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Different Effects of CFTR Activity: "Little to no" vs "residual" CFTR activity

The degree to which a CFTR mutation reduces CFTR quantity or function (or both) at the cell surface determines the total CFTR activity of the cell. A mutation can affect the components of CFTR protein activity (e.g., quantity, open probability, conductance) to varying degrees of severity; this affects the extent to which total CFTR activity is reduced.1,2

CFTR mutations that result in little to no total CFTR activity

Severe reduction in CFTR protein quantity or function results in little to no CFTR activity

Little to no CFTR quantity

Severe reduction in CFTR protein quantity or function results in little to no CFTR activity

Little to no CFTR function

Some CFTR mutations reduce CFTR protein quantity or function at the cell surface to such an extent that the result is little to no total CFTR activity.1-4

  • CFTR mutations that cause a defect in protein synthesis due to nonsense mutations (e.g., G542X) or a splicing abnormality that results in a premature stop codon (e.g., 621+1G->T) result in no CFTR protein at the cell surface
  • CFTR mutations that affect processing (e.g., F508del) result in little to no delivery of CFTR protein to the cell surface
  • CFTR mutations that produce CFTR protein with decreased stability (e.g., 4326delTC) result in functional CFTR channels that rapidly degrade at the cell surface, leaving little to no CFTR protein at the surface
  • CFTR mutations that severely affect gating (e.g., G551D) or conductance (e.g., R334W) result in a normal quantity of CFTR channels at the cell surface that have little to no function

CFTR mutations that result in residual total CFTR activity

Some reduction in CFTR protein quantity or function results in residual CFTR activity

Some CFTR quantity
(but less than normal)

Some reduction in CFTR protein quantity or function results in residual CFTR activity

Some CFTR function
(but less than normal)

Some CFTR mutations result in reduced CFTR protein quantity or function at the cell surface that can produce residual, or partial, total CFTR activity.1,2,5

  • Some CFTR mutations that cause a defect in mRNA splicing (e.g., 2789+5G->A) can result in reduced protein synthesis but delivery of some functional CFTR proteins to the cell surface
  • CFTR mutations that reduce conductance and/or gating (e.g., R117H) can result in a normal quantity of CFTR channels at the cell surface that have some level of function and ion transport

Explore the effects of common CFTR mutations on CFTR protein and activity.

    References:
  1. Sheppard DN, Rich DP, Ostedgaard LS, Gregory RJ, Smith AE, Welsh MJ. Mutations in CFTR associated with mild-disease-form Cl- channels with altered pore properties. Nature. 1993;362(6416):160-164.
  2. Zielenski J. Genotype and phenotype in cystic fibrosis. Respiration. 2000;67(2):117‐133.
  3. Welsh MJ, Smith AE. Molecular mechanisms of CFTR chloride channel dysfunction in cystic fibrosis. Cell. 1993;73(7):1251-1254.
  4. Haardt M, Benharouga M, Lechardeur D, Kartner N, Lukacs GL. C-terminal truncations destabilize the cystic fibrosis transmembrane conductance regulator without impairing its biogenesis. A novel class of mutation. J Biol Chem. 1999;274(31):21873-21877.
  5. Green DM, McDougal KE, Blackman SM, et al. Mutations that permit residual CFTR function delay acquisition of multiple respiratory pathogens in CF patients. Respir Res. 2010;11(140). doi:10.1186/1465-9921-11-140.