Increased Wnt and Notch signaling: a clue to the renal disease in Schimke immuno-osseous dysplasia?
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.
Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.|Child & Family Research Institute, Vancouver, BC, Canada.
Marie
M
Morimoto
Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.|Child & Family Research Institute, Vancouver, BC, Canada.
Clara
C
Myung
Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.|Child & Family Research Institute, Vancouver, BC, Canada.
Kimberly
K
Beirnes
Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.|Child & Family Research Institute, Vancouver, BC, Canada.
Kunho
K
Choi
Department of Endocrinology & Metabolism, Kanagawa Children's Medical Center, Yokohama, Japan.
Yumi
Y
Asakura
Department of Pediatric Nephrology, VU University Medical Center, Amsterdam, The Netherlands.
Arend
A
Bokenkamp
Département de Biochimie et Génétique, Centre Hospitalier Universitaire d'Angers, Angers, France.
Dominique
D
Bonneau
Department of Pediatrics, University of Verona, Verona, Italy.
Milena
M
Brugnara
Division of Genetics, Birth Defects and Metabolism, Ann and Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Joel
J
Charrow
Département de Biochimie et Génétique, Centre Hospitalier Universitaire d'Angers, Angers, France.
Estelle
E
Colin
Seattle Children's Hospital, Seattle, WA, USA.
Amira
A
Davis
Département de Pédiatrie, Hôpital Robert Debré, Paris, France.
Georges
G
Deschenes
Department of Medical Genetics, Hospital Di Venere - ASL Bari, Bari, Italy.
Mattia
M
Gentile
Pediatric Nephrology and Dialysis Unit, Ospedale Pediatrico Giovanni XXIII, Bari, Italy.
Mario
M
Giordano
Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
Andrew K
AK
Gormley
Department of Pediatrics and Child Health, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa.
Rajeshree
R
Govender
Department of Pediatric Nephrology, Phoenix Children's Hospital, Phoenix, AZ, USA.
Mark
M
Joseph
Child Development and Rehabiliation Center, Oregon Institute on Disability & Development, Oregon Health & Science University, Portland, OR, USA.
Kory
K
Keller
Department of Pathology, University Hospitals Leuven, Leuven, Belgium.
Evelyne
E
Lerut
Department of Pediatric Nephrology, University Hospitals Leuven, Leuven, Belgium.
Elena
E
Levtchenko
Division of Nephrology, Bambino Gesù Children's Hospital and Research Institute, Rome, Italy.
Laura
L
Massella
Warren Clinic Family Medicine, Tulsa, OK, USA.
Christy
C
Mayfield
Department of Pathology, University of Washington, Seattle, WA, USA.
Behzad
B
Najafian
Department of Pathology, Children's Hospital Los Angeles and Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
David
D
Parham
Children's Hospital, University of Mainz, Mainz, Germany.
Jurgen
J
Spranger
Department of Pathology, Oregon Health and Science University, Portland, OR, USA.
Peter
P
Stenzel
Department of Pediatrics, Division of Child Neurology, Dokuz Eylül University, School of Medicine, İzmir, Turkey.
Uluc
U
Yis
Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
Zhongxin
Z
Yu
Child Development and Rehabiliation Center, Oregon Institute on Disability & Development, Oregon Health & Science University, Portland, OR, USA.
Jonathan
J
Zonana
Department of Anatomic Pathology, Children's and Women's Health Centre of British Columbia, Vancouver, BC, Canada.
Glenda
G
Hendson
Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada. cboerkoel@gmail.com.|Child & Family Research Institute, Vancouver, BC, Canada. cboerkoel@gmail.com.|Provincial Medical Genetics Program, Department of Medical Genetics, Children's and Women's Health Centre of British Columbia, 4500 Oak Street, Room C234, Vancouver, BC, V6H 3N1, Canada. cboerkoel@gmail.com.
Cornelius F
CF
Boerkoel
D000818:Animals; D001161:Arteriosclerosis / Q000235:genetics / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism; D019084:Fluorescent Antibody Technique, Indirect; D005923:Glomerulosclerosis, Focal Segmental / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics / Q000378:metabolism*; D007674:Kidney Diseases / Q000235:genetics / Q000378:metabolism*; D008297:Male; D009404:Nephrotic Syndrome / Q000235:genetics / Q000378:metabolism*; D010009:Osteochondrodysplasias / Q000235:genetics / Q000378:metabolism*; D000081207:Primary Immunodeficiency Diseases; D011655:Pulmonary Embolism / Q000235:genetics / Q000378:metabolism*; D051880:Receptors, Notch / Q000378:metabolism*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*
D051880:Receptors, Notch; D051153:Wnt Proteins; C412482:SMARCAL1 protein, human; D004265:DNA Helicases
Focal segmental glomerulosclerosis; Notch signaling pathway; SMARCAL1 protein; Schimke immuno-osseous dysplasia; Wnt signaling pathway