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

Satu Wedenoja; Ahlam Khamaysi; Liana Shimshilashvili; Shireen Anbtawe-Jomaa; Outi Elomaa; Jorma Toppari; Pia Höglund; Kristiina Aittomäki; Christer Holmberg; Outi Hovatta; Juha S Tapanainen; Ehud Ohana; Juha Kere

doi:10.1038/s41598-017-14606-3

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

Sci Rep. 2017 Oct 27;7(1):14208. doi: 10.1038/s41598-017-14606-3.

Authors

Satu Wedenoja¹, Ahlam Khamaysi², Liana Shimshilashvili², Shireen Anbtawe-Jomaa², Outi Elomaa³, Jorma Toppari⁴, Pia Höglund⁵, Kristiina Aittomäki⁶, Christer Holmberg⁷, Outi Hovatta⁸, Juha S Tapanainen^{9

10}, Ehud Ohana¹¹, Juha Kere^{3

12

13}

Affiliations

¹ Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, FI-00014, Helsinki, Finland. satu.wedenoja@helsinki.fi.
² Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
³ Folkhälsan Institute of Genetics, and Molecular Neurology Research Program, University of Helsinki, FI-00014, Helsinki, Finland.
⁴ Department of Physiology, Institute of Biomedicine, University of Turku, and Department of Pediatrics, Turku University Hospital, FI-20014, Turku, Finland.
⁵ City of Kauniainen, Health Care Services, FI-02700, Kauniainen, Finland.
⁶ HUSLAB, Laboratory of Genetics, Helsinki University Hospital, and Genome-Scale Biology research program, University of Helsinki, FI-00029, Helsinki, Finland.
⁷ Hospital for Children and Adolescents, University of Helsinki and Helsinki University Hospital, FI-00014, Helsinki, Finland.
⁸ Department of Clinical Science, Karolinska Institutet, SE-17177, Stockholm, Sweden.
⁹ Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, FI-00014, Helsinki, Finland.
¹⁰ Obstetrics and Gynecology, University of Oulu and Oulu University Hospital, FI-90220, Oulu, Finland.
¹¹ Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel. ohanaeh@bgu.ac.il.
¹² Department of Biosciences and Nutrition, Karolinska Institutet, SE-14183, Huddinge, Sweden.
¹³ Department of Medical & Molecular Genetics, King's College London, London, SE1 9RT, England.

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Sequence
Chloride-Bicarbonate Antiporters / chemistry
Chloride-Bicarbonate Antiporters / genetics*
Cystic Fibrosis Transmembrane Conductance Regulator / metabolism*
Heterozygote
Humans
Infertility, Male / genetics*
Male
Models, Molecular
Mutation, Missense*
Protein Conformation
Sulfate Transporters / chemistry
Sulfate Transporters / genetics*

Substances

CFTR protein, human
Chloride-Bicarbonate Antiporters
SLC26A3 protein, human
Sulfate Transporters
Cystic Fibrosis Transmembrane Conductance Regulator