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Increased Wnt and Notch signaling: a clue to the renal disease in Schimke immuno-osseous dysplasia? Morimoto, Marie; Myung, Clara; Beirnes, Kimberly; Choi, Kunho; Asakura, Yumi; Bokenkamp, Arend; Bonneau, Dominique; Brugnara, Milena; Charrow, Joel; Colin, Estelle; et al.

Abstract

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.

Item Metadata

Title
Increased Wnt and Notch signaling: a clue to the renal disease in Schimke immuno-osseous dysplasia?
Creator
Morimoto, Marie; Myung, Clara; Beirnes, Kimberly; Choi, Kunho; Asakura, Yumi; Bokenkamp, Arend; Bonneau, Dominique; Brugnara, Milena; Charrow, Joel; Colin, Estelle; Davis, Amira; Deschenes, Georges; Gentile, Mattia; Giordano, Mario; Gormley, Andrew K; Govender, Rajeshree; Joseph, Mark; Keller, Kory; Lerut, Evelyne; Levtchenko, Elena; Massella, Laura; Mayfield, Christy; Najafian, Behzad; Parham, David; Spranger, Jurgen; Stenzel, Peter; Yis, Uluc; Yu, Zhongxin; Zonana, Jonathan; Hendson, Glenda; Boerkoel, Cornelius F
Contributor
Child and Family Research Institute
Publisher
BioMed Central
Date Issued
2016-11-05
Description
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.
Subject
Schimke immuno-osseous dysplasia; SMARCAL1 protein; Focal segmental glomerulosclerosis; Wnt signaling pathway; Notch signaling pathway
Genre
Article
Type
Text
Language
eng
Date Available
2018-05-16
Provider
Vancouver : University of British Columbia Library
Rights
Attribution 4.0 International (CC BY 4.0)
DOI
10.14288/1.0366889
URI
http://hdl.handle.net/2429/65943
Affiliation
Medicine, Faculty of; Other UBC; Non UBC; Medical Genetics, Department of
Citation
Orphanet Journal of Rare Diseases. 2016 Nov 05;11(1):149
Publisher DOI
10.1186/s13023-016-0519-7
Peer Review Status
Reviewed
Scholarly Level
Faculty
Copyright Holder
The Author(s).
Rights URI
http://creativecommons.org/licenses/by/4.0/
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Attribution 4.0 International (CC BY 4.0)