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

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.

Importance of SLC26 Transmembrane Anion Exchangers in Sperm Post-testicular Maturation and Fertilization Potential

“…As observed in the context of the sperm cells, although present within the epididymal ductus, SLC26A6 function seems to be dispensable for epididymal cytoarchitecture and functionality. Lastly, SLC26A8 protein was found absent from the epididymal tract (Kujala et al, 2007; Wedenoja et al, 2017; El Khouri et al, 2018) and rationally no epididymal phenotype was observed in the knock-out mice (Touré et al, 2007).…”

“…Among those, the CatSPER channel (cation channel sperm associated) is a multiprotein complex, which exclusively locates to the plasma membrane of the principal piece in human and mouse sperm flagellum, and mediates Ca 2+ influxes (Figure 4; see review Singh and Rajender, 2015). In consistence with their restricted expression and function during capacitation, mutations in some genes encoding for some of the above ionic transporters (CatSPER1, CatSPER2, SLC26A3, and SLC26A8) were associated with male infertility due to asthenozoospermia, a pathology defined by reduced or absence of sperm motility (Hildebrand et al, 2010; Ray et al, 2017; Wedenoja et al, 2017).…”

SLC26A3 inhibitor identified in small molecule screen blocks colonic fluid absorption and reduces constipation

“…Renal insufficiency is observed in ~25% of CLD subjects, although this likely results from delayed diagnosis and consequent chronic volume and salt depletion (15). SLC26A3 mutations are also associated with male subfertility, although available evidence suggests that impaired SLC26A3-CFTR interaction and consequent impaired CFTR activity are responsible (43). In general, with appropriate salt-replacement therapy, the long-term health in CLD is good, suggesting the absence of significant tumor and nongastrointestinal problems with SLC26A3 mutation (40).…”

Novel Human Polymorphisms Define a Key Role for the SLC26A6-STAS Domain in Protection From Ca2+-Oxalate Lithogenesis

“…As a result, human mutations within the STAS domain of many SLC26 family members can cause diseases (Rapp et al, 2017). For example, a specific STAS domain mutation in SLC26A3, which is associated with male subfertility, impairs SLC26A3 interaction with CFTR (Wedenoja et al, 2017). Another study showed that a specific SLC26A2-STAS mutation associated with the skeletal disease, diastrophic dysplasia, impairs SLC26A2 trafficking to the plasma membrane (Rapp et al, 2017).…”

“…This underscores the quintessential role that STAS plays in controlling SLC26 function and expression (Ko et al, 2004;Dorwart et al, 2008;Ohana et al, 2013;Geertsma et al, 2015). Remarkably, numerous human mutations were identified in the STAS domain of different SLC26 transporters causing many diseases including, diastrophic dysplasia (SLC26A2) (Cai et al, 2015), congenital chloride diarrhea (SLC26A3) (Dorwart et al, 2008), Pendred syndrome (SLC26A4) (Everett et al, 1997), and infertility (SLC26A8/A3) (Dirami et al, 2013;Rapp et al, 2017;Wedenoja et al, 2017). Notably, the Slc26a6/Nadc-1 complex was shown to control blood pressure by regulating succinate reabsorption at the proximal tubule, which, in turn, regulates the reninangiotensin system (Khamaysi et al, 2019).…”