Abstract
Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause cystic fibrosis (CF) and are associated with congenital bilateral absence of the vas deferens (CBAVD), which is the major cause of infertility in male patients with CF. However, most Taiwanese patients with CBAVD do not carry major CFTR mutations. Some patients have a single copy deletion of the solute carrier family 9 isoform 3 (SLC9A3) gene. SLC9A3 is a Na+/H+ exchanger, and depleted Slc9a3 in male mice causes infertility due to the abnormal dilated lumen of the rete testis and efferent ductules. Furthermore, SLC9A3 interacts with CFTR in the pancreatic duct and functions as a genetic modifier of CF. However, SLC9A3 function and its relation to CFTR expression in the male reproductive tract in vivo remain elusive. In the present study, we found that CFTR expression was dramatically decreased in the epididymis and vas deferens of Slc9a3 knockout mice. Adult Slc9a3-/- mice showed not only significantly decreased epididymis and vas deferens weight but also increased testis weight. Furthermore, Slc9a3-/- mice developed obstructive azoospermia because of abnormal abundant secretions and calcification in the lumen of the reproductive tract. Ultrastructural analysis of the epithelium in Slc9a3–/–epididymis and vas deferens displayed disorganized and reduced number of stereocilia and numerous secretory apparatuses. Our data revealed that interdependence between SLC9A3 and CFTR is critical for maintaining a precise microenvironment in the epithelial cytoarchitecture of the male reproductive tract. The Slc9a3-deficient mice with impaired male excurrent ducts in this study provide proof for our clinical findings that some Taiwanese of CBAVD carry SLC9A3 deletion but without major CFTR mutations.
Highlights
Pathology of cystic fibrosis and congenital bilateral absence of the vas deferens Cystic fibrosis (CF), characterized by mutations in transmembrane conductance regulator (CFTR) gene, is the most common autosomal recessive disorder in Caucasians [1,2,3,4]
Most male patients with CF are infertile due to congenital bilateral absence of the vas deferens (CBAVD), which leads to obstructive azoospermia
We have identified a potential candidate, SLC9A3, of which a single copy is lost in Taiwanese patients with CBAVD
Summary
Pathology of cystic fibrosis and congenital bilateral absence of the vas deferens Cystic fibrosis (CF), characterized by mutations in transmembrane conductance regulator (CFTR) gene, is the most common autosomal recessive disorder in Caucasians [1,2,3,4]. CFTR is an apical membrane Cl- channel and is responsible for anion secretion in the lungs, pancreas, male reproductive tract, and other epithelial cells. Loss of CFTR activity causes dehydration of the apical membrane and impairs the clearance of mucus from the respiratory tract [5]. Most patients with congenital bilateral absence of the vas deferens (CBAVD) have mutations in and/ or susceptible variants of the 5T allele in intron 8 of CFTR [6,7,8]. We previously performed genome-wide mapping of copy-number variations through oligonucleotide arraybased comparative genomic hybridization (CGH) and identified loss of solute carrier family 9 isoform 3 (SLC9A3) allele in Taiwanese men with CBAVD (in two of seven Taiwanese men with CBAVD) [17]
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