Mutations in the Cystic Fibrosis Transmembrane Regulator Gene andIn VivoTransepithelial Potentials

Abstract

Aim: To examine the relationship between cystic fibrosis transmembrane regulator gene mutations (CFTR) and in vivo transepithelial potentials. Methods: We prospectively evaluated 162 men including 31 healthy subjects, 21 obligate heterozygotes, 60 with congenital bilateral absence of the vas deferens (CBAVD) and 50 with CF by extensive CFTR genotyping, sweat chloride and nasal potential difference testing. Results: Six (10%) men with CBAVD carried no CFTR mutations, 18 (30%) carried one mutation, including the 5T variant, and 36 (60%) carried mutations on both alleles, for a significantly higher rate carrying one or more mutations than healthy controls (90% versus 19%, p Ͻ 0.001). There was an overlapping spectrum of ion channel measurements among the men with CBAVD, ranging from values in the control and obligate heterozygote range at one extreme, to values in the CF range at the other. All pancreatic-sufficient patients with CF and 34 of 36 patients with CBAVD with mutations on both alleles carried at least one mild mutation. However, the distribution of mild mutations in the two groups differed greatly. Genotyping, sweat chloride and nasal potential difference (alone or in combination) excluded CF in all CBAVD men with no mutations. CF was confirmed in 56% and 67% of CBAVD men carrying 1 and 2 CFTR mutations, respectively. Conclusion: Abnormalities of CFTR transepithelial function correlate with the number and severity of CFTR gene mutations.Keywords: CFTR mutations; congenital bilateral absence of the vas deferens; cystic fibrosis; nasal potential difference; sweat chlorideThe heterogeneity of cystic fibrosis (CF) disease is partially explained by more than 1,300 different mutations in the CFTR gene (1). Most classically diagnosed patients with CF carry severe loss-of-function mutations on both alleles and have evidence of pancreatic insufficiency (PI) (2). Those with nonclassic CF carry a mild CFTR gene mutation on at least one allele, and usually retain sufficient residual pancreatic function to confer pancreatic sufficiency (PS) (3-6). Patients with PS are usually diagnosed in adolescence or adulthood with less severe symptoms and variable but generally milder pulmonary disease. Most men with CF are infertile due to obstructive azoospermia, which in its severest form presents as congenital bilateral absence of the vas deferens (CBAVD) (7-10). CBAVD also occurs in 1 to 2% of infertile males who are otherwise healthy, the majority of whom carry CFTR gene mutations on one or both alleles (11)(12)(13)(14)(15)(16)(17)(18)(19)(20). Typically, the CFTR genotype in men with CBAVD includes at least one "mild" missense or splice variant. Similar combinations of CFTR gene mutations have been observed in patients with other CFTRassociated phenotypes, including idiopathic chronic pancreatitis (21-23) and chronic sinusitis (24), but the frequency of gene mutations in these patients is lower than in men with CBAVD.The relation between the number and severity of CFTR gene mutations and the degree of CFTR-mediated dysfunc...

CFTR: A new horizon in the pathomechanism and treatment of pancreatitis

“…Thus, the more mild mutations are associated with increased risk of pancreatitis. Similar observations have been made in individuals with other CF-like phenotypes, such as men with infertility due to congenital bilateral absence of the vas deferens, who are known to carry a high frequency of CFTR mutations [51]. A relatively large population was examined and similar to the patients with idiopathic pancreatitis a wide range of electrophysiological abnormalities was observed.…”

The Cystic Fibrosis of Exocrine Pancreas

“…Similar observations have been made in individuals with other CF-like phenotypes, such as men with infertility caused by congenital bilateral absence of the vas deferens who are known to carry a high frequency of CFTRgene mutations (Wilschanski et al 2006). A relatively large population was examined, and similar to the patients with idiopathic pancreatitis, a wide range of electrophysiological abnormalities was observed.…”

Relationships among CFTR expression, HCO 3 − secretion, and host defense may inform gene- and cell-based cystic fibrosis therapies

“…One approach to answering this question is to study airway epithelia from people who are heterozygous for a CF-causing mutation (CF carriers). A few studies in humans and mice measured transepithelial voltage (Vt) across nasal epithelia before and during perfusion of a solution that is Cl − -free and contains an agent to increase cellular levels of cAMP to phosphorylate and activate CFTR (15)(16)(17)(18). Two reports also studied cultured mouse and human cells (17,18).…”