title: Identification and characterization of polymorphic variations of the ataxia telangiectasia mutated (ATM) gene in childhood Hodgkin disease.
abstract: There are conflicting reports about the involvement of single nucleotide polymorphisms (SNPs) of the ataxia telangiectasia mutated (ATM) gene with cancer, and the consequences of these SNPs for ATM function remain unclear. We therefore sought to identify SNPs of the ATM gene in pediatric Hodgkin disease (HD) and to analyze ATM function in cells from patients with these SNPs. We have identified SNPs of the ATM gene in 5 of 14 children (S1455R, n = 1; H1380Y, n = 1; N1650S, n = 2; and I709I, n = 1). One patient had nonsense-associated altered splicing of the ATM gene. Lymphoblastoid cell lines expressing the S1455R and N1650S exhibited defective ATM-mediated p53 phosphorylation and Chk2 activation; cells expressing the H1380Y exhibited defective c-Abl activation after X-irradiation. Expression of the N1650S in ATM-null fibroblasts conferred only partial hyperradiosensitivity. Furthermore, the introduction of N1650S ATM into U2OS cells, which express wild-type ATM, showed reduced p53-Ser15 phosphorylation, suggesting a dominant-negative effect of the N1650S over the wild-type ATM protein. We conclude that the rare polymorphic variants of the ATM gene that we identified in children with HD encode functionally abnormal proteins, and we discuss the possible genetic risk factors for childhood HD.
authors.affiliation: Department of Pediatrics and Developmental Biology, Postgraduate Medical School, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Takagi
authors.forename: Rika
authors.initials: R
authors.lastname: Tsuchida
authors.forename: Kaoru
authors.initials: K
authors.lastname: Oguchi
authors.forename: Teruko
authors.initials: T
authors.lastname: Shigeta
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Nakada
authors.forename: Kimiko
authors.initials: K
authors.lastname: Shimizu
authors.forename: Misao
authors.initials: M
authors.lastname: Ohki
authors.forename: Domenico
authors.initials: D
authors.lastname: Delia
authors.forename: Luciana
authors.initials: L
authors.lastname: Chessa
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Taya
authors.forename: Makoto
authors.initials: M
authors.lastname: Nakanishi
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Tsunematsu
authors.forename: Fumio
authors.initials: F
authors.lastname: Bessho
authors.forename: Keiichi
authors.initials: K
authors.lastname: Isoyama
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Hayashi
authors.forename: Kazuko
authors.initials: K
authors.lastname: Kudo
authors.forename: Jun
authors.initials: J
authors.lastname: Okamura
authors.forename: Shuki
authors.initials: S
authors.lastname: Mizutani
mesh_terms: D000483:Alleles; D064007:Ataxia Telangiectasia Mutated Proteins; D001483:Base Sequence; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D002648:Child; D018389:Codon, Nonsense; D004273:DNA, Neoplasm / Q000235:genetics; D004268:DNA-Binding Proteins; D005312:Fetal Blood / Q000378:metabolism; D005787:Gene Frequency; D014644:Genetic Variation; D006689:Hodgkin Disease / Q000235:genetics*; D006801:Humans; D007231:Infant, Newborn; D010766:Phosphorylation; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012326:RNA Splicing / Q000235:genetics; D012307:Risk Factors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins
chemical_list: D018797:Cell Cycle Proteins; D018389:Codon, Nonsense; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases