Evaluation of all non-synonymous single nucleotidepolymorphisms (SNPs) in the genes encoding humandeoxyribonuclease I and I-like 3 as a functional SNPpotentially implicated in autoimmunity

摘要

The objectives of this study were to evaluate all the non-synonymous singlenucleotide polymorphisms (SNPs) in the DNase I and DNase I-like 3 (1L3)genes potentially implicated in autoimmune diseases as a functional SNP interms of alteration of the activity levels. We examined the genotype distributionsof the 32 and 20 non-synonymous SNPs in DNASE1 and DNASE1L3,respectively, in three ethnic groups, and the effect of these SNPs on theDNase activities. Among a total of 44 and 25 SNPs including those characterizedin our previous studies [Yasuda et al., Int J Biochem Cell Biol 42(2010) 1216–1225; Ueki et al. Electrophoresis 32 (2012) 1465–1472], only fourand one, respectively, exhibited genetic heterozygosity in one or all of the ethnicgroups examined. On the basis of alterations in the activity levels resultingfrom the corresponding amino acid substitutions, 11 activity-abolishingand 11 activity-reducing SNPs in DNASE1 and two activity-abolishing andfive activity-reducing SNPs in DNASE1L3 were confirmed as a functionalSNP. Phylogenetic analysis showed that all of the amino acid residues inactivity-abolishing SNPs were completely or well conserved in animal DNaseI and 1L3 proteins. Although almost all non-synonymous SNPs in bothgenes that affected the catalytic activity showed extremely low genetic heterogeneity,it seems plausible that a minor allele of 13 activity-abolishing SNPsproducing a loss-of-function variant in both the DNase genes would be adirect genetic risk factor for autoimmune diseases. These findings may haveclinical implications in relation to the prevalence of autoimmune diseases.