A recurrent ZSWIM7 mutation causes male infertility resulting from decreased meiotic recombination.
Study Question: Are mutations in the zinc finger SWIM domain-containing protein 7 gene (ZSWIM7) associated with human male infertility?Summary Answer: The homozygous frameshift mutation (c.231_232del) in ZSWIM7 causes decreased meiotic recombination, spermatogenesis arrest, and infertility in men.Wh...
| Published in: | Human Reproduction Vol. 36; no. 5; pp. 1436 - 1446 |
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| Main Authors: | , , , , , , , |
| Format: | research Journal Article |
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Oxford University Press / USA
May2021
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| Online Access: | View this record in EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=149971827&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 149971827 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 02681161 N5F jtl: Human Reproduction issn: 02681161 maglogo: N pubinfo: dt: May2021 vid: 36 iid: 5 pid: 622 pub: Oxford University Press / USA artinfo: ui: 149971827 149971827 NLM33713115 149971827 10.1093/humrep/deab046 NLM33713115 149971827 ppf: 1436 ppct: 10 formats: tig: atl: A recurrent ZSWIM7 mutation causes male infertility resulting from decreased meiotic recombination. aug: au: Li, Yang Wu, Yufan Zhou, Jianteng Zhang, Huan Zhang, Yuanwei Ma, Hui Jiang, Xiaohua Shi, Qinghua affil: Division of Reproduction and Genetics, First Affiliated Hospital of USTC, Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, CAS Center for Excellence in Molecular Cell Science, Collaborative Innovation Center of Genetics and Development, University of Science and Technology of China , Hefei, China sug: subj: Infertility Mice Animal Studies Human Mutation China Male Female Cell Physiology Comparative Studies Multicenter Studies Evaluation Research Validation Studies Male Female ab: Study Question: Are mutations in the zinc finger SWIM domain-containing protein 7 gene (ZSWIM7) associated with human male infertility?Summary Answer: The homozygous frameshift mutation (c.231_232del) in ZSWIM7 causes decreased meiotic recombination, spermatogenesis arrest, and infertility in men.What Is Known Already: ZSWIM7 is a SWIM domain-containing Shu2/SWS1 protein family member and a subunit of the Shu complex. Zswim7 knockout mice were infertile due to impaired meiotic recombination. However, so far there is no direct evidence that mutations of ZSWIM7 cause human infertility.Study Design, Size, Duration: Screening for mutations of ZSWIM7 was performed using in-house whole-exome sequencing data from 60 men with non-obstructive azoospermia (NOA). Mice with a corresponding Zswim7 mutation were generated for functional verification.Participants/materials, Setting, Methods: Sixty Chinese patients, who were from different regions of China, were enrolled. All the patients were diagnosed with NOA owing to spermatocyte maturation arrest based on histopathological analyses and/or immunostaining of spermatocyte chromosome spreads. ZSWIM7 mutations were screened from the whole-exome sequencing data of these patients, followed by functional verification in mice.Main Results and the Role Of Chance: A homozygous frameshift mutation (c.231_232del) in ZSWIM7 was found in two out of the 60 unrelated NOA patients. Both patients displayed small testicular size and spermatocyte maturation arrest in testis histology. Spermatocyte chromosome spreads of one patient revealed meiotic maturation arrest in a pachytene-like stage, with incomplete synapsis and decreased meiotic recombination. Male mice carrying a homozygous mutation similar to that of our patients were generated and also displayed reduced recombination, meiotic arrest and azoospermia, paralleling the spermatogenesis defects in our patients.Limitations, Reasons For Caution: As Zswim7 is also essential for meiosis in female mice, future studies should evaluate the ZSWIM7 mutations more in depth and in larger cohorts of infertile patients, including males and females, to validate the findings.Wider Implications Of the Findings: These findings provide direct clinical and functional evidence that the recurrent ZSWIM7 mutation (c.231_232del) causes decreased meiotic recombination and leads to male infertility, illustrating the genotype-phenotype correlations of meiotic recombination defects in humans.Study Funding/competing Interest(s): This work was supported by the National Natural Science Foundation of China (31890780, 31630050, 32061143006, 82071709, and 31871514), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB19000000), and the National Key Research and Developmental Program of China (2018YFC1003900 and 2019YFA0802600).Trial Registration Number: Not applicable. pubtype: Academic Journal doctype: research Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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