A biochemical and genetic study on all non-synonymous single nucleotide polymorphisms of the gene encoding human deoxyribonuclease I potentially relevant to autoimmunity
A biochemical and genetic study on all non-synonymous single nucleotide polymorphisms of the gene encoding human deoxyribonuclease I potentially relevant to autoimmunity
复制标题
对可能与自身免疫相关的人脱氧核糖核酸酶 I 编码基因的所有非同义单核苷酸多态性的生化和遗传学研究
DOI：
10.1016/j.biocel.2010.04.012
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发表时间：
2010
期刊：
影响因子：
--
通讯作者：
Panduro A
中科院分区：
文献类型：
--
作者：
Yasuda T;Ueki M;Takeshita H;Fujihara J;Kimura-Kataoka K;Iida R;Tsubota E;Soejima M;Koda Y;Kato H;Panduro A
据报道，自身免疫性疾病患者血清中脱氧核糖核酸酶I(DNase I)活性水平降低。这项研究的目的是阐明人类基因(DNase1)中12个非同义SNPs的遗传和生化方面的问题，这些SNPs可能导致体内DNaseI活性水平的变化。采用新开发的方法对3个民族15个群体的健康受试者进行了非同义SNPs的基因分型。其中，仅有R-21S、Y95S、G105R和Q222R 4个SNPs在全部或部分群体中具有多态性，亚洲群体表现出较低的遗传多样性。此外，还将常见SNP Q222R的分布模式划分为三个民族。与野生型相比，R-21S、G105R、P132A和P197S 4个SNPs的氨基酸取代型DNase I的活性水平显著高于野生型，SNPs R-21S和G105R的多态导致了一个高活性的DNase I亚型。另一方面，Q35H、R85G、V89M、C209Y、Q222R和A224P的SNP活性水平显著较低，但除Q222R外，这些SNP均未在任何群体中分布。然而，由于这些SNP可能在体内产生潜在的低水平的DNase I活性，每个SNP中的一个微小等位基因将被用作自身免疫性疾病的遗传风险因素。这些关于DNase1中非同义SNPs的发现可能为阐明DNase I与疾病的可能关系提供了生化遗传学基础。
A reduction of deoxyribonuclease I (DNase I) activity levels in the serum of patients with autoimmune diseases has been reported. The objectives of this study were to clarify genetic and biochemical aspects of 12 non-synonymous SNPs in the human gene (DNASE1), potentially giving rise to an alteration in the in vivo DNase I activity levels. Genotyping of all the non-synonymous SNPs was performed in healthy subjects of three ethnic groups including 15 populations using newly developed methods. Among them, only four SNPs, R-21S, Y95S, G105R, and Q222R were polymorphic in all or some populations; Asian group showed a relatively low genetic diversity of these SNPs. Furthermore, the distribution pattern of the common SNP Q222R was classified into three ethnic groups. The activity levels of the amino acid-substituted DNase I forms derived from SNPs R-21S, G105R, P132A, and P197S were significantly high compared with that of the wild-type; the polymorphic SNPs R-21S and G105R gave rise to a high activity-harboring DNase I isoform. On the other hand, activity levels from Q35H, R85G, V89M, C209Y, Q222R, and A224P were significantly low, but these SNPs, except Q222R, were not distributed in any of the populations. However, since these SNPs may produce potentially low levels of in vivo DNase I activity, a minor allele in each SNP will be served as a genetic risk factor for autoimmune diseases. These findings on non-synonymous SNPs in DNASE1 may provide a biochemical-genetic basis for the clarification of a possible relationship between DNase I and the diseases.