Abstract
Non-obstructive azoospermia (NOA) and premature ovarian insufficiency (POI) represent the most serious forms of human infertility caused by gametogenic failure. Although whole-exome sequencing (WES) has uncovered multiple monogenic causes of human infertility, our knowledge of the genetic basis of human gametogenesis defects remains at a rudimentary stage. Coiled-coil-domain-containing protein 155 (CCDC155) encodes a core component of the linker of the nucleoskeleton and cytoskeleton complex that is essential for modulating telomere-led chromosome movements during the meiotic prophase of mice. Additionally, Ccdc155 deficiency in mice causes infertility in both sexes with meiotic arrest. In this study, we applied WES to identify the pathogenic genes for 15 NOA and POI patients whose parents were consanguineous and identified a novel homozygous missense mutation in CCDC155 [c.590T>C (p.Leu197Pro)] in a pair of familial NOA and POI patients whose parents were first cousins. The affected spermatocytes were unable to complete meiotic division coupled with unresolved repair of the DNA double-strand break. This rare missense mutation with lesions in the conserved CC domain of CCDC155 blocked nuclear envelope (NE) distribution and subsequently prevented NE-specific enrichment of Sad1- and UNC84-domain-containing 1 either ex vivo or in vitro, eventually leading to disruptive NE anchoring of chromosome-induced meiotic arrest in both sexes. This study presents the first evidence of the necessity of the SUN1–CCDC155 complex during human meiosis and provides insight into the CCDC155 CC domain, thereby expanding the genetic spectrum of human NOA and POI and promoting adequate genetic counselling and appropriate fertility guidance for these patients.
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Original data of the present study are available from the corresponding author upon reasonable request.
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The authors thank all of the individuals involved in this study.
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This study was supported by the National Natural Science Foundation of China (nos. 81901541, 32070842, 81971441, and 32000584), University Synergy Innovation Program of Anhui Province (GXXT-2019-044), Natural Science Foundation of Jiangsu Province (no. BK20190081), the Qing Lan Project, and the Nonprofit Central Research Institute Fund of the Chinese Academy of Medical Sciences (no. 2019PT310002). The sponsors of this work played no role in study design; the collection, analysis, and interpretation of data; the writing of the report; or the decision to submit the article for publication.
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HW, XZ, and RH performed the biochemical experiments, participated in critical discussions, and drafted the manuscript; KL, YG, and ML analyzed the genetic data and performed Sanger sequencing; YL, CL YL, and QS performed the in vitro experiments; GW and YX prepared all biological samples; ML, YC, and XH designed the study, participated in critical discussions, and modified the manuscript.
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Wu, H., Zhang, X., Hua, R. et al. Homozygous missense mutation in CCDC155 disrupts the transmembrane distribution of CCDC155 and SUN1, resulting in non-obstructive azoospermia and premature ovarian insufficiency in humans. Hum Genet 141, 1795–1809 (2022). https://doi.org/10.1007/s00439-022-02459-4
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DOI: https://doi.org/10.1007/s00439-022-02459-4