Primary Ovarian Insufficiency and Azoospermia in Carriers of a Homozygous PSMC3IP Stop Gain Mutation
Primary Ovarian Insufficiency and Azoospermia in Carriers of a Homozygous PSMC3IP Stop Gain Mutation
复制标题
DOI：
10.1210/jc.2017-01966
复制
发表时间：
2018-02-01
影响因子：
5.8
通讯作者：
Welt, Corrine K.
中科院分区：
文献类型：
--
作者：
Al-Agha, Abdulmoein Eid;Ahmed, Ihab Abdulhamed;Welt, Corrine K.
背景：原发性卵巢功能不全（POI）的病因在大多数情况下仍然未知。目标：我们试图找出基因引起POI.Design：这项研究是一个家族遗传学研究。设置：这项研究是在两个学术机构进行的。患者：我们确定了一个血亲也门家庭，其中四个女儿有POI。一个兄弟有无精子症。干预：DNA进行全基因组测序。使用Truploidy鉴定共享的纯合性区域，并使用变体注释、分析和搜索工具与来自387名健康受试者的对照数据进行优先排序。结果：这对姐妹篇在PSMC 3 IP基因第6外显子有一个纯合的终止获得突变（c.489C> G，p.Tyr163Ter），在CLPP基因第1外显子有一个错义突变（c.100C > T，p.Pro34Ser）。受影响的兄弟也携带纯合子PSMC 3 IP突变。功能研究表明，在感染CLPP突变的细胞中存在线粒体片段化。结论：PSMC 3 IP突变提供了额外的证据，证明减数分裂同源重组和DNA修复基因的突变导致不同的女性和男性生殖表型，包括青春期延迟和原发性闭经引起的POI（XX性腺发育不全）的女性，但孤立无精子症与正常青春期发育的男性。研究结果还表明，CLPP的N-末端错义突变不会导致线粒体功能障碍或以寡基因方式导致卵巢功能不全。
Context: The etiology of primary ovarian insufficiency (POI) remains unknown in most cases. Objective: We sought to identify the genes causing POI.Design: The study was a familial genetic study.Setting: The study was performed at two academic institutions.Patients: We identified a consanguineous Yemeni family in which four daughters had POI. A brother had azoospermia.Intervention: DNA was subjected to whole genome sequencing. Shared regions of homozygosity were identified using Truploidy and prioritized using the Variant Annotation, Analysis, and Search Tool with control data from 387 healthy subjects. Imaging and quantification of protein localization and mitochondrial function were examined in cell lines.Main Outcome: Homozygous recessive gene variants shared by the four sisters.Results: The sisters shared a homozygous stop gain mutation in exon 6 of PSMC3IP (c.489 C > G, p.Tyr163Ter) and a missense variant in exon 1 of CLPP (c.100C > T, p.Pro34Ser). The affected brother also carried the homozygous PSMC3IP mutation. Functional studies demonstrated mitochondrial fragmentation in cells infected with the CLPP mutation. However, no abnormality was found in mitochondrial targeting or respiration.Conclusions: The PSMC3IP mutation provides additional evidence that mutations in meiotic homologous recombination and DNA repair genes result in distinct female and male reproductive phenotypes, including delayed puberty and primary amenorrhea caused by POI (XX gonadal dysgenesis) in females but isolated azoospermia with normal pubertal development in males. The findings also suggest that the N-terminal missense mutation in CLPP does not cause substantial mitochondrial dysfunction or contribute to ovarian insufficiency in an oligogenic manner.