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.
Highlights
15% of couples face infertility, to which male factor is a major contributor in 30–40% of the cases[1]
A compromised function of the SLC26 family members is associated with the primary defect of cystic fibrosis (CF [MIM: 219700])—impaired Cl− absorption in conjunction with aberrant HCO3− and fluid secretion—through the inability of CFTR mutants to activate the Cl−/HCO3− exchange mediated by the SLC26 family members, most notably SLC26A3 and/or SLC26A614,15,24–27
Either one or two CFTR mutations appear in approximately 80% of the congenital bilateral absence of the vas deferens (CBAVD) cases without CF, and non-CBAVD related male infertility with reduced sperm quality is associated with homozygosity or heterozygosity for less-pathogenic CFTR mutations[29,30,31,32,33,34,35,36]
Summary
15% of couples face infertility, to which male factor is a major contributor in 30–40% of the cases[1]. A rare autosomal recessive disorder with male subfertility is congenital chloride diarrhea (CLD [MIM: 214700]) It is caused by homozygous or compound heterozygous mutations in the solute carrier family 26 member 3 (SLC26A3 alias DRA) gene (MIM: 126650) which disrupt the apical epithelial Cl− absorption and HCO3− secretion in the intestinal epithelia and at multiple sites of the male reproductive tract[4,5,6,7]. A shortened tract of five thymines (5 T) on the splicing region of intron 8 (IVS8) of CFTR explains up to 40% of CBAVD cases without CF, and due to its incomplete penetrance, appears in healthy individuals or in patients with non-classic CF30,32,37–39 The importance of both CFTR and SLC26A3 functions in the physiology of male fertility is supported by their molecular interaction, by the male infertility phenotypes of CF and CLD, and by their role in rodent sperm motility and capacitation[11,12,13]. These findings prompted us to study whether SLC26A3 variants are associated with idiopathic male infertility, similar to CFTR variants that cause male infertility without CF
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