Identification and characterization of polymorphic variations of the ataxia telangiectasia mutated (ATM) gene in childhood Hodgkin disease.
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.
Takagi
Masatoshi
M
Department of Pediatrics and Developmental Biology, Postgraduate Medical School, Tokyo Medical and Dental University, Tokyo, Japan.
Tsuchida
Rika
R
Oguchi
Kaoru
K
Shigeta
Teruko
T
Nakada
Shinichiro
S
Shimizu
Kimiko
K
Ohki
Misao
M
Delia
Domenico
D
Chessa
Luciana
L
Taya
Yoichi
Y
Nakanishi
Makoto
M
Tsunematsu
Yukiko
Y
Bessho
Fumio
F
Isoyama
Keiichi
K
Hayashi
Yoshiki
Y
Kudo
Kazuko
K
Okamura
Jun
J
Mizutani
Shuki
S
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
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