Arg206Cys substitution in DNASE1L3 causes a defect in DNASE1L3 protein secretion that confers risk of systemic lupus erythematosus
| Autor: | Coke, Latanya N, Wen, Hongxiu, Comeau, Mary, Ghanem, Mustafa H, Shih, Andrew, Metz, Christine N, Li, Wentian, Langefeld, Carl D, Gregersen, Peter K, Simpfendorfer, Kim R |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
rheumatoid Genotype Immunology Mutation Missense Single-nucleotide polymorphism Locus (genetics) Systemic Lupus Erythematosus Polymorphism Single Nucleotide General Biochemistry Genetics and Molecular Biology polymorphism 03 medical and health sciences 0302 clinical medicine Rheumatology Polymorphism (computer science) medicine Humans Lupus Erythematosus Systemic Immunology and Allergy SNP Missense mutation scleroderma Genetic Predisposition to Disease skin and connective tissue diseases 030203 arthritis & rheumatology Endodeoxyribonucleases Lupus erythematosus business.industry autoimmunity Haplotype systemic medicine.disease HEK293 Cells 030104 developmental biology arthritis Haplotypes Case-Control Studies genetic business lupus erythematosus |
| Zdroj: | Annals of the Rheumatic Diseases |
| ISSN: | 1468-2060 0003-4967 |
| DOI: | 10.1136/annrheumdis-2020-218810 |
| Popis: | Objectives To determine if the polymorphism encoding the Arg206Cys substitution in DNASE1L3 explains the association of the DNASE1L3/PXK gene locus with systemic lupus erythematosus (SLE) and to examine the effect of the Arg206Cys sequence change on DNASE1L3 protein function. Methods Conditional analysis for rs35677470 was performed on cases and controls with European ancestry from the SLE Immunochip study, and genotype and haplotype frequencies were compared. DNASE1L3 protein levels were measured in cells and supernatants of HEK293 cells and monocyte-derived dendritic cells expressing recombinant and endogenous 206Arg and 206Cys protein variants. Results Conditional analysis on rs35677470 eliminated the SLE risk association signal for lead single-nucleotide polymorphisms (SNPs) rs180977001 and rs73081554, which are found to tag the same risk haplotype as rs35677470. The modest effect sizes of the SLE risk genotypes (heterozygous risk OR=1.14 and homozygous risk allele OR=1.68) suggest some DNASE1L3 endonuclease enzyme function is retained. An SLE protective signal in PXK (lead SNP rs11130643) remained following conditioning on rs35677470. The DNASE1L3 206Cys risk variant maintained enzymatic activity, but secretion of the artificial and endogenous DNASE1L3 206Cys protein was substantially reduced. Conclusions SLE risk association in the DNASE1L3 locus is dependent on the missense SNP rs35677470, which confers a reduction in DNASE1L3 protein secretion but does not eliminate its DNase enzyme function. |
| Databáze: | OpenAIRE |
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