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

Scientific Reports
Satu WedenojaJ Kere

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 reta...Continue Reading

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Citations

Feb 7, 2020·Human Genetics·Eric BiethRoger Mieusset
Jun 6, 2019·Cellular and Molecular Life Sciences : CMLS·Raquel L BernardinoPedro F Oliveira
Nov 21, 2020·Nature Reviews. Urology·Huafeng WangJean-Ju Chung
Mar 27, 2021·Journal of Crohn's & Colitis·Lorenzo NorsaFrank M Ruemmele

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Methods Mentioned

BETA
Exome Sequencing
co-immunoprecipitation
immunoprecipitation
transfection
Protein Assay

Software Mentioned

Robetta
NIS elements
PyMol
PolyPhen

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