Five haplotypes account for fifty-five percent of ATM mutations in Brazilian patients with ataxia telangiectasia: Seven new mutations

Five haplotypes account for fifty-five percent of ATM mutations in Brazilian patients with ataxia telangiectasia: Seven new mutations

Author Coutinho, G. Google Scholar
Mitui, M. Google Scholar
Campbell, C. Google Scholar
Carvalho, BTC Google Scholar
Nahas, S. Google Scholar
Sun, X Google Scholar
Huo, Y. Google Scholar
Lai, C. H. Google Scholar
Thorstenson, Y. Google Scholar
Tanouye, R. Google Scholar
Raskin, S. Google Scholar
Kim, C. A. Google Scholar
Llerena, J. Google Scholar
Gatti, R. A. Google Scholar
Institution David Geffen Sch Med
Universidade Federal do Rio de Janeiro (UFRJ)
Universidade Federal de São Paulo (UNIFESP)
Stanford Univ
Universidade de São Paulo (USP)
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 3,056 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 haplo-typed 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. (C) 2003 Wiley-Liss, Inc.
Keywords ataxia telangiectasia
ATM haplotypes
ATM mutations
Brazilian families
Language English
Date 2004-04-01
Published in American Journal of Medical Genetics Part A. New York: Wiley-liss, v. 126A, n. 1, p. 33-40, 2004.
ISSN 0148-7299 (Sherpa/Romeo, impact factor)
Publisher Wiley-Blackwell
Extent 33-40
Access rights Closed access
Type Article
Web of Science ID WOS:000220577300005

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