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

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



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.
Date made available2016

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