Cystic Fibrosis: CFTR Mutation & Ion Transport Defect
Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in the CFTR gene (chromosome 7q31.2), encoding the cystic fibrosis transmembrane conductance regulator protein.
Normal CFTR Function
- cAMP-activated Cl⁻ channel in apical membrane of epithelial cells
- Regulates Cl⁻ secretion and inhibits ENaC (epithelial Na⁺ channel) → limits Na⁺ absorption
- Net effect: luminal hydration via osmotic water flow
- Also transports HCO₃⁻ (bicarbonate) → critical for mucus pH, viscosity
Organ-Specific Consequences of CFTR Dysfunction
| Organ | Defect | Clinical Manifestation |
|---|---|---|
| Airways | ↓ Cl⁻ secretion, ↑ Na⁺ absorption → dehydrated ASL | Thick mucus, impaired mucociliary clearance, chronic infection (P. aeruginosa, S. aureus), bronchiectasis |
| Pancreas | ↓ HCO₃⁻ secretion → acidic, viscous secretions | Ductal plugging, autodigestion, pancreatic insufficiency (85%), diabetes (CFRD) |
| Intestine | Dehydrated luminal contents | Meconium ileus (newborns), DIOS, intussusception, constipation |
| Sweat glands | ↓ Cl⁻ reabsorption in duct | High sweat [Cl⁻] (>60 mmol/L) = diagnostic |
| Vas deferens | Developmental absence (CBAVD) | Male infertility (98%) |
| Liver/biliary | Inspissated bile | Focal biliary cirrhosis, gallstones |