Pediatric Department, King Abdulaziz University Hospital, Jeddah, Saudi Arabia.
Howard Hughes Medical Institute and Department of Biochemistry, University of Utah, Salt Lake City, Utah.
J Clin Endocrinol Metab. 2018 Feb 1;103(2):555-563. doi: 10.1210/jc.2017-01966.
The etiology of primary ovarian insufficiency (POI) remains unknown in most cases.
We sought to identify the genes causing POI.
The study was a familial genetic study.
The study was performed at two academic institutions.
We identified a consanguineous Yemeni family in which four daughters had POI. A brother had azoospermia.
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.
Homozygous recessive gene variants shared by the four sisters.
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.
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.
大多数情况下，原发性卵巢功能不全（POI）的病因仍不清楚。
我们试图确定导致 POI 的基因。
这项研究是一项家族遗传研究。
这项研究在两所学术机构进行。
我们在一个也门的近亲家庭中发现了四名患有 POI 的女儿和一名患有无精子症的兄弟。
对 DNA 进行全基因组测序。使用 Truploidy 识别同源性纯合区域，并使用 Variant Annotation、Analysis 和 Search Tool 对其进行优先级排序，使用 387 名健康受试者的对照数据。在细胞系中检查蛋白质定位和线粒体功能的成像和定量。
四姐妹共享的纯合隐性基因变异。
姐妹四人共享 PSMC3IP 外显子 6 中的纯合终止获得突变（c.489C>G，p.Tyr163Ter）和 CLPP 外显子 1 中的错义变异（c.100C>T，p.Pro34Ser）。受影响的兄弟也携带纯合 PSMC3IP 突变。功能研究表明，CLPP 突变感染的细胞中线粒体碎片化。然而，在线粒体靶向或呼吸方面没有发现异常。
PSMC3IP 突变提供了额外的证据，表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，包括女性的青春期延迟和原发性闭经引起的 POI（XX 性腺发育不全），但男性的正常青春期发育伴孤立的无精子症。研究结果还表明，CLPP 的 N 端错义突变不会导致明显的线粒体功能障碍，也不会以寡基因方式导致卵巢功能不全。
