{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T03:40:32Z","timestamp":1788234032413,"version":"build-2803163510"},"reference-count":59,"publisher":"The Endocrine Society","issue":"3","license":[{"start":{"date-parts":[[2022,1,12]],"date-time":"2022-01-12T00:00:00Z","timestamp":1641945600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["APP1120356"],"award-info":[{"award-number":["APP1120356"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["APP1157680"],"award-info":[{"award-number":["APP1157680"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001779","name":"Monash University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001779","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"German Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,3,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Testicular-derived inhibin B (\u03b1\/\u03b2\u200aB dimers) acts in an endocrine manner to suppress pituitary production of follicle-stimulating hormone (FSH), by blocking the actions of activins (\u03b2\u200aA\/B\/\u03b2\u200aA\/B dimers). Previously, we identified a homozygous genetic variant (c.1079T&amp;gt;C:p.Met360Thr) arising from uniparental disomy of chromosome 2 in the INHBB gene (\u03b2\u200aB-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&amp;gt;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.<\/jats:p>","DOI":"10.1210\/endocr\/bqab269","type":"journal-article","created":{"date-parts":[[2022,1,12]],"date-time":"2022-01-12T23:29:58Z","timestamp":1642030198000},"source":"Crossref","is-referenced-by-count":6,"title":["Human\n                    <i>INHBB<\/i>\n                    Gene Variant (c.1079T&amp;gt;C:p.Met360Thr) Alters Testis Germ Cell Content, but Does Not Impact Fertility in Mice"],"prefix":"10.1210","volume":"163","author":[{"given":"Brendan J","family":"Houston","sequence":"first","affiliation":[{"name":"School of Biological Sciences, Faculty of Science, Monash University , Clayton ,","place":["Australia"]},{"name":"School of BioSciences and Bio21 Institute, Faculty of Science, University of Melbourne , Parkville ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne E","family":"O\u2019Connor","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, Faculty of Science, Monash University , Clayton ,","place":["Australia"]},{"name":"School of BioSciences and Bio21 Institute, Faculty of Science, University of Melbourne , Parkville ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Degang","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Physiology, Monash Biomedicine Discovery Institute, Monash University , Clayton ,","place":["Australia"]},{"name":"The Affiliated Zhongshan Boai Hospital of Southern Medical University , Guangdong ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgia","family":"Goodchild","sequence":"additional","affiliation":[{"name":"Department of Physiology, Monash Biomedicine Discovery Institute, Monash University , Clayton ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D Jo","family":"Merriner","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, Faculty of Science, Monash University , Clayton ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haitong","family":"Luan","sequence":"additional","affiliation":[{"name":"Department of Physiology, Monash Biomedicine Discovery Institute, Monash University , Clayton ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Don F","family":"Conrad","sequence":"additional","affiliation":[{"name":"Oregon National Primate Research Center, Oregon Health and Science University , Beaverton, OR ,","place":["USA"]},{"name":"Genetics of Male Infertility Initiative, GEMINI , Portland, OR ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liina","family":"Nagirnaja","sequence":"additional","affiliation":[{"name":"Oregon National Primate Research Center, Oregon Health and Science University , Beaverton, OR ,","place":["USA"]},{"name":"Genetics of Male Infertility Initiative, GEMINI , Portland, OR ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth I","family":"Aston","sequence":"additional","affiliation":[{"name":"Genetics of Male Infertility Initiative, GEMINI , Portland, OR ,","place":["USA"]},{"name":"Department of Surgery (Urology Division) University of Utah School of Medicine , Salt Lake City, UT ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabine","family":"Kliesch","sequence":"additional","affiliation":[{"name":"Department of Clinical and Surgical Andrology, Centre of Reproductive Medicine and Andrology, University Hospital \u00a0 M\u00fcnster, M\u00fcnster ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margot J","family":"Wyrwoll","sequence":"additional","affiliation":[{"name":"Institute