University of Oulu

Wedenoja, S., Khamaysi, A., Shimshilashvili, L., Anbtawe-Jomaa, S., Elomaa, O., Toppari, J., Höglund, P., Aittomäki, K., Holmberg, C., Hovatta, O., Tapanainen, J., Ohana, E., Kere, J. (2017) A missense mutation in SLC26A3 is associated with human male subfertility and impaired activation of CFTR. Scientific Reports, 7 (1). doi:10.1038/s41598-017-14606-3

A missense mutation in SLC26A3 is associated with human male subfertility and impaired activation of CFTR

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Author: Wedenoja, Satu1; Khamaysi, Ahlam2; Shimshilashvili, Liana2;
Organizations: 1Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital
2Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev
3Folkhälsan Institute of Genetics, and Molecular Neurology Research Program, University of Helsinki
4Department of Physiology, Institute of Biomedicine, University of Turku
5City of Kauniainen, Health Care Services
6HUSLAB, Laboratory of Genetics, Helsinki University Hospital, and Genome-Scale Biology research program, University of Helsinki
7Hospital for Children and Adolescents, University of Helsinki and Helsinki University Hospital
8Department of Clinical Science, Karolinska Institutet
9Obstetrics and Gynecology, University of Oulu and Oulu University Hospital
10Department of Biosciences and Nutrition, Karolinska Institutet
11Department of Medical & Molecular Genetics, King’s College London
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 1.8 MB)
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Language: English
Published: Springer Nature, 2017
Publish Date: 2018-01-10


Chloride absorption and bicarbonate excretion through exchange by the solute carrier family 26 member 3 (SLC26A3) and cystic fibrosis transmembrane conductance regulator (CFTR) are crucial for many tissues including sperm and epithelia of the male reproductive tract. Homozygous SLC26A3 mutations cause congenital chloride diarrhea with male subfertility, while homozygous CFTR mutations cause cystic fibrosis with male infertility. Some homozygous or heterozygous CFTR mutations only manifest as male infertility. Accordingly, we studied the influence of SLC26A3 on idiopathic infertility by sequencing exons of SLC26A3 in 283 infertile and 211 control men. A heterozygous mutation c.2062 G > C (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 (P < 0.05) and over 120,000 global alleles (P < 0.0001) (ExAC database). Functional studies showed that while SLC26A3 is a strong activator of CFTR-dependent anion transport, SLC26A3-p.Asp688His mutant retains normal Cl⁻/HCO₃⁻ exchange activity but suppresses CFTR, despite unaffected domain binding and expression. These results suggest a novel mechanism for human male infertility─impaired anion transport by the coupled SLC26A3 and CFTR.

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Series: Scientific reports
ISSN: 2045-2322
ISSN-E: 2045-2322
ISSN-L: 2045-2322
Volume: 7
Issue: 1
Article number: 14208
DOI: 10.1038/s41598-017-14606-3
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
1184 Genetics, developmental biology, physiology
Funding: This work was supported by grants from the Finnish Medical Foundation (to S.W.), Sigrid Jusélius Foundation (to J.K., J.S.T., J.T.), Academy of Finland (J.S.T., J.T.), and by the ISRAEL SCIENCE FOUNDATION (grants 271/16 and 2164/16 to E.O). J.K. is a recipient of The Royal Society Wolfson Research Merit Award.
Copyright information: © The Author(s) 2017. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.