• PMID: 23582645
• Gene Name: SLC26A8
• Condition: Asthenozoospermia
• Association: Associated
• Mutation: c.260G>A (p.Arg87Gln), c.2434G>A (p.Glu812Lys), and c.2860C>T (p.Arg954Cys)
• Population size: 267
• Population details: 267 (146 men presenting with asthenozoospermia, 121 controls)
• Sex: Male
• Infertility type: Male infertility
• Other associated phenotypes: Asthenozoospermia

Missense mutations in SLC26A8, encoding a sperm-specific activator of CFTR, are associated with human asthenozoospermia

Dirami T, Rode B, Jollivet M, Da Silva N, Escalier D, Gaitch N, Norez C, Tuffery P, Wolf JP, Becq F, Ray PF, Dulioust E, Gacon G, Bienvenu T, Touré A.

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. CI - Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved. FAU - Dirami, Thassadite AU - Dirami T AD - Institut National de la Santé et de la Recherche Médicale U1016, Institut Cochin, 75014 Paris, France. FAU - Rode, Baptiste AU - Rode B FAU - Jollivet, Mathilde AU - Jollivet M FAU - Da Silva, Nathalie AU - Da Silva N FAU - Escalier, Denise AU - Escalier D FAU - Gaitch, Natacha AU - Gaitch N FAU - Norez, Caroline AU - Norez C FAU - Tuffery, Pierre AU - Tuffery P FAU - Wolf, Jean-Philippe AU - Wolf JP FAU - Becq, Frédéric AU - Becq F FAU - Ray, Pierre F AU - Ray PF FAU - Dulioust, Emmanuel AU - Dulioust E FAU - Gacon, Gérard AU - Gacon G FAU - Bienvenu, Thierry AU - Bienvenu T