Dataset Information

Pathogenesis of enamel-renal syndrome associated gingival fibromatosis: a proteomic approach

ABSTRACT: The enamel renal syndrome (ERS) is a rare disorder featured by amelogenesis imperfecta, gingival fibromatosis and nephrocalcinosis. Gingival fibromatosis is a hallmark of the disease; it is characterized by the accumulation of a collagen-rich, dense connective tissue and of mineral deposits throughout the gingiva. ERS is caused by biallelic mutations in the FAM20A gene encoding a pseudokinase, likely acting as an allosteric activator of FAM20C, the Golgi casein kinase. How mutations in FAM20A may modify the gingival connective tissue homeostasis and cause fibromatosis is currently unknown. Conditioned media of gingival fibroblasts (GF) obtained from four unrelated ERS patients carrying distinct mutations and three control subjects were used. Secretomic analysis identified 109 dysregulated proteins whose abundance had increased (69 proteins) or decreased (40 proteins) at least 1.5-fold compared to control GF. Gene Ontology (GO) analysis revealed biological processes significantly over-represented or under-represented in the ERS GF. Proteins over-represented were mainly involved in extracellular matrix organization, collagen fibril assembly, and biomineralization whereas those under-represented were extracellular matrix-associated proteins. Accordingly, GO disease analysis indicated un significant enrichment of tumoral angiogenesis and fibrosis.

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Suspension Culture, Fibroblast

SUBMITTER: Clement GUILLOU

LAB HEAD: Kozyraki Renata

PROVIDER: PXD028003 | Pride | 2022-02-17

REPOSITORIES: Pride

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Pathogenesis of Enamel-Renal Syndrome Associated Gingival Fibromatosis: A Proteomic Approach.

Simancas Escorcia Victor V Guillou Clément C Abbad Lilia L Derrien Louise L Rodrigues Rezende Costa Claudio C Cannaya Vidjea V Benassarou Mourad M Chatziantoniou Christos C Berdal Ariane A Acevedo Ana Carolina AC Cases Olivier O Cosette Pascal P Kozyraki Renata R

Frontiers in endocrinology 20211029

The enamel renal syndrome (ERS) is a rare disorder featured by amelogenesis <i>imperfecta</i>, gingival fibromatosis and nephrocalcinosis. ERS is caused by bi-allelic mutations in the secretory pathway pseudokinase FAM20A. How mutations in <i>FAM20A</i> may modify the gingival connective tissue homeostasis and cause fibromatosis is currently unknown. We here analyzed conditioned media of gingival fibroblasts (GFs) obtained from four unrelated ERS patients carrying distinct mutations and control ...[more]

PMID: 34777248

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Project description:The long noncoding RNA CDKN2B-AS1 harbors a major coronary artery disease risk haplotype, which is also associated with progressive forms of the oral inflammatory disease periodontitis as well as myocardial infarction (MI). Despite extensive research, there is currently no broad consensus on the function of CDKN2B-AS1 that would explain a common molecular role of this lncRNA in these diseases. Our aim was to investigate the role of CDKN2B-AS1 in gingival cells to better understand the molecular mechanisms underlying the increased risk of progressive periodontitis. We downregulated CDKN2B-AS1 transcript levels in primary gingival fibroblasts with LNA GapmeRs. Following RNA-sequencing, we performed differential expression, gene set enrichment analyses and Western Blotting. Putative causal alleles were searched by analyzing associated DNA sequence variants for changes of predicted transcription factor binding sites. We functionally characterized putative functional alleles using luciferase-reporter and antibody electrophoretic mobility shift assays in gingival fibroblasts and HeLa cells. Of all gene sets analysed, collagen biosynthesis was most significantly upregulated (Padj=9.7x10-5 (AUC>0.65) with the CAD and MI risk gene COL4A1 showing strongest upregulation of the enriched gene sets (Fold change = 12.13, Padj = 4.9 x 10-25). The inflammatory "TNFA signaling via NFKB" gene set was downregulated the most (Padj=1x10-5 (AUC=0.60). On the single gene level, CAPNS2, involved in extracellular matrix organization, was the top upregulated protein coding gene (Fold change=48.5, P<9x10-24). The risk variant rs10757278 altered a binding site of the pathogen responsive transcription factor STAT1 (P=5.8x10-6). rs10757278-G allele reduced STAT1 binding 14.4% and rs10757278-A decreased luciferase activity in gingival fibroblasts 41.2% (P=0.0056), corresponding with GTEx data. CDKN2B-AS1 represses collagen gene expression in gingival fibroblasts. Dysregulated collagen biosynthesis through allele-specific CDKN2B-AS1 expression in response to inflammatory factors may affect collagen synthesis, and in consequence tissue barrier and atherosclerotic plaque stability.

			Action	DRS
	Control_1.msf	Msf
	Control_1.raw	Raw
	Control_2.msf	Msf
	Control_2.raw	Raw
	Control_3.msf	Msf