Severe deficiency of cystic fibrosis transmembrane conductance regulator messenger RNA carrying nonsense mutations R553X and W1316X in respiratory epithelial cells of patients with cystic fibrosis.

Abstract

Cystic fibrosis (CF) is the most common, lethal inherited disorder in the Caucasian population. We have recently reported two African-American patients with nonsense mutations in each CF gene and severe pancreatic disease, but mild pulmonary disease. In order to examine the effect of these nonsense mutations on CF gene expression, bronchial and nasal epithelial cells were obtained from one of these patients (no. 246), a compound heterozygote for nonsense mutations R553X and W1316X; a healthy normal individual; a patient (no. 528) homozygous for the common CF mutation (AF508); and a CF patient (no. 272) who carries the R553X mutation and a missense mutation, S549N. When mRNA from bronchial cells of the normal individual, the AF508 homozygote, and the S549N/

Determinants of mild clinical symptoms in cystic fibrosis patients. Residual chloride secretion measured in rectal biopsies in relation to the genotype.

“…Since in other stop codon mutants no CFTR mRNA was detectable (42), the residual chloride secretion in the two homozygous G542X patients most likely results from compensatory non-CF-affected chloride channel species (26) in the apical membrane, rather than from the presence of some functional CFTR.…”

Assessing the Disease-Liability of Mutations in CFTR

“…PTC mutations generally cause the loss of messenger RNA because of nonsense-mediated RNA decay (NMRD) (Frischmeyer and Dietz 1999). Mutations in CFTR including G542X, R553X ( p.Arg553X), and W1282X have been shown to lead to NMRD in primary airway cells (Hamosh et al 1991(Hamosh et al , 1992bWill et al 1995). There are a few exceptions to the concept that PTC mutations cause NMRD.…”

Novel pharmacologic therapies for cystic fibrosis

“…Attempts have been made to estimate severity of disease based on mRNA transcript level (48); however, strict correlations between mRNA transcript level and a functional CFTR protein at the cell surface cannot be made. Nevertheless, the clinical phenotype seen with Class IV mutations suggests that treatments aimed at promoting CFTR trafficking and activating or increasing chloride conductance would tend to support a milder course.…”