van den Heuvel
mesh_terms: D000293:Adolescent; D019943:Amino Acid Substitution / Q000235:genetics; D001260:Ataxia Telangiectasia / Q000235:genetics*; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D002460:Cell Line; D002648:Child; D018076:DNA, Complementary / Q000302:isolation & purification; D004268:DNA-Binding Proteins; D005091:Exons; D005260:Female; D005347:Fibroblasts; D006801:Humans; D008297:Male; D009426:Netherlands; D017354:Point Mutation; D017346:Protein Serine-Threonine Kinases; D017433:Protein Structure, Secondary; D011506:Proteins / Q000737:chemistry / Q000235:genetics*; D025521:Tumor Suppressor Proteins
chemical_list: D018797:Cell Cycle Proteins; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D011506:Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases