{"doi":"10.1210/endocr/bqab269","title":"Human <i>INHBB</i> Gene Variant (c.1079T&amp;gt;C:p.Met360Thr) Alters Testis Germ Cell Content, but Does Not Impact Fertility in Mice","abstract":"Testicular-derived inhibin B (α/β B dimers) acts in an endocrine manner to suppress pituitary production of follicle-stimulating hormone (FSH), by blocking the actions of activins (β A/B/β A/B dimers). Previously, we identified a homozygous genetic variant (c.1079T>C:p.Met360Thr) arising from uniparental disomy of chromosome 2 in the INHBB gene (β B-subunit of inhibin B and activin B) in a man suffering from infertility (azoospermia). In this study, we aimed to test the causality of the p.Met360Thr variant in INHBB and testis function. Here, we used CRISPR/Cas9 technology to generate InhbbM364T/M364T mice, where mouse INHBB p.Met364 corresponds with human p.Met360. Surprisingly, we found that the testes of male InhbbM364T/M364T mutant mice were significantly larger compared with those of aged-matched wildtype littermates at 12 and 24 weeks of age. This was attributed to a significant increase in Sertoli cell and round spermatid number and, consequently, seminiferous tubule area in InhbbM364T/M364T males compared to wildtype males. Despite this testis phenotype, male InhbbM364T/M364T mutant mice retained normal fertility. Serum hormone analyses, however, indicated that the InhbbM364T variant resulted in reduced circulating levels of activin B but did not affect FSH production. We also examined the effect of this p.Met360Thr and an additional INHBB variant (c.314C>T: p.Thr105Met) found in another infertile man on inhibin B and activin B in vitro biosynthesis. We found that both INHBB variants resulted in a significant disruption to activin B in vitro biosynthesis. Together, this analysis supports that INHBB variants that limit activin B production have consequences for testis composition in males.","journal":"Endocrinology","year":2022,"id":283066,"datarank":0.33015555136311797,"base_score":1.9459101490553132,"endowment":1.9459101490553132,"self_citation_contribution":0.29188652235829704,"citation_network_contribution":0.03826902900482093,"self_endowment_contribution":0.29188652235829704,"citer_contribution":0.03826902900482093,"corpus_percentile":null,"corpus_rank":null,"citation_count":6,"citer_count":2,"citers_with_citation_signal":2,"citers_with_endowment":2,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9535,"is_data_producer":true,"deposit_databanks":{"figshare":["10.6084/m9.figshare.17306138"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":959485,"name":"Anne E. 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Wyrwoll","orcid":"0000-0002-7651-2403","position":10,"is_corresponding":false},{"id":254962,"name":"Corinna Friedrich","orcid":"0000-0001-8848-3366","position":11,"is_corresponding":false},{"id":254971,"name":"Frank Tüttelmann","orcid":"0000-0003-2745-9965","position":12,"is_corresponding":false},{"id":356563,"name":"Craig A. Harrison","orcid":"0000-0003-1059-3682","position":13,"is_corresponding":false},{"id":345404,"name":"Moira K. O’Bryan","orcid":"0000-0001-7298-4940","position":14,"is_corresponding":false},{"id":356557,"name":"Kelly L. Walton","orcid":"0000-0003-0627-2958","position":15,"is_corresponding":false},{"id":345403,"name":"Brendan J. 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