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.
Highlights
Deoxyribonuclease (DNase)-mediated clearance of cell debris resulting from apoptosis and/or necrosis has been suggested to be primarily implicated in the prevention of autoimmune diseases such as systemic lupus erythematosus (SLE)[1,2]
We have been examining the effects of amino acid substitutions resulting from a series of missense single nucleotide polymorphisms (SNPs) located in DNase 1 gene (DNASE1) on deoxyribonuclease I (DNase I) activity, and previously clarified the functional effects of 61 missense SNPs in DNASE113–16
In order to evaluate the missense SNPs newly registered in the database, 70 expression vectors producing the amino acid-substituted DNase I protein encoded by the minor allele in each SNP were constructed and transiently expressed in COS-7 cells, and the resulting DNase I activity in the transfected cells was determined by the single radial enzyme diffusion (SRED) method
Summary
Deoxyribonuclease (DNase)-mediated clearance of cell debris resulting from apoptosis and/or necrosis has been suggested to be primarily implicated in the prevention of autoimmune diseases such as systemic lupus erythematosus (SLE)[1,2]. It has been demonstrated that the same allele in the corresponding SNP, leading to decrease in in vivo DNase I activity, is associated with a higher incidence of myocardial infarction (MI)[12]. These findings strongly suggest that genetic variants in DNASE1 resulting in reduction or loss of in vivo DNase I activity might be substantially involved in the genetic backgrounds determining susceptibility to such diseases. 19 nonsense SNPs, and 16 insertion/deletion (indel) (inframe) variants in DNASE1 are evident in the Ensembl database It remains to be clarified whether these 95 genetic variants could affect the DNase I activity. A genetic characterization of CNVs in DNASE1 has not been performed
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