Genetics of CFTR and male infertility

Abstract

Cystic fibrosis (CF) is a rare autosomal-recessive disorder manifested as multisystem organ dysfunction. The cystic fibrosis transmembrane conductance regulator (CFTR) protein functions as an ion transporter on the epithelium of exocrine glands, regulating secretion viscosity. The CFTR gene, encoded on chromosome 7, is required for the production and trafficking of the intact and functional CFTR protein.Literally thousands of human CFTR allelic mutations have been identified, each with varying impact on protein quality and quantity. As a result, individuals harboring CFTR mutations present with a spectrum of symptoms ranging from CF to normal phenotypes. Those with loss of function but without full CF may present with CFTR-related disorders (CFTR-RDs) including male infertility, sinusitis, pancreatitis, atypical asthma and bronchitis. Studies have demonstrated associations between higher rates of CFTR mutations and oligospermia, epididymal obstruction, congenital bilateral absence of the vas deferens (CBAVD), and idiopathic ejaculatory duct obstruction (EDO). Genetic variants are detected in over three-quarters of men with CBAVD, the reproductive abnormality most classically associated with CFTR aberrations. Likewise, nearly all men with clinical CF will have CBAVD. Current guidelines from multiple groups recommend CFTR screening in all men with clinical CF or CBAVD though a consensus on the minimum number of variants for which to test is lacking. CFTR testing is not recommended as routine screening for men with other categories of infertility. While available CFTR panels include 30 to 96 of the most common variants, complete gene sequencing should be considered if there is a high index of suspicion in a high-risk couple (e.g., partner is CFTR mutation carrier). CF treatments to date have largely targeted end-organ complications.Novel CFTR-modulator treatments aim to directly target CFTR protein dysfunction, effectively circumventing downstream complications, and possibly preventing symptoms like vasal atresia at a young age. Future gene therapies may also hold promise in preventing or reversing genetic changes that lead to CF and CFTR-RD.

Differential Diagnosis of Azoospermia in Men with Infertility

“…Cystic fibrosis transmembrane conductance regulator gene mutations usually result in CBAVD and, consequently, the affected patients have OA [ 12 , 55 ]. Over 2000 mutations have been discovered in the CFTR gene [ 56 ].…”

Translational aspects of novel findings in genetics of male infertility—status quo 2021

“… 14 Diagnostic yield of genetic tests of CBAVD/OA is high, >80% in bilateral and >30% in unilateral cases ( Table 1 ). 14 , 15 CBAVD/OA does not usually affect the process of spermatogenesis. Clinical management of most cases uses TESE-ICSI with reported live-birth rates ~18–36%.…”

“… 13 , 14 CFTR is characterized by high allelic heterogeneity and broad phenotypic expressivity of pathogenic variants ranging from classic cystic fibrosis (CF) with the lung and pancreatic phenotype to cases with only seminal duct obstruction. 15 Proper genetic diagnosis is important as some men with the primary diagnosis of CFTR -related male reproductive disorders may also express mild CF symptoms, such as recurrent respiratory tract or pancreatic infections. 14 Diagnostic yield of genetic tests of CBAVD/OA is high, >80% in bilateral and >30% in unilateral cases ( Table 1 ).…”

New insights into CFTR modulation in reproduction: testicular microenvironment imbalance leads to over-activated caspase signalling in spermatogenesis and adversely affects fertility

“…A well-configured CFTR behaves as a cyclic AMP-triggered ion channel, participating in bicarbonate and chloride exchange, generating a water current, and reducing the viscous secretions in various organ systems. Secreting viscous substances is a vital physiological function of the lungs, exocrine pancreas, gastrointestinal system, and male reproductive tract ( Bieniek et al ., 2021 ). Loss of CFTR function leads to intrinsic inflammation, dehydration, and impaired mucus clearance from the respiratory airway and reproductive duct, leading to cystic fibrosis (CF) and the absence of vas deferens ( Caballero et al ., 2020 ).…”