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SMARCAL1 deficiency predisposes to non‐Hodgkin lymphoma and hypersensitivity to genotoxic agents in vivo
Author(s) -
BaradaranHeravi Alireza,
Raams Anja,
Lubieniecka Joanna,
Cho Kyoung Sang,
DeHaai Kristi A.,
Basiratnia Mitra,
Mari PierreOlivier,
Xue Yutong,
Rauth Michael,
Olney Ann Haskins,
Shago Mary,
Choi Kunho,
Weksberg Rosanna A.,
Nowaczyk Malgorzata J.M.,
Wang Weidong,
Jaspers Nicolaas G.J.,
Boerkoel Cornelius F.
Publication year - 2012
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.35532
Subject(s) - etoposide , medicine , cancer research , dna damage , in vivo , immunology , biology , dna , genetics , chemotherapy
Schimke immuno‐osseous dysplasia (SIOD) is a multisystemic disorder with prominent skeletal, renal, immunological, and ectodermal abnormalities. It is caused by mutations of SMARCAL1 (SWI/SNF‐related, matrix‐associated, actin‐dependent regulator of chromatin, subfamily a‐like 1), which encodes a DNA stress response protein. To determine the relationship of this function to the SIOD phenotype, we profiled the cancer prevalence in SIOD and assessed if defects of nucleotide excision repair (NER) and nonhomologous end joining (NHEJ), respectively, explained the ectodermal and immunological features of SIOD. Finally, we determined if Smarcal1 del/del mice had hypersensitivity to irinotecan (CPT‐11), etoposide, and hydroxyurea (HU) and whether exposure to these agents induced features of SIOD. Among 71 SIOD patients, three had non‐Hodgkin lymphoma (NHL) and one had osteosarcoma. We did not find evidence of defective NER or NHEJ; however, Smarcal1‐deficient mice were hypersensitive to several genotoxic agents. Also, CPT‐11, etoposide, and HU caused decreased growth and loss of growth plate chondrocytes. These data, which identify an increased prevalence of NHL in SIOD and confirm hypersensitivity to DNA damaging agents in vivo, provide guidance for the management of SIOD patients. © 2012 Wiley Periodicals, Inc.