The cystic fibrosis transmembrane conductance regulator (CFTR) is present in mature sperm and is required for sperm motility and capacitation. Both these processes are controlled by ions fluxes and are essential for fertilization. We have shown that SLC26A8, a sperm-specific member of the SLC26 family of anion exchangers, associates with the CFTR channel and strongly stimulates its activity. This suggests that the two proteins cooperate to regulate the anion fluxes required for correct sperm motility and capacitation. Here, we report on three heterozygous SLC26A8 missense mutations identified in a cohort of 146 men presenting with asthenozoospermia: c.260G>A (p.Arg87Gln), c.2434G>A (p.Glu812Lys), and c.2860C>T (p.Arg954Cys). These mutations were not present in 121 controls matched for ethnicity, and statistical analysis on a control population of 8,600 individuals (from dbSNP and 1000 Genomes) showed them to be associated with asthenozoospermia with a power > 95%. By cotransfecting Chinese hamster ovary (CHO)-K1 cells with SLC26A8 variants and CFTR, we showed that the physical interaction between the two proteins was partly conserved but that the capacity to activate CFTR-dependent anion transport was completely abolished for all mutants. Biochemical studies revealed the presence of much smaller amounts of protein for all variants, but these amounts were restored to wild-type levels upon treatment with the proteasome inhibitor MG132. Immunocytochemistry also showed the amounts of SLC26A8 in sperm to be abnormally small in individuals carrying the mutations. These mutations might therefore impair formation of the SLC26A8-CFTR complex, principally by affecting SLC26A8 stability, consistent with an impairment of CFTR-dependent sperm-activation events in affected individuals.
Background: Cystic fibrosis (CF) can be revealed during fetal life by diverse ultrasound digestive abnormalities (USDA) such as fetal echogenic bowel or fetal intestinal loop dilatation, nonvisualization of the fetal gallbladder (NVFGB) being rarely observed in isolation. Only 6 cases of CF revealed by isolated NVFGB have been reported so far in the literature. Furthermore, recent studies suggested that this sign is of poor predictive value for CF. Methods: We report on the results of a 6-year French tricenter study on 1,124 cases of fetal USDA for whom a comprehensive molecular study was performed for CF. Results: Among the 37 CF fetuses, 5 (13.5%) presented with isolated NVFGB at ultrasound (US) examination at 24–31 weeks of gestation. This sign was more frequently observed in CF fetuses than in non-CF fetuses, with a likelihood ratio of 2.7. The genotypes included three c.1521_1523del (F508del) homozygous cases and two compound heterozygous cases for a frequent and a rare CF-causing variant. Discussion: These observations highlight the importance to report on the presence and aspect of the fetal gallbladder at the second trimester US scan and to consider prenatal CFTR molecular analysis in cases of isolated NVFGB.
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