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Homozygous<jats:italic>SLC26A3<\/jats:italic>mutations cause congenital chloride diarrhea with male subfertility, while homozygous<jats:italic>CFTR<\/jats:italic>mutations cause cystic fibrosis with male infertility. Some homozygous or heterozygous<jats:italic>CFTR<\/jats:italic>mutations only manifest as male infertility. Accordingly, we studied the influence of<jats:italic>SLC26A3<\/jats:italic>on idiopathic infertility by sequencing exons of<jats:italic>SLC26A3<\/jats:italic>in 283 infertile and 211 control men. A heterozygous mutation c.2062\u2009G\u2009&gt;\u2009C (p.Asp688His) appeared in nine (3.2%) infertile men, and additionally, in two (0.9%) control men, whose samples revealed a sperm motility defect. The p.Asp688His mutation is localized in the CFTR-interacting STAS domain of SLC26A3 and enriched in Finland, showing a significant association with male infertility in comparison with 6,572 Finnish (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.05) and over 120,000 global alleles (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.0001) (ExAC database). Functional studies showed that while SLC26A3 is a strong activator of CFTR-dependent anion transport, SLC26A3-p.Asp688His mutant retains normal Cl<jats:sup>\u2212<\/jats:sup>\/HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup>exchange activity but suppresses CFTR, despite unaffected domain binding and expression. These results suggest a novel mechanism for human male infertility\u2500impaired anion transport by the coupled SLC26A3 and CFTR.<\/jats:p>","DOI":"10.1038\/s41598-017-14606-3","type":"journal-article","created":{"date-parts":[[2017,10,23]],"date-time":"2017-10-23T16:16:44Z","timestamp":1508775404000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["A missense mutation in SLC26A3 is associated with human male subfertility and impaired activation of CFTR"],"prefix":"10.1038","volume":"7","author":[{"given":"Satu","family":"Wedenoja","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahlam","family":"Khamaysi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liana","family":"Shimshilashvili","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shireen","family":"Anbtawe-Jomaa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Outi","family":"Elomaa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2228-334X","authenticated-orcid":false,"given":"Jorma","family":"Toppari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pia","family":"H\u00f6glund","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristiina","family":"Aittom\u00e4ki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christer","family":"Holmberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5395-3807","authenticated-orcid":false,"given":"Outi","family":"Hovatta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juha S.","family":"Tapanainen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ehud","family":"Ohana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1974-0271","authenticated-orcid":false,"given":"Juha","family":"Kere","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,10,27]]},"reference":[{"key":"14606_CR1","unstructured":"Rowe, P., Compare, F., Hargreaves, T. & Mahmoud, A. 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