Abstract
The pathogenic variant Phe508del of the CFTR-gene is the most frequent cause of cystic fibrosis (CF). Whereas male CF-patients are infertile due to bilateral agenesis of the efferent ducts, the fertility status of male heterozygous carriers is uncertain. We aimed at demonstrating the involvement of the CFTR-ion channel during sperm capacitation and to potentially select variant-free spermatozoa in heterozygous carriers of the CFTR-variant using flow cytometry (FC). Using FC and sorting, single cell polymerase chain reaction, immuno-fluorescent staining an experimental study was performed on nine fertile semen donors and three heterozygous infertile men carrying the Phe508del gene variant. Chemical inhibition of CFTR interfered with sperm capacitation. Most viable spermatozoa of heterozygous carriers of the Phe508del variant of the CFTR-gene show immune-fluorescent CFTR. Sperm capacitation in Phe508del carriers was similar to that in healthy semen donors. Distribution of the Phe508del allele in trio data of CF-affected families corresponded to the expected recessive inheritance pattern. Infertility in Phe508del heterozygous men is unlikely to be caused by the pathogenic variant although some contribution cannot be excluded. Normal sperm capacitation in carriers of pathogenic variants of the Phe508del-gene may in part explain the high prevalence of a potentially lethal recessive disorder.
Highlights
The pathogenic variant Phe508del of the CFTR-gene is the most frequent cause of cystic fibrosis (CF)
The pathogenic variant Phe508del represents a deletion of 3 base pairs resulting in the loss of codon 508 encoding phenylalanine and in consequence in altered phosphoregulation of the CFTR-protein resulting in the increased retention of p.Phe508del in the endocytoplasmic reticulum, in rapid degradation at the cell surface and in reduced recycling of p.Phe508del to the cell surface[8]
Male CF patients are infertile presenting with obstructive azoospermia due to congenital bilateral absence of the efferent ducts (CBAVD)[9]
Summary
The pathogenic variant Phe508del of the CFTR-gene is the most frequent cause of cystic fibrosis (CF). We aimed at demonstrating the involvement of the CFTR-ion channel during sperm capacitation and to potentially select variant-free spermatozoa in heterozygous carriers of the CFTR-variant using flow cytometry (FC). Normal sperm capacitation in carriers of pathogenic variants of the Phe508del-gene may in part explain the high prevalence of a potentially lethal recessive disorder. Conflicting reports have been published with respect to the fertility of heterozygous male individuals carrying one or more pathogenic variants of the CFTR-gene[14–16] (for review see[17]). We aimed at demonstrating the involvement of the CFTR-ion channel during capacitation of human spermatozoa and, if so, at selecting pathogenic variantfree spermatozoa in infertile men heterozygous for the Phe508del, that can be used in assisted reproduction
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