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Despite its ubiquitous physiological significance, ITPR1 mutations have thus far been linked to primarily movement disorders. Surprisingly, most disease\u2010associated ITPR1 mutations generate a loss of function. This leaves our understanding of ITPR1\u2010associated pathology oddly one\u2010sided, as little is known about the pathological consequences of ITPR1 gain of function (GOF). To this end, we generated an ITPR1 gating domain mutation (D2594K) that substantially enhanced the inositol trisphosphate\u00a0(IP<jats:sub>3<\/jats:sub>)\u2010sensitivity of ITPR1, and a mouse model expressing this ITPR1\u2010D2594K<jats:sup>+\/<\/jats:sup><jats:sup>\u2212<\/jats:sup> GOF mutation. We found that heterozygous ITPR1\u2010D2594K<jats:sup>+\/<\/jats:sup><jats:sup>\u2212<\/jats:sup> mutant mice exhibited male infertility, azoospermia, and acrosome loss. Furthermore, we functionally characterized a human ITPR1 variant V494I identified in the UK Biobank database as potentially associated with disorders of the testis. We found that the ITPR1\u2010V494I variant significantly enhanced IP<jats:sub>3<\/jats:sub>\u2010induced Ca<jats:sup>2+<\/jats:sup> release in HEK293 cells. Thus, ITPR1 hyperactivity may increase the risk of testicular dysfunction.<\/jats:p>","DOI":"10.1002\/jcp.30783","type":"journal-article","created":{"date-parts":[[2022,5,27]],"date-time":"2022-05-27T10:56:10Z","timestamp":1653648970000},"page":"3305-3316","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["A gain\u2010of\u2010function mutation in the ITPR1 gating domain causes male infertility in mice"],"prefix":"10.1002","volume":"237","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7830-132X","authenticated-orcid":false,"given":"Bo","family":"Sun","sequence":"first","affiliation":[{"name":"Department of Physiology and Pharmacology, Libin Cardiovascular Institute University of Calgary Calgary Alberta Canada"},{"name":"Laboratory of Molecular Pharmacology, Medical School Kunming University of Science and Technology Kunming 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