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 journalArticle

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 - Jan 1 2004

Fingerprint

Ataxia Telangiectasia
Polymorphism
Hodgkin Disease
Nucleotides
Genes
Phosphorylation
Single Nucleotide Polymorphism
Ataxia Telangiectasia Mutated Proteins
Chemical activation
Cells
Pediatrics
Fibroblasts
Irradiation
Neoplasm Genes
Proteins
Cell Line

ASJC Scopus subject areas

  • Hematology

Cite this

Identification and characterization of polymorphic variations of the ataxia telangiectasia mutated (ATM) gene in childhood Hodgkin disease. / Takagi, Masatoshi; Tsuchida, Rika; Oguchi, Kaoru; Shigeta, Teruko; Nakada, Shinichiro; Shimizu, Kimiko; Ohki, Misao; Delia, Domenico; Chessa, Luciana; Taya, Yoichi; Nakanishi, Makoto; Tsunematsu, Yukiko; Bessho, Fumio; Isoyama, Keiichi; Hayashi, Yoshiki; Kudo, Kazuko; Okamura, Jun; Mizutani, Shuki.

In: Blood, Vol. 103, No. 1, 01.01.2004, p. 283-290.

Research output: Contribution to journalArticle

Takagi, M, Tsuchida, R, Oguchi, K, Shigeta, T, Nakada, S, Shimizu, K, Ohki, M, Delia, D, Chessa, L, Taya, Y, Nakanishi, M, Tsunematsu, Y, Bessho, F, Isoyama, K, Hayashi, Y, Kudo, K, Okamura, J & Mizutani, S 2004, 'Identification and characterization of polymorphic variations of the ataxia telangiectasia mutated (ATM) gene in childhood Hodgkin disease', Blood, vol. 103, no. 1, pp. 283-290. https://doi.org/10.1182/blood-2003-01-0094
Takagi, Masatoshi ; Tsuchida, Rika ; Oguchi, Kaoru ; Shigeta, Teruko ; Nakada, Shinichiro ; Shimizu, Kimiko ; Ohki, Misao ; Delia, Domenico ; Chessa, Luciana ; Taya, Yoichi ; Nakanishi, Makoto ; Tsunematsu, Yukiko ; Bessho, Fumio ; Isoyama, Keiichi ; Hayashi, Yoshiki ; Kudo, Kazuko ; Okamura, Jun ; Mizutani, Shuki. / Identification and characterization of polymorphic variations of the ataxia telangiectasia mutated (ATM) gene in childhood Hodgkin disease. In: Blood. 2004 ; Vol. 103, No. 1. pp. 283-290.
@article{f543b80e1f444b9187cad1a278fef430,
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 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.",
author = "Masatoshi Takagi and Rika Tsuchida and Kaoru Oguchi and Teruko Shigeta and Shinichiro Nakada and Kimiko Shimizu and Misao Ohki and Domenico Delia and Luciana Chessa and Yoichi Taya and Makoto Nakanishi and Yukiko Tsunematsu and Fumio Bessho and Keiichi Isoyama and Yoshiki Hayashi and Kazuko Kudo and Jun Okamura and Shuki Mizutani",
year = "2004",
month = "1",
day = "1",
doi = "10.1182/blood-2003-01-0094",
language = "English",
volume = "103",
pages = "283--290",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "1",

}

TY - JOUR

T1 - Identification and characterization of polymorphic variations of the ataxia telangiectasia mutated (ATM) gene in childhood Hodgkin disease

AU - Takagi, Masatoshi

AU - Tsuchida, Rika

AU - Oguchi, Kaoru

AU - Shigeta, Teruko

AU - Nakada, Shinichiro

AU - Shimizu, Kimiko

AU - Ohki, Misao

AU - Delia, Domenico

AU - Chessa, Luciana

AU - Taya, Yoichi

AU - Nakanishi, Makoto

AU - Tsunematsu, Yukiko

AU - Bessho, Fumio

AU - Isoyama, Keiichi

AU - Hayashi, Yoshiki

AU - Kudo, Kazuko

AU - Okamura, Jun

AU - Mizutani, Shuki

PY - 2004/1/1

Y1 - 2004/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=9144228756&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=9144228756&partnerID=8YFLogxK

U2 - 10.1182/blood-2003-01-0094

DO - 10.1182/blood-2003-01-0094

M3 - Article

VL - 103

SP - 283

EP - 290

JO - Blood

JF - Blood

SN - 0006-4971

IS - 1

ER -