CFTR — Cystic Fibrosis Transmembrane Conductance Regulator

Gene & Protein

CFTR is located on chromosome 7q31.2 and encodes a ~1,480 amino acid membrane glycoprotein that belongs to the ABC (ATP-binding cassette) transporter superfamily. It functions primarily as a cAMP-regulated anion (Cl⁻/HCO₃⁻) channel on the apical (luminal) plasma membrane of epithelial cells, regulating the volume and composition of exocrine secretions (Harrison's, p. 8006).

Protein domains:

Domain	Function
2× Membrane-spanning domains (MSD1, MSD2)	Form the ion channel pore
2× Nucleotide-binding domains (NBD1, NBD2)	Bind/hydrolyze ATP; gate the channel
Regulatory (R) domain	PKA phosphorylation site; required for activation

Mutation Classes

Six functional classes of CFTR mutations are recognized, each disrupting the protein at a different step:

Six classes of CFTR mutations in an epithelial cell

Class	Defect	Example Mutation	Result
I	No protein synthesis	G542X, W1282X (nonsense/frameshift)	Absent CFTR
II	Misfolding → proteasomal degradation	F508del (most common, ~70% of alleles)	No surface CFTR
III	Reaches membrane but gating defect	G551D	Non-functional channel
IV	Reduced conductance through pore	R117H	Partial function
V	Reduced transcription/splicing	3849+10kbC→T	Low but functional CFTR
VI	Reduced stability at cell surface	4326delTC	Accelerated degradation

(Harrison's, p. 8014)

Pathophysiology in Cystic Fibrosis (CF)

CF is autosomal recessive — two defective CFTR alleles required. Loss of CFTR function leads to:

Airways: Impaired Cl⁻/HCO₃⁻ secretion + hyperactive ENaC (Na⁺ absorption) → dehydrated, viscous mucus → mucus plugging, chronic bacterial infection (Pseudomonas aeruginosa, S. aureus) → bronchiectasis
Pancreas: Ductal obstruction → exocrine insufficiency (malabsorption, fat-soluble vitamin deficiency), endocrine failure (CF-related diabetes, CFRD)
Liver: Inspissated bile → focal biliary cirrhosis
Sweat glands: Failure to reabsorb Cl⁻ → elevated sweat chloride (diagnostic hallmark, >60 mmol/L)
Reproductive tract: Congenital bilateral absence of vas deferens (CBAVD) in males; reduced fertility in females

Diagnosis

Test	Finding in CF
Newborn screen	Elevated immunoreactive trypsinogen (IRT), followed by DNA analysis
Sweat chloride	≥60 mmol/L (diagnostic); 40–59 borderline
CFTR mutation analysis	Identifies pathogenic variants on both alleles
Nasal potential difference	Functional CFTR assay; used in borderline cases

CFTR Modulator Therapy

Modern small-molecule modulators target specific defect classes:

Drug Class	Mechanism	Agent(s)	Target Mutation(s)
Potentiators	Improve gating of surface CFTR	Ivacaftor (VX-770)	Class III (G551D, etc.)
Correctors	Rescue misfolded protein trafficking	Lumacaftor, Tezacaftor, Elexacaftor	Class II (F508del)
Combination	Corrector(s) + potentiator	Elexacaftor/tezacaftor/ivacaftor (ETI, Trikafta)	F508del (one or two alleles); most CF patients eligible
Read-through agents (investigational)	Suppress premature stop codons	Ataluren	Class I

Elexacaftor/tezacaftor/ivacaftor (ETI) is now the standard of care for eligible patients (~90% of CF patients), producing ~10-point improvements in ppFEV₁ and dramatic reductions in pulmonary exacerbations.

Key Clinical Points

F508del accounts for ~70% of mutant alleles worldwide; homozygous F508del is the most common CF genotype
Disease severity correlates imperfectly with genotype — modifier genes and environment matter
CFTR is also expressed in the gut, liver, reproductive tract, and sweat glands, explaining the multi-organ phenotype
CBAVD without lung disease can be caused by milder CFTR variants (e.g., 5T allele) — CFTR testing is part of male infertility workup
Pancreatic-sufficient patients (Classes IV/V) generally have better pulmonary prognosis and slower lung decline

CFTR

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CFTR — Quick Reference

Cystic Fibrosis Transmembrane Conductance Regulator is a cAMP-activated Cl⁻/HCO₃⁻ anion channel on the apical surface of epithelial cells. Loss-of-function mutations (autosomal recessive) cause cystic fibrosis (CF).

Mutation Classes (Harrison's, p. 8014)

Class	Defect	Prototype
I	No synthesis	G542X
II	Misfolding/degradation	F508del (~70% of alleles)
III	Gating failure at membrane	G551D
IV	Reduced conductance	R117H
V	Reduced transcripts	3849+10kbC→T
VI	Accelerated turnover	4326delTC

End-Organ Effects of CFTR Dysfunction

Lungs: Dehydrated mucus → chronic Pseudomonas infection → bronchiectasis (see below)
Pancreas: Exocrine insufficiency, CFRD
Liver: Focal biliary cirrhosis
Sweat glands: Elevated sweat Cl⁻ (≥60 mmol/L — diagnostic)
Male reproductive: CBAVD → infertility

Gross lung specimen in end-stage CF showing cystic bronchiectasis with purulent secretions filling dilated bronchi

CFTR Modulators (Harrison's, p. 8017)

Agent(s)	Class	Mechanism	Eligible Genotype
Ivacaftor	Potentiator	Increases channel open probability	Class III (G551D, etc.)
Lumacaftor/tezacaftor + ivacaftor	Corrector + potentiator	Rescues F508del trafficking	Homozygous F508del
Elexacaftor/tezacaftor/ivacaftor (ETI, Trikafta)	Next-gen corrector + potentiator	Dual corrector mechanism + gating	≥1 F508del allele; >90% of CF patients

ETI is the current standard of care, yielding ~10-point ppFEV₁ gains and major reductions in exacerbations.

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