How do CFTR mutations cause cystic fibrosis (CF)?

Updated: Oct 22, 2019
  • Author: Girish D Sharma, MD, FCCP, FAAP; Chief Editor: Kenan Haver, MD  more...
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CFTR mutations result in abnormalities of cAMP-regulated chloride transport across epithelial cells on mucosal surfaces. The failure of chloride conductance by epithelial cells and associated water transport abnormalities result in viscid secretions in the respiratory tract, pancreas, GI tract, sweat glands, and other exocrine tissues. Increased viscosity of these secretions makes them difficult to clear.

Genotype-phenotype correlation demonstrates that ΔF508 homozygosity nearly always confers a pancreatic exocrine insufficiency. Individuals with 1 or 2 copies of missense mutations (eg, R117H) tend to be pancreatic sufficient and have milder disease.

The incidence of meconium ileus is higher in patients who are homozygous for ΔF508 or who have ΔF508 plus G542X. Conversely, not all patients with these genotypes have meconium ileus, so other non -CFTR factors must be involved in meconium ileus pathogenesis.

The incomplete correlation of genotype with phenotype suggests either an environmental component of organ dysfunction or modifying genes that are only recently being characterized. [14] The role of modifier genes is supported by the fact that neonates with cystic fibrosis who have intestinal obstruction most commonly have abnormalities in 2 or more CFTR modifier genes. In contrast, older children develop obstruction mostly as a result of environmental factors, such as introduction of pancreatic enzymes causing a stricture. [15, 16]

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