SMARCAL1 deficiency predisposes to non-Hodgkin lymphoma and hypersensitivity to genotoxic agents in vivo.
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.
Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
Alireza
A
Baradaran-Heravi
Anja
A
Raams
Joanna
J
Lubieniecka
Kyoung Sang
KS
Cho
Kristi A
KA
DeHaai
Mitra
M
Basiratnia
Pierre-Olivier
PO
Mari
Yutong
Y
Xue
Michael
M
Rauth
Ann Haskins
AH
Olney
Mary
M
Shago
Kunho
K
Choi
Rosanna A
RA
Weksberg
Malgorzata J M
MJ
Nowaczyk
Weidong
W
Wang
Nicolaas G J
NG
Jaspers
Cornelius F
CF
Boerkoel
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002460:Cell Line; D059766:DNA End-Joining Repair; D004265:DNA Helicases / Q000235:genetics*; D004260:DNA Repair; D006801:Humans; D020287:In Situ Nick-End Labeling; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy* / Q000235:genetics*; D051379:Mice
C412482:SMARCAL1 protein, human; D004265:DNA Helicases