Identification and characterization of polymorphic variations of the ataxia telangiectasia mutated (ATM) gene in childhood Hodgkin disease

Masatoshi Takagi, Rika Tsuchida, Kaoru Oguchi, Teruko Shigeta, Shinichiro Nakada, Kimiko Shimizu, Misao Ohki, Domenico Delia, Luciana Chessa, Yoichi Taya, Makoto Nakanishi, Yukiko Tsunematsu, Fumio Bessho, Keiichi Isoyama, Yoshiki Hayashi, Kazuko Kudo, Jun Okamura, Shuki Mizutani

Research output: Contribution to journalArticlepeer-review

27 Citations (Scopus)

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 17091, n = 1). One patient had nonsense-associated altered splicing of the ATM gene. Lymphoblastold 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.

Original languageEnglish
Pages (from-to)283-290
Number of pages8
JournalBlood
Volume103
Issue number1
DOIs
Publication statusPublished - 01-01-2004

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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