title: Predominance of null mutations in ataxia-telangiectasia.
abstract: Ataxia-telangiectasia (A-T) is an autosomal recessive disorder involving cerebellar degeneration, immunodeficiency, chromosomal instability, radiosensitivity and cancer predisposition. The responsible gene, ATM, was recently identified by positional cloning and found to encode a putative 350 kDa protein with a Pl 3-kinase-like domain, presumably involved in mediating cell cycle arrest in response to radiation-induced DNA damage. The nature and location of A-T mutations should provide insight into the function of the ATM protein and the molecular basis of this pleiotropic disease. Of 44 A-T mutations identified by us to date, 39 (89%) are expected to inactivate the ATM protein by truncating it, by abolishing correct initiation or termination of translation, or by deleting large segments. Additional mutations are four smaller in-frame deletions and insertions, and one substitution of a highly conserved amino acid at the Pl 3-kinase domain. The emerging profile of mutations causing A-T is thus dominated by those expected to completely inactivate the ATM protein. ATM mutations with milder effects may result in phenotypes related, but not identical, to A-T.
authors.affiliation: Department of Human Genetics, Sackler School of Medicine, Tel Aviv University, Ramat Aviv, Israel.
authors.forename: S
authors.initials: S
authors.lastname: Gilad
authors.forename: R
authors.initials: R
authors.lastname: Khosravi
authors.forename: D
authors.initials: D
authors.lastname: Shkedy
authors.forename: T
authors.initials: T
authors.lastname: Uziel
authors.forename: Y
authors.initials: Y
authors.lastname: Ziv
authors.forename: K
authors.initials: K
authors.lastname: Savitsky
authors.forename: G
authors.initials: G
authors.lastname: Rotman
authors.forename: S
authors.initials: S
authors.lastname: Smith
authors.forename: L
authors.initials: L
authors.lastname: Chessa
authors.forename: T J
authors.initials: TJ
authors.lastname: Jorgensen
authors.forename: R
authors.initials: R
authors.lastname: Harnik
authors.forename: M
authors.initials: M
authors.lastname: Frydman
authors.forename: O
authors.initials: O
authors.lastname: Sanal
authors.forename: S
authors.initials: S
authors.lastname: Portnoi
authors.forename: Z
authors.initials: Z
authors.lastname: Goldwicz
authors.forename: N G
authors.initials: NG
authors.lastname: Jaspers
authors.forename: R A
authors.initials: RA
authors.lastname: Gatti
authors.forename: G
authors.initials: G
authors.lastname: Lenoir
authors.forename: M F
authors.initials: MF
authors.lastname: Lavin
authors.forename: K
authors.initials: K
authors.lastname: Tatsumi
authors.forename: R D
authors.initials: RD
authors.lastname: Wegner
authors.forename: Y
authors.initials: Y
authors.lastname: Shiloh
authors.forename: A
authors.initials: A
authors.lastname: Bar-Shira
mesh_terms: D000595:Amino Acid Sequence; D001260:Ataxia Telangiectasia / Q000378:metabolism*; D064007:Ataxia Telangiectasia Mutated Proteins; D001483:Base Sequence; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D004247:DNA; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D016133:Polymerase Chain Reaction; D017346:Protein Serine-Threonine Kinases; D011506:Proteins / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D025521:Tumor Suppressor Proteins
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D011506:Proteins; D025521:Tumor Suppressor Proteins; D004247:DNA; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases