五例原发性远端肾小管酸中毒患儿的基因突变分析  

Mutation analysis of 5 children with primary distal renal tubular acidosis

作　　者：张瑞晓 郎艳华 高延霞 陈泽庆 王翠[1] 逯静茹 邵乐平[1] Zhang Ruixiao;Lang Yanhua;Gao Yanxia;Chen Zeqing;Wang Cui;Lu Jingru;Shao Leping(Department of Nephrology,Affiliated Hospital,Qingdao University,Qingdao 266003,Chin)

机构地区：[1]青岛大学附属医院肾内科,266003 [2]青岛大学附属医院护理部,266003 [3]青岛大学附属医院中心实验室,266003 [4]山东大学齐鲁医院(青岛)泌尿内科

出　　处：《中华肾脏病杂志》2018年第6期410-417,共8页Chinese Journal of Nephrology

基　　金：国家自然科学基金面上项目(81170653);山东省自然科学基金(ZR2014JL054)

摘　　要：目的分析并确定原发性远端。肾小管酸中毒患儿的致病基因，进行基因型和表型的相关性研究，以提高对该病的认识。方法通过全外显子组测序的方法对来自5个家系的5例患儿进行致病基因突变分析。结果2例患儿共携带4个ATP6VOA4基因突变，包括1个新的杂合内含子突变（c．639＋1G〉A），1个已报道过的杂合无义突变（e0580C〉T，p．Arg194＊）和2个新的杂合重复突变（c．1504dupT，p．Tyr502Leufs＊22；c．2351dupT，p．Phe785Ilefs＊28）；1例患儿携带ATP6VIB1基因2个新的杂合错义突变（c．409C〉T，p．Pr0137Ser；c．904C〉T，p．Arg302Trp）；1例患儿携带SLC4A1基因1个已报道过的杂合错义突变（c．1765C〉A，p．Arg589Ser）；1例患儿未发现相关致病基因的突变。其中，前3例患儿均为致病基因的复合杂合突变，符合常染色体隐性遗传模式，第4例患儿基因突变为新发生突变。结论本研究共发现7个突变位点，其中5个新突变位点，丰富了人类基因突变库，有利于遗传咨询和对该病发病机制的更好理解。Objective To analyze the mutations of causal genes in 5 children with primary distal renal tubular acidosis （dRTA）, and explore their association of genotype and phenotype, so as to raise the awareness of the disease. Methods The whole exome sequencing was used to identify mutations in these 5 children from 5 families. Results A total of 4 different mutations of ATP6VOA4 gene were found in 2 dRTA children, including a novel heterozygous intron mutation （c.639 ＋ 1G〉 A）, a reported heterozygous nonsense variant （c.580C 〉 T, p.Arg194＊） and 2 novel heterozygous duplications （c.1504dupT, p.Tyr502Leufs＊22; c.2351dupT, p.Phe785Ilefs＊28）. Two novel heterozygous missense mutations of ATP6V 1B 1 gene （c.409C 〉 T, p.Pro 137Set; c.904C 〉 T, p.Arg302Trp） were identified in the third child, and a heterozygous missense mutation of SLC4A1 gene （c.1765C 〉 A, p.Arg589Ser） previously reported was found in the fourth child. No mutation of the dRTA- related causal genes was found in the fifth child. Furthermore, the mutations of causal genes in each of the first three children were compound heterozygous, which were consistent with the autosomal recessive inheritance pattern, and the variant from the fourth child was de novo. Conclusions The present study has found 7 mutations, including 5 novel variants, which enriches the human gene mutation database （HGMD） and contributes to a better understanding of the disease mechanisms.

关 键 词：酸中毒 肾小管性 突变 SLC4A1基因 ATP6VOA4基因 ATP6V181基因 

分 类 号：R726.9[医药卫生—儿科]