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

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 LevtchenkoLaura Massella, Christy Mayfield, Behzad Najafian, David Parham, Jurgen Spranger, Peter Stenzel, Uluc Yis, Zhongxin Yu, Jonathan (Jon) Zonana, Glenda Hendson, Cornelius F. Boerkoel

Research output: Contribution to journalArticle

5 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1-12
Number of pages12
JournalOrphanet Journal of Rare Diseases
Volume11
Issue number1
DOIs
StatePublished - Nov 5 2016

Fingerprint

Kidney
Chromatin
Actins
Focal Segmental Glomerulosclerosis
Wnt Signaling Pathway
Gene Expression
Drosophila
Schimke immunoosseous dysplasia
Catenins
Arteriosclerosis
Genes
T-Lymphocytes
Mutation

Keywords

  • Focal segmental glomerulosclerosis
  • Notch signaling pathway
  • Schimke immuno-osseous dysplasia
  • SMARCAL1 protein
  • Wnt signaling pathway

ASJC Scopus subject areas

  • Medicine(all)
  • Genetics(clinical)
  • Pharmacology (medical)

Cite this

Morimoto, M., Myung, C., Beirnes, K., Choi, K., Asakura, Y., Bokenkamp, A., ... Boerkoel, C. F. (2016). Increased Wnt and Notch signaling: a clue to the renal disease in Schimke immuno-osseous dysplasia? Orphanet Journal of Rare Diseases, 11(1), 1-12. https://doi.org/10.1186/s13023-016-0519-7

Increased Wnt and Notch signaling : a clue to the renal disease in Schimke immuno-osseous dysplasia? / Morimoto, Marie; Myung, Clara; Beirnes, Kimberly; Choi, Kunho; Asakura, Yumi; Bokenkamp, Arend; Bonneau, Dominique; Brugnara, Milena; Charrow, Joel; Colin, Estelle; Davis, Amira; Deschenes, Georges; Gentile, Mattia; Giordano, Mario; Gormley, Andrew K.; Govender, Rajeshree; Joseph, Mark; Keller, Kory; Lerut, Evelyne; Levtchenko, Elena; Massella, Laura; Mayfield, Christy; Najafian, Behzad; Parham, David; Spranger, Jurgen; Stenzel, Peter; Yis, Uluc; Yu, Zhongxin; Zonana, Jonathan (Jon); Hendson, Glenda; Boerkoel, Cornelius F.

In: Orphanet Journal of Rare Diseases, Vol. 11, No. 1, 05.11.2016, p. 1-12.

Research output: Contribution to journalArticle

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, AK, 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, JJ, Hendson, G & Boerkoel, CF 2016, 'Increased Wnt and Notch signaling: a clue to the renal disease in Schimke immuno-osseous dysplasia?', Orphanet Journal of Rare Diseases, vol. 11, no. 1, pp. 1-12. https://doi.org/10.1186/s13023-016-0519-7
Morimoto, Marie ; Myung, Clara ; Beirnes, Kimberly ; Choi, Kunho ; Asakura, Yumi ; Bokenkamp, Arend ; Bonneau, Dominique ; Brugnara, Milena ; Charrow, Joel ; Colin, Estelle ; Davis, Amira ; Deschenes, Georges ; Gentile, Mattia ; Giordano, Mario ; Gormley, Andrew K. ; Govender, Rajeshree ; Joseph, Mark ; Keller, Kory ; Lerut, Evelyne ; Levtchenko, Elena ; Massella, Laura ; Mayfield, Christy ; Najafian, Behzad ; Parham, David ; Spranger, Jurgen ; Stenzel, Peter ; Yis, Uluc ; Yu, Zhongxin ; Zonana, Jonathan (Jon) ; Hendson, Glenda ; Boerkoel, Cornelius F. / Increased Wnt and Notch signaling : a clue to the renal disease in Schimke immuno-osseous dysplasia?. In: Orphanet Journal of Rare Diseases. 2016 ; Vol. 11, No. 1. pp. 1-12.
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AU - Morimoto, Marie

AU - Myung, Clara

AU - Beirnes, Kimberly

AU - Choi, Kunho

AU - Asakura, Yumi

AU - Bokenkamp, Arend

AU - Bonneau, Dominique

AU - Brugnara, Milena

AU - Charrow, Joel

AU - Colin, Estelle

AU - Davis, Amira

AU - Deschenes, Georges

AU - Gentile, Mattia

AU - Giordano, Mario

AU - Gormley, Andrew K.

AU - Govender, Rajeshree

AU - Joseph, Mark

AU - Keller, Kory

AU - Lerut, Evelyne

AU - Levtchenko, Elena

AU - Massella, Laura

AU - Mayfield, Christy

AU - Najafian, Behzad

AU - Parham, David

AU - Spranger, Jurgen

AU - Stenzel, Peter

AU - Yis, Uluc

AU - Yu, Zhongxin

AU - Zonana, Jonathan (Jon)

AU - Hendson, Glenda

AU - Boerkoel, Cornelius F.

PY - 2016/11/5

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N2 - 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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