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Analysis of cystic fibrosis–associated P67L CFTR illustrates barriers to personalized therapeutics for orphan diseases
Carleen M. Sabusap, … , Jeong S. Hong, Eric J. Sorscher
Carleen M. Sabusap, … , Jeong S. Hong, Eric J. Sorscher
Published September 8, 2016
Citation Information: JCI Insight. 2016;1(14):e86581. https://doi.org/10.1172/jci.insight.86581.
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Research Article Cell biology Therapeutics

Analysis of cystic fibrosis–associated P67L CFTR illustrates barriers to personalized therapeutics for orphan diseases

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Abstract

Emerging knowledge indicates the difficulty in categorizing unusual cystic fibrosis (CF) mutations, with regard to both pathogenic mechanism and theratype. As case in point, we present data concerning P67L mutation of the cystic fibrosis transmembrane conductance regulator (CFTR), a defect carried by a small number of individuals with CF and sometimes attributed to a channel conductance abnormality. Findings from our laboratory and others establish that P67L causes protein misfolding, disrupts maturation, confers gating defects, is thermally stable, and exhibits near normal conductance. These results provide one framework by which rare CF alleles such as P67L can be more comprehensively profiled vis-à-vis molecular pathogenesis. We also demonstrate that emerging CF treatments — ivacaftor and lumacaftor — can mediate pronounced pharmacologic activation of P67L CFTR. Infrequent CF alleles are often improperly characterized, in part, due to the small numbers of patients involved. Moreover, access to new personalized treatments among patients with ultra-orphan genotypes has been limited by difficulty arranging phase III clinical trials, and off-label prescribing has been impaired by high drug cost and difficulty arranging third party reimbursement. Rare CFTR mutations such as P67L are emblematic of the challenges to “precision” medicine, including use of the best available mechanistic knowledge to treat patients with unusual forms of disease.

Authors

Carleen M. Sabusap, Wei Wang, Carmel M. McNicholas, W. Joon Chung, Lianwu Fu, Hui Wen, Marina Mazur, Kevin L. Kirk, James F. Collawn, Jeong S. Hong, Eric J. Sorscher

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Figure 1

The P67L mutant confers reduced expression of mature cystic fibrosis transmembrane conductance regulator (CFTR).

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The P67L mutant confers reduced expression of mature cystic fibrosis tra...
(A) Fischer rat thyroid (FRT) cells stably expressing WT, F508del mutant, or P67L mutant CFTR from an identical genomic integration site were treated with 3 μM lumacaftor. After 24 hours, cells were lysed, and total cellular protein was analyzed by Western blotting with anti-human CFTR antibodies (10B6.2). Decreased post-ER compartment, fully glycosylated (band C) CFTR was observed in the P67L sample compared with that in the WT sample and was efficiently rescued by lumacaftor (n = 3 technical replicates, *P = 0.0008 via 2-sample t test) (ER-localized, core-glycosylated CFTR is designated as B). The baseline defect observed for untreated P67L CFTR shown here is consistent with previous biochemical observations for this mutant (27). Data are mean ± SEM; some error bars are hidden by symbols. (B) In FRT cells biotinylated to detect surface CFTR, incubation with 3 μM lumacaftor increased plasma membrane abundance. This experiment was repeated with similar results.

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