title: Five haplotypes account for fifty-five percent of ATM mutations in Brazilian patients with ataxia telangiectasia: seven new mutations.
abstract: We have studied the molecular genetics of 27 Brazilian families with ataxia telangiectasia (AT). Five founder effect haplotypes accounted for 55.5% of the families. AT is an autosomal recessive disorder of childhood onset characterized by progressive cerebellar ataxia, ocular apraxia, telangiectasia, immunodeficiency, radiation sensitivity, chromosomal instability, and predisposition to cancer. The ATM gene spans more than 150 kb on chromosome region 11q23.1 and encodes a product of 3056 amino acids. The ATM protein is a member of the phosphatidylinositol 3-kinase (PI-3K) family of proteins and is involved in cell cycle control and DNA repair pathways. DNA was isolated from lymphoblastoid cell lines and haplotyped using four STR markers (D11S1818, NS22, D11S2179, D11S1819) within and flanking the ATM gene; all allele sizes were standardized in advance. In addition to the STR haplotypes, SNP haplotypes were determined using 10 critical polymorphisms. The entire gene was screened sequentially by protein truncation testing (PTT), single strand conformation polymorphism (SSCP), and then denaturing high performance liquid chromatography (dHPLC) to identify the disease-causing mutations. Of the expected 54 mutations, 50 were identified. All mutations but one, led to a truncated or null form of the ATM protein (nonsense, splice site, or frameshift). Five families (18.5%) carried a deletion of 3450nt (from IVS28 to Ex31), making this one of the two most common Brazilian mutations. Mutations were located throughout the entire gene, with no clustering or hotspots. Standardized STR haplotype analysis greatly enhanced the efficiency of mutation screening.
authors.affiliation: Department of Pathology and Laboratory Medicine, The David Geffen School of Medicine, Los Angeles, California 90095-1732, USA.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Coutinho
authors.forename: Midori
authors.initials: M
authors.lastname: Mitui
authors.forename: Catarina
authors.initials: C
authors.lastname: Campbell
authors.forename: Beatriz T
authors.initials: BT
authors.lastname: Costa Carvalho
authors.forename: Shareef
authors.initials: S
authors.lastname: Nahas
authors.forename: Xia
authors.initials: X
authors.lastname: Sun
authors.forename: Yong
authors.initials: Y
authors.lastname: Huo
authors.forename: Chih-Hung
authors.initials: CH
authors.lastname: Lai
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Thorstenson
authors.forename: Robert
authors.initials: R
authors.lastname: Tanouye
authors.forename: Salmo
authors.initials: S
authors.lastname: Raskin
authors.forename: Chong A
authors.initials: CA
authors.lastname: Kim
authors.forename: Juan
authors.initials: J
authors.lastname: Llerena
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gatti
mesh_terms: D001260:Ataxia Telangiectasia / Q000235:genetics*; D064007:Ataxia Telangiectasia Mutated Proteins; D001938:Brazil; D018797:Cell Cycle Proteins; D002851:Chromatography, High Pressure Liquid; D004268:DNA-Binding Proteins; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D009154:Mutation / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D018807:Polymorphism, Single-Stranded Conformational; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D025521:Tumor Suppressor Proteins
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases