Primary Ovarian Insufficiency and Azospermia in Carriers of a Homozygous PSMC3IP Stop Gain Mutation.

Primary Ovarian Insufficiency and Azospermia in Carriers of a Homozygous PSMC3IP Stop Gain Mutation.

J Clin Endocrinol Metab. 2017 Dec 12;:

Authors: Al-Agha AE, Ahmed IA, Nuebel E, Moriwaki M, Moore B, Peacock KA, Mosbruger T, Neklason DW, Jorde LB, Yandell M, Welt CK

Abstract
Context: The etiology of primary ovarian insufficiency (POI) remains unknown in a majority of cases.
Objective: We sought to identify genes causing POI.
Design: The study was a familial genetic study.
Setting: The study was performed in two academic institutions.
Patients: We identified a consanguineous Yemeni family in which 4 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 (VAAST) 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, there was no abnormality in mitochondrial targeting or respiration.
Conclusion: The PSMC3IP mutation provides additional evidence that mutations in meiotic homologous recombination and DNA repair genes result in distinct female and male reproductive phenotypes; delayed puberty and primary amenorrhea caused by POI (XX gonadal dysgenesis) in females but isolated azoospermia with normal pubertal development in males. The study also suggests that the N-terminal missense mutation in CLPP does not cause significant mitochondrial dysfunction or contribute to ovarian insufficiency in an oligogenic manner.

PMID: 29240891 [PubMed - as supplied by publisher]

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