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Increased Wnt and Notch signaling: A clue to the renal disease in Schimke immuno-osseous dysplasia? [array]

ABSTRACT: Schimke immuno-osseous dysplasia (SIOD) is a multisystemic disorder caused by biallelic mutations in SWI/SNF-related matrix associated actin-dependent regulator of chromatin, subfamily A-like protein 1 (SMARCAL1). Changes in gene expression appear to underlie the immunodeficiency and arteriosclerosis of SIOD; therefore, we hypothesized that SMARCAL1 deficiency alters renal gene expression to cause the focal segmental glomerulosclerosis (FSGS) of SIOD, and that these gene expression alterations would be comparable to those observed in isolated FSGS. We tested this hypothesis by gene expression microarray analysis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE81156 | GEO | 2016/10/31

SECONDARY ACCESSION(S): PRJNA320766

REPOSITORIES: GEO

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Increased Wnt and Notch signaling: A clue to the renal disease in Schimke immuno-osseous dysplasia? [RNA-Seq]

Project description:Schimke immuno-osseous dysplasia (SIOD) is a multisystemic disorder caused by biallelic mutations in SWI/SNF-related matrix associated actin-dependent regulator of chromatin, subfamily A-like protein 1 (SMARCAL1). Changes in gene expression appear to underlie the immunodeficiency and arteriosclerosis of SIOD; therefore, we hypothesized that SMARCAL1 deficiency alters renal gene expression to cause the focal segmental glomerulosclerosis (FSGS) of SIOD. We tested this hypothesis by transcriptome analysis and quantitative reverse transcription PCR (qRT-PCR) of an SIOD patient kidney, a genetic screen and immunofluorescence. These showed increased expression of genes in the Wnt and Notch signaling pathways in an SIOD patient kidney, interaction of Marcal1 with genes encoding components of the Wnt and Notch signaling pathways, and increased levels of unphosphorylated b-catenin and Notch1 intracellular domain (NICD) in the glomeruli of SIOD patient kidneys. Given that increased Wnt and Notch activity are established causes of FSGS, we hypothesize that SMARCAL1 deficiency increases the activity of one or both of these pathways to cause the renal disease of most SIOD patients.

2016-10-31 | GSE75061 | GEO

Penetrance of biallelic SMARCAL1 mutations is associated with environmental and genetic disturbances of gene expression (1)

Project description:Biallelic mutations of the DNA annealing helicase SMARCAL1 (SWI/SNF-related matrix-associated actin-dependent regulator of chromatin, subfamily a-like 1) cause Schimke immuno-osseous dysplasia (SIOD, MIM 242900), an incompletely penetrant autosomal recessive disorder. Using human, Drosophila, and mouse models, we show that the proteins encoded by SMARCAL1 orthologues localize to transcriptionally active chromatin and modulate gene expression. We also show that similar to SIOD patients, deficiency of the SMARCAL1 orthologues alone is insufficient to cause disease in fruit flies and mice although such deficiency causes modest diffuse alterations in gene expression. Rather, disease manifests when SMARCAL1 deficiency interacts with genetic and environmental factors that further alter gene expression. We conclude that the SMARCAL1 annealing helicase buffers fluctuations in gene expression and that alterations in gene expression contribute to the penetrance of SIOD. For analysis of gene expression in primary cultured human dermal fibroblasts, 5.0 Î¼g of total RNA from three biologically independent replicates was extracted from two SIOD (SD8 and SD60) and a control skin fibroblast cell lines, labeled and hybridized to Affymetrix Human Genome U133 Plus 2.0 Arrays.

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Penetrance of biallelic SMARCAL1 mutations is associated with environmental and genetic disturbances of gene expression (3)

2012-04-05 | GSE35553 | GEO

Penetrance of biallelic SMARCAL1 mutations is associated with environmental and genetic disturbances of gene expression (2)

2012-04-05 | GSE35552 | GEO

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2012-04-05 | GSE35551 | GEO

Penetrance of biallelic SMARCAL1 mutations is associated with environmental and genetic disturbances of gene expression (3)

Project description:Biallelic mutations of the DNA annealing helicase SMARCAL1 (SWI/SNF-related matrix-associated actin-dependent regulator of chromatin, subfamily a-like 1) cause Schimke immuno-osseous dysplasia (SIOD, MIM 242900), an incompletely penetrant autosomal recessive disorder. Using human, Drosophila, and mouse models, we show that the proteins encoded by SMARCAL1 orthologues localize to transcriptionally active chromatin and modulate gene expression. We also show that similar to SIOD patients, deficiency of the SMARCAL1 orthologues alone is insufficient to cause disease in fruit flies and mice although such deficiency causes modest diffuse alterations in gene expression. Rather, disease manifests when SMARCAL1 deficiency interacts with genetic and environmental factors that further alter gene expression. We conclude that the SMARCAL1 annealing helicase buffers fluctuations in gene expression and that alterations in gene expression contribute to the penetrance of SIOD. The RNA sequencing libraries were constructed from the liver RNA of 3-4-month Smarcal1del/del and wt female mice (n=3/group) at 20M-BM-0C and after 1 hour at 39.5M-BM-0C. These libraries were sequenced using the whole transcriptome shotgun sequencing procedure.

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Penetrance of biallelic SMARCAL1 mutations is associated with environmental and genetic disturbances of gene expression (2)

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SMARCAL1 modulates cellular triglyceride storage and expenditure in response to cell growth states via interaction with ANGPTL3 (RNA-Seq 2)

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