of Reproductive Genetics, University of M\u00fcnster , M\u00fcnster ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corinna","family":"Friedrich","sequence":"additional","affiliation":[{"name":"Institute of Reproductive Genetics, University of M\u00fcnster , M\u00fcnster ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2745-9965","authenticated-orcid":false,"given":"Frank","family":"T\u00fcttelmann","sequence":"additional","affiliation":[{"name":"Institute of Reproductive Genetics, University of M\u00fcnster , M\u00fcnster ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Craig","family":"Harrison","sequence":"additional","affiliation":[{"name":"Department of Physiology, Monash Biomedicine Discovery Institute, Monash University , Clayton ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7298-4940","authenticated-orcid":false,"given":"Moira K","family":"O\u2019Bryan","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, Faculty of Science, Monash University , Clayton ,","place":["Australia"]},{"name":"School of BioSciences and Bio21 Institute, Faculty of Science, University of Melbourne , Parkville ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0627-2958","authenticated-orcid":false,"given":"Kelly","family":"Walton","sequence":"additional","affiliation":[{"name":"Department of Physiology, Monash Biomedicine Discovery Institute, Monash University , Clayton ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2022,1,12]]},"reference":[{"issue":"1","key":"2026032302324497400_CIT0001","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1007\/BF00300588","article-title":"Proliferation of spermatogonia and Sertoli cells in maturing mice","volume":"169","author":"Kluin","year":"1984","journal-title":"Anat Embryol (Berl)."},{"issue":"6072","key":"2026032302324497400_CIT0002","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1038\/321776a0","article-title":"Purification and characterization of an FSH releasing protein from porcine ovarian follicular fluid","volume":"321","author":"Vale","year":"1986","journal-title":"Nature."},{"issue":"6776","key":"2026032302324497400_CIT0003","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1038\/35006129","article-title":"Betaglycan binds inhibin and can mediate functional antagonism of activin signalling","volume":"404","author":"Lewis","year":"2000","journal-title":"Nature."},{"issue":"51","key":"2026032302324497400_CIT0004","doi-asserted-by":"crossref","first-page":"eabl4391","DOI":"10.1126\/sciadv.abl4391","article-title":"TGFBR3L is an inhibin B co-receptor that regulates female fertility","volume":"7","author":"Brule","year":"2021","journal-title":"Sci Adv."},{"issue":"6","key":"2026032302324497400_CIT0005","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1016\/0092-8674(91)90549-E","article-title":"Expression cloning of an activin receptor, a predicted transmembrane serine kinase","volume":"65","author":"Mathews","year":"1991","journal-title":"Cell."},{"issue":"5052","key":"2026032302324497400_CIT0006","doi-asserted-by":"crossref","first-page":"1702","DOI":"10.1126\/science.1313188","article-title":"Cloning of a second type of activin receptor and functional characterization in Xenopus embryos","volume":"255","author":"Mathews","year":"1992","journal-title":"Science."},{"issue":"1","key":"2026032302324497400_CIT0007","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1530\/REP-09-0377","article-title":"Effect of FSH on testicular morphology and spermatogenesis in gonadotrophin-deficient hypogonadal mice lacking androgen receptors","volume":"139","author":"O\u2019Shaughnessy","year":"2010","journal-title":"Reproduction."},{"issue":"2","key":"2026032302324497400_CIT0008","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1038\/ng0297-201","article-title":"Follicle stimulating hormone is required for ovarian follicle maturation but not male fertility","volume":"15","author":"Kumar","year":"1997","journal-title":"Nat Genet."},{"issue":"5","key":"2026032302324497400_CIT0009","doi-asserted-by":"crossref","first-page":"1795","DOI":"10.1210\/endo.141.5.7456","article-title":"The effect of a null mutation in the follicle-stimulating hormone receptor gene on mouse reproduction","volume":"141","author":"Abel","year":"2000","journal-title":"Endocrinology."},{"issue":"5","key":"2026032302324497400_CIT0010","doi-asserted-by":"crossref","first-page":"1146","DOI":"10.1095\/biolreprod62.5.1146","article-title":"Qualitative and quantitative decline in spermatogenesis of the follicle-stimulating hormone receptor knockout (FORKO) mouse","volume":"62","author":"Krishnamurthy","year":"2000","journal-title":"Biol Reprod."