TY - JOUR
T1 - Increased Wnt and Notch signaling
T2 - a clue to the renal disease in Schimke immuno-osseous dysplasia?
AU - Morimoto, Marie
AU - Myung, Clara
AU - Beirnes, Kimberly
AU - Choi, Kunho
AU - Asakura, Yumi
AU - Bokenkamp, Arend
AU - Bonneau, Dominique
AU - Brugnara, Milena
AU - Charrow, Joel
AU - Colin, Estelle
AU - Davis, Amira
AU - Deschenes, Georges
AU - Gentile, Mattia
AU - Giordano, Mario
AU - Gormley, Andrew K.
AU - Govender, Rajeshree
AU - Joseph, Mark
AU - Keller, Kory
AU - Lerut, Evelyne
AU - Levtchenko, Elena
AU - Massella, Laura
AU - Mayfield, Christy
AU - Najafian, Behzad
AU - Parham, David
AU - Spranger, Jurgen
AU - Stenzel, Peter
AU - Yis, Uluc
AU - Yu, Zhongxin
AU - Zonana, Jonathan
AU - Hendson, Glenda
AU - Boerkoel, Cornelius F.
N1 - Publisher Copyright:
© 2016 The Author(s).
PY - 2016/11/5
Y1 - 2016/11/5
N2 - Background: Schimke immuno-osseous dysplasia (SIOD) is a multisystemic disorder caused by biallelic mutations in the SWI/SNF-related matrix-associated actin-dependent regulator of chromatin, subfamily A-like 1 (SMARCAL1) gene. Changes in gene expression underlie the arteriosclerosis and T-cell immunodeficiency of SIOD; therefore, we hypothesized that SMARCAL1 deficiency causes the focal segmental glomerulosclerosis (FSGS) of SIOD by altering renal gene expression. We tested this hypothesis by gene expression analysis of an SIOD patient kidney and verified these findings through immunofluorescent analysis in additional SIOD patients and a genetic interaction analysis in Drosophila. Results: We found increased expression of components and targets of the Wnt and Notch signaling pathways in the SIOD patient kidney, increased levels of unphosphorylated β-catenin and Notch1 intracellular domain in the glomeruli of most SIOD patient kidneys, and genetic interaction between the Drosophila SMARCAL1 homologue Marcal1 and genes of the Wnt and Notch signaling pathways. Conclusions: We conclude that increased Wnt and Notch activity result from SMARCAL1 deficiency and, as established causes of FSGS, contribute to the renal disease of most SIOD patients. This further clarifies the pathogenesis of SIOD and will hopefully direct potential therapeutic approaches for SIOD patients.
AB - Background: Schimke immuno-osseous dysplasia (SIOD) is a multisystemic disorder caused by biallelic mutations in the SWI/SNF-related matrix-associated actin-dependent regulator of chromatin, subfamily A-like 1 (SMARCAL1) gene. Changes in gene expression underlie the arteriosclerosis and T-cell immunodeficiency of SIOD; therefore, we hypothesized that SMARCAL1 deficiency causes the focal segmental glomerulosclerosis (FSGS) of SIOD by altering renal gene expression. We tested this hypothesis by gene expression analysis of an SIOD patient kidney and verified these findings through immunofluorescent analysis in additional SIOD patients and a genetic interaction analysis in Drosophila. Results: We found increased expression of components and targets of the Wnt and Notch signaling pathways in the SIOD patient kidney, increased levels of unphosphorylated β-catenin and Notch1 intracellular domain in the glomeruli of most SIOD patient kidneys, and genetic interaction between the Drosophila SMARCAL1 homologue Marcal1 and genes of the Wnt and Notch signaling pathways. Conclusions: We conclude that increased Wnt and Notch activity result from SMARCAL1 deficiency and, as established causes of FSGS, contribute to the renal disease of most SIOD patients. This further clarifies the pathogenesis of SIOD and will hopefully direct potential therapeutic approaches for SIOD patients.
KW - Focal segmental glomerulosclerosis
KW - Notch signaling pathway
KW - SMARCAL1 protein
KW - Schimke immuno-osseous dysplasia
KW - Wnt signaling pathway
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U2 - 10.1186/s13023-016-0519-7
DO - 10.1186/s13023-016-0519-7
M3 - Article
C2 - 27816064
AN - SCOPUS:84993960680
SN - 1750-1172
VL - 11
SP - 1
EP - 12
JO - Orphanet journal of rare diseases
JF - Orphanet journal of rare diseases
IS - 1
ER -