Evaluation of the functional effects of genetic variants‒missense and nonsense SNPs, indels and copy number variations‒in the gene encoding human deoxyribonuclease I potentially implicated in autoimmunity

Abstract

Genetic variants, such as single nucleotide polymorphisms (SNPs), in the deoxyribonuclease I (DNase I) gene which remarkably reduce or abolish the activity are assumed to be substantially responsible for the genetic backgrounds determining susceptibility to autoimmune dysfunction. Here, we evaluated many genetic variants, including missense and nonsense SNPs, and indel (inframe) variants in the gene, potentially implicated in autoimmune diseases as functional variants resulting in altered activity levels. Eighteen missense and 7 nonsense SNPs, and 9 indel (inframe) variants were found to result in loss of function and disappearance of DNase I activity. Furthermore, considering the positions in the DNase I protein corresponding to the various nonsense SNPs, all of the other nonsense SNPs and frameshift variants registered in the Ensembl database (https://asia.ensembl.org) appear likely to exert a pathogenetic effect through loss of the activity. Accordingly, a total of 60 genetic variants in the DNase 1 gene (DNASE1) inducing abolishment or marked reduction of the DNase I activity could be identified as genetic risk factors for autoimmunity, irrespective of how sparsely they were distributed in the population. It was noteworthy that SNP p.Gln244Arg, reportedly associated with autoimmunity and reducing the activity to about half of that of the wild type, and SNP p.Arg107Gly, abolishing the activity completely, were distributed worldwide and in African populations at the polymorphic level, respectively. On the other hand, with regard to copy number variations in DNASE1 where loss of copy leads to a reduction of the in vivo enzyme activity, only 2 diploid copy numbers were distributed in Japanese and German populations, demonstrating no loss of copy. These exhaustive data for genetic variants in DNASE1 resulting in loss or marked reduction of the DNase I activity are highly informative when considering genetic predisposition leading to autoimmune dysfunction.

Deoxyribonucleases and Their Applications in Biomedicine

“…Recently, 18 missense, 7 nonsense and 9 indel mutations in the DNASE1 gene were described, which lead to a decreased activity or no activity of the enzyme. Some of the SNPs, such as p.Gln244Arg and p.Arg107Gly, are interspersed worldwide, and some are restricted to certain populations [16]. The polypeptide chain of DNase I contains 260 amino acid residues.…”

Oxidative Stress and Lipid Mediators Modulate Immune Cell Functions in Autoimmune Diseases

“…However, they are activated by “foreign” nucleic acids and not by the own human nucleic acids. Human DNA is normally digested by deoxyribonucleases (DNases) and a lack of DNase 1 is an important factor for the onset of autoimmune diseases [ 12 ]. Moreover, TLR-7 and TLR-9 are endosomal receptors so they can only be activated by DNA or RNA that has been taken up by cells through endocytosis.…”

Host/genetic factors associated with COVID-19 call for precision medicine

“…Exhaustive listing of gene variants candidates is, therefore, impossible. That said, as an illustration of the potential influence of NETs in varying host COVID-19 susceptibility, we offer the following examples of the various stages of the phenomena: (i) as NADPH oxidase is required for generation of NETs, it may illustrate how genetic variants of NET stimuli effectors may be involved in NETosis dysregulation, 33 as observed in COVID-19 28 ; (ii) the W620 polymorphism in PTPN22 was found to disrupt its interaction with peptidylarginine deiminase Type 4 (PAD4), 34 thus enhancing citrullination and NETosis; (iii) evaluation of the functional effects of genetic variants, missense and nonsense SNPs, indels, and copy number variations in the gene encoding human deoxyribonuclease I (DNase1), were recently identified as having potential implications for autoimmunity as well as COVID-19 susceptibility 35 ; (iv) IL-26 has been identified as a potential cargo for extracellular DNA cell entry, leading to the release of pro-inflammatory cytokines in a STING and inflammasome-dependent pathway 36 ; the identification of alternative splicing for IL-26 in a species in which the gene has not been inactivated has also been reported 37 ; (v) as vasculitis has been associated with exacerbated NETs formation, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) may be triggered by NETs and their remnants 38 ; and (vi) a single nucleotide polymorphism (SNP, rs7151526) in SERPINA1 gene leads to decreased production of alpha-1 anti-trypsin (A1AT), the main protein 3 (PR3), and elastase inhibitor. 22 , 39 We are convinced that elastase is one of the critical factors for epithelial and endothelial cell toxicity, micro-thrombosis, and vasculitis, and consequently believe that research on elastase genetic variants 40 should be promoted.…”