},{"issue":"12","key":"2026032302324497400_CIT0011","doi-asserted-by":"crossref","first-page":"5311","DOI":"10.1210\/endo.136.12.7588276","article-title":"Induction of spermatogenesis by androgens in gonadotropin-deficient (hpg) mice","volume":"136","author":"Singh","year":"1995","journal-title":"Endocrinology"},{"issue":"23","key":"2026032302324497400_CIT0012","doi-asserted-by":"crossref","first-page":"10526","DOI":"10.1073\/pnas.1000318107","article-title":"Activin A, a product of fetal Leydig cells, is a unique paracrine regulator of Sertoli cell proliferation and fetal testis cord expansion","volume":"107","author":"Archambeault","year":"2010","journal-title":"Proc Natl Acad Sci USA."},{"issue":"6402","key":"2026032302324497400_CIT0013","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1038\/360313a0","article-title":"Alpha-inhibin is a tumour-suppressor gene with gonadal specificity in mice","volume":"360","author":"Matzuk","year":"1992","journal-title":"Nature."},{"issue":"6520","key":"2026032302324497400_CIT0014","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1038\/374356a0","article-title":"Different phenotypes for mice deficient in either activins or activin receptor type II","volume":"374","author":"Matzuk","year":"1995","journal-title":"Nature."},{"issue":"4","key":"2026032302324497400_CIT0015","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1101\/gad.8.4.414","article-title":"Activin\/inhibin beta B subunit gene disruption leads to defects in eyelid development and female reproduction","volume":"8","author":"Vassalli","year":"1994","journal-title":"Genes Dev."},{"issue":"2","key":"2026032302324497400_CIT0016","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1111\/j.1365-2605.1996.tb00438.x","article-title":"Testicular germ cell populations in the adult rat after continuous in-vivo testicular infusion of inhibin-A and activin-A","volume":"19","author":"Adeeko","year":"1996","journal-title":"Int J Androl."},{"issue":"11","key":"2026032302324497400_CIT0017","doi-asserted-by":"crossref","first-page":"4994","DOI":"10.1210\/endo.142.11.8481","article-title":"Reproductive deficiencies in transgenic mice expressing the rat inhibin alpha-subunit gene","volume":"142","author":"Cho","year":"2001","journal-title":"Endocrinology."},{"issue":"11","key":"2026032302324497400_CIT0018","doi-asserted-by":"crossref","first-page":"5005","DOI":"10.1210\/endo.142.11.8472","article-title":"Gonadal pathologies in transgenic mice expressing the rat inhibin alpha-subunit","volume":"142","author":"McMullen","year":"2001","journal-title":"Endocrinology."},{"issue":"8","key":"2026032302324497400_CIT0019","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1515\/CCLM.1998.118","article-title":"Follitropin (FSH) deficiency in an infertile male due to FSHbeta gene mutation: a syndrome of normal puberty and virilization but underdeveloped testicles with azoospermia, low FSH but high lutropin and normal serum testosterone concentrations","volume":"36","author":"Lindstedt","year":"1998","journal-title":"Clin Chem Lab Med."},{"issue":"2","key":"2026032302324497400_CIT0020","first-page":"751","article-title":"Mutational analysis of the follicle-stimulating hormone (FSH) receptor in normal and infertile men: identification and characterization of two discrete FSH receptor isoforms","volume":"84","author":"Simoni","year":"1999","journal-title":"J Clin Endocrinol Metab."},{"issue":"2","key":"2026032302324497400_CIT0021","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1038\/ng0297-205","article-title":"Men homozygous for an inactivating mutation of the follicle-stimulating hormone (FSH) receptor gene present variable suppression of spermatogenesis and fertility","volume":"15","author":"Tapanainen","year":"1997","journal-title":"Nat Genet."},{"issue":"6","key":"2026032302324497400_CIT0022","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1210\/mend.13.6.0301","article-title":"Fertility and infertility: genetic contributions from the hypothalamic-pituitary-gonadal axis","volume":"13","author":"Achermann","year":"1999","journal-title":"Mol Endocrinol."},{"issue":"2","key":"2026032302324497400_CIT0023","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/j.gene.2015.01.041","article-title":"Polymorphisms in inhibin alpha gene promoter associated with male infertility","volume":"559","author":"Li","year":"2015","journal-title":"Gene."},{"issue":"6","key":"2026032302324497400_CIT0024","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1111\/j.1365-2265.2009.03567.x","article-title":"A new \u201ctotal\u201d activin B enzyme-linked immunosorbent assay (ELISA): development and validation for human samples","volume":"71","author":"Ludlow","year":"2009","journal-title":"Clin Endocrinol (Oxf)."