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

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

doi:10.1186/s13023-016-0519-7

Abstract

BackgroundSchimke 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.ResultsWe 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.ConclusionsWe 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-016-0519-7) contains supplementary material, which is available to authorized users.

Highlights

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
We suggest that the upregulation of the Wnt and/or Notch pathways contributes to the renal disease in SIOD
We used RNA-seq to compare the transcriptomes of kidney tissue from a 5.4year-old male SIOD patient and a 3-year-old unaffected male

Summary

Introduction

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; 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. Biallelic mutations of the SWI/SNF-related matrix-associated actin-dependent regulator of chromatin, subfamily A-like 1 (SMARCAL1) gene cause SIOD [7]. SMARCAL1 recognizes DNA structure, binds to open chromatin, is involved in the DNA damage response [9, 10] and DNA replication fork restart [11, 12], and, along with genetic and environmental factors, alters gene expression [13]

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