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 Levtchenko; Laura Massella; Christy Mayfield; Behzad Najafian; David Parham; Jurgen Spranger; Peter Stenzel; Uluc Yis; Zhongxin Yu; Jonathan Zonana; Glenda Hendson; Cornelius F. Boerkoel

doi:10.1186/s13023-016-0519-7

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 Zonana, Glenda Hendson, Cornelius F. Boerkoel^*

^*Corresponding author for this work

Pediatrics

Research output: Contribution to journal › Article › peer-review

9 Scopus citations

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 language	English (US)
Pages (from-to)	1-12
Number of pages	12
Journal	Orphanet journal of rare diseases
Volume	11
Issue number	1
DOIs	https://doi.org/10.1186/s13023-016-0519-7
State	Published - Nov 5 2016

Funding

This work was supported in part by the New Investigator Award jointly sponsored by the SickKids Foundation and the Canadian Institutes of Health Research Institute of Human Development, Child and Youth Health (XG09-025 to CFB); the Michael Smith Foundation for Health Research (CI-SCH-O1899(07\u2013 1) to CFB); The Little Giants Foundation (CFB); and the Asociacion Espa\u00F1ola de Displasias Oseas Minoritarias (CFB). Human fetal tissue was obtained through the Laboratory of Developmental Biology project supported by the National Institutes of Health Award Number 5R24HD000836 from the Eunice Kennedy Shriver National Institute of Child Health & Human Development. MM was supported by a Four Year Doctoral Fellowship from the University of British Columbia. CFB is a scholar of the Michael Smith Foundation for Health Research and a Clinical Investigator of the Child & Family Research Institute.

Keywords

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

ASJC Scopus subject areas

Genetics(clinical)
Pharmacology (medical)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1186/s13023-016-0519-7

Cite this

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., ... 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

@article{0b9e855d49ca44eca1e77d09b62c5275,

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

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.",

keywords = "Focal segmental glomerulosclerosis, Notch signaling pathway, SMARCAL1 protein, Schimke immuno-osseous dysplasia, Wnt signaling pathway",

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

note = "Publisher Copyright: {\textcopyright} 2016 The Author(s).",

year = "2016",

month = nov,

day = "5",

doi = "10.1186/s13023-016-0519-7",

language = "English (US)",

volume = "11",

pages = "1--12",

journal = "Orphanet journal of rare diseases",

issn = "1750-1172",

publisher = "BioMed Central",

number = "1",

}

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, J, 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

TY - JOUR

T1 - Increased Wnt and Notch signaling

T2 - a clue to the renal disease in Schimke immuno-osseous dysplasia?

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

AU - Hendson, Glenda

AU - Boerkoel, Cornelius F.

PY - 2016/11/5

Y1 - 2016/11/5

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.

AB - 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.

KW - Focal segmental glomerulosclerosis

KW - Notch signaling pathway

KW - SMARCAL1 protein

KW - Schimke immuno-osseous dysplasia

KW - Wnt signaling pathway

UR - http://www.scopus.com/inward/record.url?scp=84993960680&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84993960680&partnerID=8YFLogxK

U2 - 10.1186/s13023-016-0519-7

DO - 10.1186/s13023-016-0519-7

M3 - Article

C2 - 27816064

AN - SCOPUS:84993960680

SN - 1750-1172

VL - 11

SP - 1

EP - 12

JO - Orphanet journal of rare diseases

JF - Orphanet journal of rare diseases

IS - 1

ER -

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

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint