F508del
Summary
Most common cystic fibrosis mutation: a three-nucleotide deletion causing loss of phenylalanine at position 508 of CFTR. Results in misfolded protein degraded in the ER, with no functional channel reaching the apical membrane.
Detail
F508del (also written ΔF508) is a Class II CFTR mutation accounting for ~70% of CF alleles in Northern European populations. The misfolded CFTR is recognized by ER quality control and targeted for proteasomal degradation, so chloride and bicarbonate secretion at apical membranes of epithelial cells is severely impaired. This produces thick, dehydrated secretions causing recurrent sinopulmonary infections (Pseudomonas, S. aureus, Burkholderia), pancreatic insufficiency, meconium ileus, infertility (CBAVD in males), and elevated sweat chloride (>60 mEq/L). Modulator therapy targets the molecular defect: lumacaftor/tezafactor/elexacaftor (correctors) help trafficking, ivacaftor (potentiator) opens channels at the surface; triple therapy (Trikafta) dramatically improves outcomes in homozygous/heterozygous F508del patients.
Sources
- First Aid for USMLE Step 1 2024
- Robbins Basic Pathology 10th ed
- Sketchy Medical
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