},{"issue":"9","key":"2026032302324497400_CIT0025","doi-asserted-by":"crossref","first-page":"3110","DOI":"10.1210\/jcem.83.9.5121","article-title":"Serum inhibin B as a marker of spermatogenesis","volume":"83","author":"Pierik","year":"1998","journal-title":"J Clin Endocrinol Metab."},{"issue":"5","key":"2026032302324497400_CIT0026","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1530\/eje.0.1450561","article-title":"Inhibin B in male reproduction: pathophysiology and clinical relevance","volume":"145","author":"Meachem","year":"2001","journal-title":"Eur J Endocrinol."},{"issue":"3","key":"2026032302324497400_CIT0027","doi-asserted-by":"crossref","first-page":"e1003349","DOI":"10.1371\/journal.pgen.1003349","article-title":"Human spermatogenic failure purges deleterious mutation load from the autosomes and both sex chromosomes, including the gene DMRT1","volume":"9","author":"Lopes","year":"2013","journal-title":"PLoS Genet."},{"issue":"7809","key":"2026032302324497400_CIT0028","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1038\/s41586-020-2308-7","article-title":"The mutational constraint spectrum quantified from variation in 141,456 humans","volume":"581","author":"Karczewski","year":"2020","journal-title":"Nature."},{"issue":"2","key":"2026032302324497400_CIT0029","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1016\/j.ajhg.2020.06.010","article-title":"Bi-allelic mutations in M1AP are a frequent cause of meiotic arrest and severely impaired spermatogenesis leading to male infertility","volume":"107","author":"Wyrwoll","year":"2020","journal-title":"Am J Hum Genet."},{"key":"2026032302324497400_CIT0030","doi-asserted-by":"crossref","DOI":"10.1093\/humupd\/dmab030","article-title":"A systematic review of the validated monogenic causes of human male infertility: 2020 update and a discussion of emerging gene-disease relationships","author":"Houston","year":"2021;28(1):15-29","journal-title":"Hum Reprod Update."},{"issue":"8","key":"2026032302324497400_CIT0031","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.1007\/s00439-021-02287-y","article-title":"Variants in GCNA, X-linked germ-cell genome integrity gene, identified in men with primary spermatogenic failure","volume":"140","author":"Hardy","year":"2021","journal-title":"Hum Genet."},{"issue":"12","key":"2026032302324497400_CIT0032","doi-asserted-by":"crossref","first-page":"1956","DOI":"10.1038\/s41436-020-0907-1","article-title":"Genetic dissection of 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Biol."},{"issue":"7","key":"2026032302324497400_CIT0035","doi-asserted-by":"crossref","first-page":"922","DOI":"10.1002\/dvdy.299","article-title":"The Sertoli cell expressed gene secernin-1 (Scrn1) is dispensable for male fertility in the mouse","volume":"250","author":"Houston","year":"2021","journal-title":"Dev Dyn."},{"issue":"2","key":"2026032302324497400_CIT0036","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1093\/humupd\/dmp032","article-title":"Phenotyping male infertility in the mouse: how to get the most out of a \u201cnon-performer.\u201d","volume":"16","author":"Borg","year":"2010","journal-title":"Hum Reprod Update."},{"issue":"Pt 1","key":"2026032302324497400_CIT0037","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1242\/jcs.02704","article-title":"FGFR-1 [corrected] signaling is involved in spermiogenesis and sperm capacitation","volume":"119","author":"Cotton","year":"2006","journal-title":"J Cell 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peptides","volume":"145","author":"Groome","year":"1991","journal-title":"J Immunol Methods."},{"issue":"4","key":"2026032302324497400_CIT0041","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1095\/biolreprod62.4.886","article-title":"Development of time-resolved immunofluorometric assays for rat follicle-stimulating hormone and luteinizing hormone and application on sera of cycling rats","volume":"62","author":"van Casteren","year":"2000","journal-title":"Biol Reprod."},{"issue":"8","key":"2026032302324497400_CIT0042","doi-asserted-by":"crossref","DOI":"10.1210\/endocr\/bqaa099","article-title":"Engineering the ovarian hormones inhibin A and inhibin B to enhance synthesis and activity","volume":"161","author":"Goney","year":"2020","journal-title":"Endocrinology."},{"issue":"7","key":"2026032302324497400_CIT0043","doi-asserted-by":"crossref","first-page":"2799","DOI":"10.1210\/en.2015-1963","article-title":"A novel, more efficient approach to generate bioactive 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