Misprocessing of theCFTRprotein leads to mild cystic fibrosis phenotype

Abstract

Cystic fibrosis (CF) is mainly caused by mutations that interfere with the biosynthetic folding of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. The aim of this study was to determine the mechanism of dysfunction of a disease-causing mutation associated with variable phenotypes. In order to attain these objectives, we studied the effect of the p.L206W mutation on CFTR protein production and function, and we examined the genotype-phenotype correlation of [p.L206W]+[p.F508del] patients. We showed that p.L206W is a processing (class II) mutation since the CFTR biosynthetic pathway was severely impaired, whereas single-channel measurements indicated ion conductance similar to the wild-type protein. These data raise the larger question of the phenotypic variability of class II mutants, including p.F508del. Since multiple potential partners could modify the processing of the CFTR protein during its course to the cell surface, environmental and other genetic factors might contribute to this variability.

Cystic fibrosis carrier screening in a North American population

“…Clain et al 25 analyzed 36 clinical cases of CF patients who were compound heterozygous for L206W and a severe CF mutation. Twelve of the cases were from the authors' own data, whereas the other 24 cases were obtained from the literature.…”

LDL-cholesterol and insulin are independently associated with body mass index in adult cystic fibrosis patients

“…Numerous studies have shown a strong correlation between genotype and exocrine pancreatic function. They also showed that the milder mutation has a dominant phenotypic effect [9,10]. Thus, patients abhorring severe mutation on both alleles were classified as "severe" while patients having as least one allele associated with a milder phenotype were classified as "moderate to mild" (http://www.genet.…”

Functional Genomic Responses to Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) and CFTRΔ508 in the Lung

“…The severity of CF-related lung disease is highly variable, even among individuals bearing the same mutations, indicating that the disorder is influenced by complex, hereditary, and environmental factors (6,7). Similarly, marked variability in the severity of gastrointestinal and pulmonary disorders is observed among various strains of mice bearing CFTR mutations (8).…”