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Morimoto, M., Myung, C., Beirnes, K., Choi, K., Asakura, Y., Bokenkamp, A., Bonneau, D., Brugnara, M., Charrow, J., Colin, E., Davis, A., Deschenes, G., Gentile, M., Giordano, M., Gormley, A.K., Govender, R., Joseph, M., Keller, K., Lerut, E., Levtchenko, E., Massella, L., Mayfield, C., Najafian, B., Parham, D., Spranger, J., Stenzel, P., Yis, U., Yu, Z., Zonana, J., Hendson, G., Boerkoel, C.F. (2016). Increased Wnt and Notch signaling: a clue to the renal disease in Schimke immuno-osseous dysplasia?  Orphanet J. Rare Dis. 11(1): 149.
FlyBase ID
FBrf0233913
Publication Type
Research paper
Abstract

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. 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. 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.

PubMed ID
PubMed Central ID
PMC5097426 (PMC) (EuropePMC)
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    Language of Publication
    English
    Additional Languages of Abstract
    Parent Publication
    Publication Type
    Journal
    Abbreviation
    Orphanet J. Rare Dis.
    Title
    Orphanet journal of rare diseases
    ISBN/ISSN
    1750-1172
    Data From Reference