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A synonymous codon change alters the drug sensitivity of ΔF508 cystic fibrosis transmembrane conductance regulator

Vedrana Bali1, Ahmed Lazrak1, Purushotham Guroji1

  • 1*Department of Cell, Developmental, and Integrative Biology, Department of Anesthesiology and Perioperative Medicine, The Lung Injury and Repair Research Center, and The Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, Alabama, USA.

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
|September 5, 2015
PubMed

Insights

Synonymous mutations in cystic fibrosis transmembrane conductance regulator (CFTR) can alter drug sensitivity. Combining corrector 4a (C4) and lumacaftor (VX-809) enhanced correction of ΔF508 CFTR variants, suggesting specific binding mechanisms.

Area of Science:

  • Molecular biology
  • Biochemistry
  • Genetics

Background:

  • The most common cystic fibrosis mutation, ΔF508 CFTR, involves deletion of Phe508.
  • Synonymous mutations can influence protein biogenesis, structure, and function, potentially altering disease phenotype.
  • Small-molecule drugs are being developed to correct ΔF508 CFTR function.

Purpose of the Study:

  • To investigate the effects of distinct correctors, corrector 4a (C4) and lumacaftor (VX-809), on the biogenesis and function of ΔF508 CFTR variants with synonymous mutations (I507-ATT and I507-ATC).
  • To understand the mechanisms of CFTR corrector drugs and the impact of synonymous mutations on drug sensitivity.

Main Methods:

  • Analysis of ΔF508 CFTR variants (I507-ATT and I507-ATC) treated with C4 and/or VX-809.
  • Biochemical assessment of protein correction and stability (Band B).
  • Functional assessment using whole-cell currents activated by forskolin and IBMX.

Main Results:

  • C4 alone stabilized I507-ATT ΔF508 CFTR but showed limited correction.
  • VX-809 provided modest biochemical correction (~10%) and functional rescue for both variants, with evidence of posttranslational stabilization.
  • Combination therapy (C4+VX-809) significantly enhanced correction and function (2-fold increase) for both I507-ATT and I507-ATC ΔF508 CFTR compared to VX-809 alone.
  • C4 showed an additive effect with VX-809 on I507-ATC, suggesting it acts on VX-809-modified CFTR.

Conclusions:

  • The binding of C4 and VX-809 to ΔF508 CFTR is conformation-specific.
  • Synonymous mutations can indeed alter the sensitivity of CFTR variants to corrector drugs.
  • Combined therapy offers enhanced therapeutic potential for specific CFTR mutations.

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