PKHD1基因新型复合杂合突变致常染色体隐性遗传多囊肾病的基因型和临床表型分析
Genotype and clinical phenotype analysis of autosomal recessive polycystic kidney disease caused by the novel compound heterozygous mutation of PKHD1 gene
杨钧岚 1彭思琪 1韦致远 1王彬 2王凤梅 2王小兵 3张晓良2
作者信息
- 1. 东南大学医学院,南京 210009;东南大学附属中大医院肾内科,南京 210009
- 2. 东南大学附属中大医院肾内科,南京 210009
- 3. 无锡市第五人民医院肾内科,无锡 214000
- 折叠
摘要
目的 分析PKHD1基因一个新型复合杂合突变致常染色体隐性遗传多囊肾病(autosomal recessive polycystic kidney disease,ARPKD)家系的突变致病性,扩充PKHD1基因突变数据库,并探讨PKHD1基因突变致ARPKD的基因型与表型关联.方法 收集PKHD1基因1个新型复合杂合突变致ARPKD的患者及家系成员的临床资料及外周血,应用高通量测序发现先证者的致病性突变,应用PCR扩增和Sanger测序对致病性突变行家系验证.应用AlphaFold软件预测突变前后蛋白结构变化,分析突变致病性.结果 患者为青年男性,7岁时因肝硬化、脾功能亢进行"脾切除术",22岁时进入终末期肾病,开始维持性腹膜透析治疗,24岁时因重症肺炎、感染性休克去世.基因检测示其PKHD1基因存在3个来自父母的复合杂合突变:1条等位基因仅携带1个来自父亲的错义突变(c.5935G＞A);另1条等位基因来自其母亲,同时携带1个错义突变(c.1187G＞A)和1个剪切突变(c.6332+1_6332+2insG).患者存在1条仅携带错义突变的等位基因,解释了其相对较长的生存期.c.6332+1_6332+2insG为既往未被报告过的新型剪切突变,可导致蛋白翻译提前终止,该发现扩充了PKHD1基因突变数据库.c.1187G＞A(p.S396N)和c.5935G＞A(p.G1979R)分别发生在蛋白的G8结构域和PA14结构域,与患者早期且严重的肝脏表型有关.结论 PKHD1基因的突变类型及氨基酸定位与ARPKD患者临床表型的异质性有关,通过预测并比较突变前后蛋白质的结构变化,可从分子层面解析突变致病性,建立基因型与表型关联,为评估患者预后和早期识别高危ARPKD患者提供重要参考.
Abstract
Objective To analyze the mutation pathogenicity of the novel compound heterozygous mutation in the PKHD1 gene causing autosomal recessive polycystic kidney disease(ARPKD)family,expand the PKHD1 gene mutation database,and explore the genotype-phenotype correlations of PKHD1 gene mutation causing ARPKD.Methods Clinical data and peripheral blood of a patient with ARPKD caused by the novel compound heterozygous mutation in the PKHD1 gene and their family members were collected.High-throughput sequencing was used to detect pathogenic mutations in the proband,and PCR amplification and Sanger sequencing were used to verify the pathogenic mutations in the family.AlphaFold software was applied to predict changes in protein structure in the present or absent mutations,and the pathogenicity of mutations was analyzed.Results The patient was a young male who underwent splenectomy due to liver cirrhosis and hypersplenism at age 7.He developed end-stage renal disease at age 22,requiring maintenance peritoneal dialysis,and died of severe pneumonia and septic shock at age 24.Genetic testing revealed three compound heterozygous mutations in the PKHD1 gene inherited from his parents:a missense mutation(c.5935G＞A)inherited from the father and a missense mutation(c.1187G＞A)and a novel splice mutation(c.6332+1_6332+2insG)from the mother.The single missense mutation allele likely contributed to the prolonged survival.c.6332+1_6332+2insG is a novel splicing mutation that has not been reported in the past,which can lead to early termination of protein translation.This discovery expands the PKHD1 gene mutation database.c.1187G＞A(p.S396N)and c.5935G＞A(p.G1979R)occur in the PA14 and G8 domains of the protein,respectively,and are associated with early and severe liver phenotypes in patients.Conclusions The mutation types and amino acid localization of the PKHD1 gene are associated with the heterogeneity of clinical phenotypes in ARPKD patients.Analyzing structural changes in proteins before and after mutations can help understand the pathogenicity at a molecular level,establishing genotype-phenotype correlations and providing valuable insights for assessing prognosis and identifying high-risk ARPKD patients early.
关键词
多囊肾,常染色体隐性/突变/遗传关联研究/PKHD1基因Key words
Polycystic kidney,autosomal recessive/Mutation/Genetic association studies/PKHD1 gene引用本文复制引用
基金项目
江苏省研究生科研与实践创新计划项目(SJCX22_0065)
江苏省重点研发计划社会发展(BE2023770)
出版年
2024
NETL
NSTL
万方数据