title: Evaluation of all non-synonymous single nucleotide polymorphisms (SNPs) in the genes encoding human deoxyribonuclease I and I-like 3 as a functional SNP potentially implicated in autoimmunity.
abstract: The objectives of this study were to evaluate all the non-synonymous single nucleotide polymorphisms (SNPs) in the DNase I and DNase I-like 3 (1L3) genes potentially implicated in autoimmune diseases as a functional SNP in terms of alteration of the activity levels. We examined the genotype distributions of the 32 and 20 non-synonymous SNPs in DNASE1 and DNASE1L3, respectively, in three ethnic groups, and the effect of these SNPs on the DNase activities. Among a total of 44 and 25 SNPs including those characterized in our previous studies [Yasuda et al., Int J Biochem Cell Biol42 (2010) 1216-1225; Ueki et al. Electrophoresis32 (2012) 1465-1472], only four and one, respectively, exhibited genetic heterozygosity in one or all of the ethnic groups examined. On the basis of alterations in the activity levels resulting from the corresponding amino acid substitutions, 11 activity-abolishing and 11 activity-reducing SNPs in DNASE1 and two activity-abolishing and five activity-reducing SNPs in DNASE1L3 were confirmed as a functional SNP. Phylogenetic analysis showed that all of the amino acid residues in activity-abolishing SNPs were completely or well conserved in animal DNase I and 1L3 proteins. Although almost all non-synonymous SNPs in both genes that affected the catalytic activity showed extremely low genetic heterogeneity, it seems plausible that a minor allele of 13 activity-abolishing SNPs producing a loss-of-function variant in both the DNase genes would be a direct genetic risk factor for autoimmune diseases. These findings may have clinical implications in relation to the prevalence of autoimmune diseases.
authors.affiliation: Division of Medical Genetics and Biochemistry, Faculty of Medical Sciences, University of Fukui, Japan.
authors.forename: Misuzu
authors.initials: M
authors.lastname: Ueki
authors.forename: Kaori
authors.initials: K
authors.lastname: Kimura-Kataoka
authors.forename: Haruo
authors.initials: H
authors.lastname: Takeshita
authors.forename: Junko
authors.initials: J
authors.lastname: Fujihara
authors.forename: Reiko
authors.initials: R
authors.lastname: Iida
authors.forename: Rie
authors.initials: R
authors.lastname: Sano
authors.forename: Tamiko
authors.initials: T
authors.lastname: Nakajima
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Kominato
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Kawai
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Yasuda
mesh_terms: D000483:Alleles; D019943:Amino Acid Substitution; D000818:Animals; D015551:Autoimmunity / Q000235:genetics*; D019556:COS Cells; D002522:Chlorocebus aethiops; D003850:Deoxyribonuclease I / Q000235:genetics*; D004706:Endodeoxyribonucleases / Q000235:genetics*; D005838:Genotype; D006801:Humans; D010802:Phylogeny; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
chemical_list: C485421:DNASE1L3 protein, human; D004706:Endodeoxyribonucleases; C085693:DNASE1 protein, human; D003850:Deoxyribonuclease I
keywords: DNase I; DNase I-like 3 (1L3); autoimmunity; functional SNP; genetic distribution