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
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
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将编码人脱氧核糖核酸酶 I 和 I-like 3 的基因中的所有非同义单核苷酸多态性 (SNP) 评估为可能与自身免疫相关的功能性 SNP
DOI：
10.1111/febs.12608
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发表时间：
2014
期刊：
影响因子：
5.4
通讯作者：
Misuzu Ueki
中科院分区：
文献类型：
--
作者：
Kei Zaitsu;Haruhiko Miyagawa;Yuki Sakamoto;Shuntaro Matsuta;Kento Tsuboi;Hiroshi Nishioka;Munehiro Katagi;Takako Sato;Michiaki Tatsuno;Hitoshi Tsuchihashi;Koichi Suzuki;Akira Ishii.;林田眞喜子,滝埜昌彦,山口晃志,植草協子,安部寛子,大野曜吉;Misuzu Ueki
本研究的目的是评估DNase I和DNase I-like 3(1L3)基因中的所有非同义单核苷酸多态(SNP)在自身免疫性疾病中作为功能性SNP的活性水平的变化。我们检测了DNASE1和DNASE1L3的32个和20个非同义SNPs在三个民族中的分布情况，以及这些SNPs对DNase活性的影响。在包括我们之前研究中描述的那些在内的总共44个和25个SNP中[Yasudaet等人，Int J Biochem Cell Biol42(2010)1216-1225；Uekiet等人。分别只有4个和1个在所调查的一个或所有种族群体中表现出遗传杂合性。根据相应的氨基酸替换引起的活性水平的变化，DNASE 1中的11个活性取消和11个活性降低的SNP和DNASE 1L3中的2个活性取消和5个活性降低的SNP被确认为功能SNP。系统进化分析表明，SNPs中所有的氨基酸残基在动物DNase I和1L3蛋白中完全或很好地保守。尽管这两个基因中几乎所有影响催化活性的非同义SNPs都表现出极低的遗传异质性，但似乎有理由认为，在这两个DNase基因中产生功能丧失变体的13个活性取消SNPs中的一个微小等位基因将是自身免疫性疾病的直接遗传风险因素。这些发现可能对自身免疫性疾病的流行有临床意义。
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 inDNASE1andDNASE1L3, 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 [Yasudaet al.,Int J Biochem Cell Biol42(2010) 1216–1225; Uekiet 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 inDNASE1and two activity‐abolishing and five activity‐reducing SNPs inDNASE1L3were 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.