Increased Wnt and Notch signaling: a clue to the renal disease in Schimke immuno-osseous dysplasia?
Posted on 2016-11-05 - 05:00
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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Morimoto, Marie; Myung, Clara; Beirnes, Kimberly; Choi, Kunho; Asakura, Yumi; Bokenkamp, Arend; et al. (2016). Increased Wnt and Notch signaling: a clue to the renal disease in Schimke immuno-osseous dysplasia?. figshare. Collection. https://doi.org/10.6084/m9.figshare.c.3622322.v1
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AUTHORS (31)
MM
Marie Morimoto
CM
Clara Myung
KB
Kimberly Beirnes
KC
Kunho Choi
YA
Yumi Asakura
AB
Arend Bokenkamp
DB
Dominique Bonneau
MB
Milena Brugnara
JC
Joel Charrow
EC
Estelle Colin
AD
Amira Davis
GD
Georges Deschenes
MG
Mattia Gentile
MG
Mario Giordano
AG
Andrew Gormley
RG
Rajeshree Govender
MJ
Mark Joseph
KK
Kory Keller
EL
Evelyne Lerut
EL
Elena Levtchenko