title: ATM haplotypes and associated mutations in Iranian patients with ataxia-telangiectasia: recurring homozygosity without a founder haplotype.
abstract: Ataxia-telangiectasia (A-T) is an autosomal recessive disorder caused by mutations in the ATM gene. The ATM gene spans more than 150 kb at chromosomal region 11q23.1 and encodes a product of 3,056 amino acids. The ATM protein is a serine/threonine protein kinase and is involved in oxidative stress, cell cycle control, and DNA repair. We analyzed the 11q22-23 haplotypes and associated mutations of 16 Iranian families. We utilized standardized short tandem repeat (STR) haplotypes to enhance mutation identification. In addition to the STR markers, single-nucleotide polymorphism haplotypes were determined, using three critical polymorphisms. The entire gene was screened sequentially by protein truncation testing, single-strand conformation polymorphism, and denaturing high-performance liquid chromatography to identify the disease-causing mutations. Of the expected 32 mutations, 25 (78%) were identified. All but two mutations led to a truncated or null form of the ATM protein (nonsense, splice site, or frameshift). Twelve mutations were identified for 15 haplotypes. Five mutations were novel. Mutations were located throughout the entire gene, with no clustering. Despite the absence of an Iranian founder mutation, three-fourths of the families were homozygous, suggesting that many undetected ATM mutations still exist in Iran. This study establishes a database for Iranian A-T families, and extends the global spectrum of ATM mutations.
authors.affiliation: The David Geffen School of Medicine, Department of Pathology, University of California, 675 Young Drive South, Los Angeles, CA 90095-1732, USA.
authors.forename: Mahnoush
authors.initials: M
authors.lastname: Babaei
authors.forename: Midori
authors.initials: M
authors.lastname: Mitui
authors.forename: Eric R
authors.initials: ER
authors.lastname: Olson
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gatti
mesh_terms: D001260:Ataxia Telangiectasia / Q000235:genetics*; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000235:genetics*; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D018703:Founder Effect; D006239:Haplotypes / Q000235:genetics; D006720:Homozygote; D006801:Humans; D007492:Iran; D008297:Male; D009154:Mutation; D018807:Polymorphism, Single-Stranded Conformational; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics*
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