An investigation of genetic polymorphisms in heparan sulfate proteoglycan core proteins and key modification enzymes in an Australian Caucasian multiple sclerosis population.

An investigation of genetic polymorphisms in heparan sulfate proteoglycan core proteins and key modification enzymes in an Australian Caucasian multiple sclerosis population.

Publication date: May 12, 2020

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease affecting the central nervous system in young adults. Heparan sulfate proteoglycans (HSPGs) are ubiquitous to the cell surface and the extracellular matrix. HSPG biosynthesis is a complex process involving enzymatic attachment of heparan sulfate (HS) chains to a core protein. HS side chains mediate specific ligand and growth factor interactions directing cellular processes including cell adhesion, migration and differentiation. Two main families of HSPGs exist, the syndecans (SDC1-4) and glypicans (GPC1-6). The SDCs are transmembrane proteins, while the GPC family are GPI linked to the cell surface. SDC1 has well-documented interactions with numerous signalling pathways. Genome-wide association studies (GWAS) have identified regions of the genome associated with MS including a region on chromosome 13 containing GPC5 and GPC6. International studies have revealed significant associations between this region and disease development. The exostosin-1 (EXT1) and sulfatase-1 (SULF1) are key enzymes contributing to the generation of HS chains. EXT1, with documented tumour suppressor properties, is involved in the initiation and polymerisation of the growing HS chain. SULF1 removes 6-O-sulfate groups from HS chains, affecting protein-ligand interactions and subsequent downstream signalling with HS modification potentially having significant effects on MS progression. In this study, we identified significant associations between single nucleotide polymorphisms in SDC1, GPC5 and GPC6 and MS in an Australian Caucasian case-control population. Further significant associations in these genes were identified when the population was stratified by sex and disease subtype. No association was found for EXT1 or SULF1.

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Concepts Keywords
Adhesion Extracellular matrix
Biosynthesis SNP
Caucasian Syndecan 1
Central Nervous System Glypican
Chromosome SULF1
Enzymatic EXT1
Extracellular Matrix Heparan sulfate
Genetic Polymorphisms Proteins
Genome Cell biology
Growth Factor Proteoglycans
Heparan Sulfate Branches of biology
Heparan Sulfate Proteoglycan
HSPGs
Ligand
Multiple Sclerosis
Polymerisation
Protein
Protein Ligand
Proteoglycans
Single Nucleotide Polymorphisms
Sulfate
Transmembrane Proteins
Tumour Suppressor

Semantics

Type Source Name
disease MESH multiple sclerosis
disease MESH demyelinating disease
disease MESH growth
drug DRUGBANK Sulfate ion
disease MESH sclerosis
disease MESH visual
drug DRUGBANK Isoxaflutole
disease MESH numbness
disease MESH depression
drug DRUGBANK Indoleacetic acid
disease MESH scar
drug DRUGBANK Polysorbate 60
disease MESH genetic markers
drug DRUGBANK Tretamine
drug DRUGBANK Basic Fibroblast Growth Factor
drug DRUGBANK Diethylstilbestrol
drug DRUGBANK Ethanol
disease MESH RFLP
drug DRUGBANK Albendazole
drug DRUGBANK Biotin
drug DRUGBANK Tromethamine
drug DRUGBANK Edetic Acid
drug DRUGBANK Acetate ion
drug DRUGBANK Water
disease MESH separation
disease MESH cancers
disease MESH risk factors
disease MESH pathology
drug DRUGBANK Esomeprazole
disease MESH ataxia
disease MESH abnormalities
disease MESH suffering
drug DRUGBANK Glycine
drug DRUGBANK Chondroitin sulfate
drug DRUGBANK Trestolone
disease MESH hepatocellular carcinoma
pathway KEGG Hepatocellular carcinoma
disease MESH syndrome
pathway KEGG Axon regeneration
pathway KEGG Axon guidance
disease MESH tic
disease MESH neurodegenerative diseases
drug DRUGBANK Hyaluronic acid
disease MESH Cognitive impairment
drug DRUGBANK (S)-Des-Me-Ampa
pathway KEGG Glycosaminoglycan degradation
disease MESH Mult
disease MESH primary sclerosing cholangitis
disease MESH carcinoma
disease MESH smokers

Original Article

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