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Orphanet Journal of Rare Diseases
Published in: Orphanet Journal of Rare Diseases 1/2016

Open Access 01-12-2016 | Research

Increased Wnt and Notch signaling: a clue to the renal disease in Schimke immuno-osseous dysplasia?

Authors: Marie Morimoto, Clara Myung, Kimberly Beirnes, Kunho Choi, Yumi Asakura, Arend Bokenkamp, Dominique Bonneau, Milena Brugnara, Joel Charrow, Estelle Colin, Amira Davis, Georges Deschenes, Mattia Gentile, Mario Giordano, Andrew K. Gormley, Rajeshree Govender, Mark Joseph, Kory Keller, Evelyne Lerut, Elena Levtchenko, Laura Massella, Christy Mayfield, Behzad Najafian, David Parham, Jurgen Spranger, Peter Stenzel, Uluc Yis, Zhongxin Yu, Jonathan Zonana, Glenda Hendson, Cornelius F. Boerkoel

Published in: Orphanet Journal of Rare Diseases | Issue 1/2016

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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.
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Metadata
Title
Increased Wnt and Notch signaling: a clue to the renal disease in Schimke immuno-osseous dysplasia?
Authors
Marie Morimoto
Clara Myung
Kimberly Beirnes
Kunho Choi
Yumi Asakura
Arend Bokenkamp
Dominique Bonneau
Milena Brugnara
Joel Charrow
Estelle Colin
Amira Davis
Georges Deschenes
Mattia Gentile
Mario Giordano
Andrew K. Gormley
Rajeshree Govender
Mark Joseph
Kory Keller
Evelyne Lerut
Elena Levtchenko
Laura Massella
Christy Mayfield
Behzad Najafian
David Parham
Jurgen Spranger
Peter Stenzel
Uluc Yis
Zhongxin Yu
Jonathan Zonana
Glenda Hendson
Cornelius F. Boerkoel
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Orphanet Journal of Rare Diseases / Issue 1/2016
Electronic ISSN: 1750-1172
DOI
https://doi.org/10.1186/s13023-016-0519-7

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