常染色体显性多囊肾病家系基因特点的研究

Genetic characteristics of family autosomal dominant polycystic kidney disease

目的探讨一个常染色体显性多囊肾病(autosomal dominant polycystic kidney disease,ADPKD)家系的多囊肾病基因1(polycystic kidney disease 1gene,PKD1)基因突变与遗传表型的关系。方法对通过临床确诊为多囊肾的先证者及其家系进行基因检测,用外显子芯片捕获及高通量测序的方法,对该家系进行突变分析。通过搜索英国卡尔地夫医学遗传研究所构建的人类基因突变数据库及千人基因组计划等数据库,进行突变位点致病性的分析。进一步通过一代测序(Sanger测序法)在家系主要成员及100例正常对照者中进行验证。结果先证者同时携带PKD1c.4015G>A、PKD1c.98G>A 2个致病突变,PKD1c.4015G>A突变位于16号染色体2161153,15号外显子,转录本为NM_001009944,在ExAC东亚人数据库携带率为0.00011,该突变导致其编码的第33位氨基酸由半胱氨酸转换成酪氨酸;PKD1c.98G>A突变位于16号染色体2185593,1号外显子,转录本为NM_001009944,在ExAC东亚人数据库携带率未知,该突变导致其编码的第1339位氨基酸由缬氨酸转换成蛋氨酸;该位点位于突变热点,人群携带率罕见。在100例正常对照者中未发现该突变位点;而其父亲表型正常,未携带该致病突变。该家系中9人为ADPKD患者,且5人因终末期肾病在65岁之前病故。结论PKD1c.4015G>A、PKD1c.98G>A双杂合突变,该位点位于突变热点,可能是该家系ADPKD的致病突变位点。

Objective To study the relationship of autosomal dominant polycystic kidney disease （ADPKD） with gene mutation and genetic phenotype in family polycystic kidney disease （PKD） gene 1. Methods The proband gene and its family were detected in clinically-established PKD. The mutation of family PKD genes captured by exsome chip and highthroughout sequencing and the pathogenicity of gene mutation points covered in HGMD and 1000 Genomes Project were ana-lyzed respectively. The major members of family PKD genes and 100 normal controls were verified by Sanger sequencing. Results The proband ADPKD genes carried 2 pathogenic mutations （PKD1 c. 4015G〉A and PKD1 c. 98G〉A）. Mutations of PKD1 c. 4015G〉A at No. 16 chromo-some 2161153 and No. 15 exsome were identified in ADPKD genes. The transcript was NM 001009944 and its carrying rate was 0. 00011 in the ExAC Eastern Asian Database. The mutations of PKD1 c. 98G〉A at No. 16 chromosome 2185593 and No. 15 exsome led to the transformation of valine to methionine at the coded 1339 amino acid located at the mutation hotpoint and was rarely detected in any population. Nine members in the family were ADPKD patients and 5 of them died when they were 〈65 years old due to end-stage renal disease. Conclusion Heterogene-ous mutation of PKD1 c. 4015G〉A and PKD1 c. 98G〉A located at the mutation hotspoint is a pathogenic mutation point in the family ADPKD genes.