title: Analysis of cystic fibrosis-associated P67L CFTR illustrates barriers to personalized therapeutics for orphan diseases.
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.affiliation: Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama, Birmingham, Alabama, USA.
authors.forename: Carleen M
authors.initials: CM
authors.lastname: Sabusap
authors.affiliation: Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama, Birmingham, Alabama, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama, Birmingham, Alabama, USA.
authors.forename: Carmel M
authors.initials: CM
authors.lastname: McNicholas
authors.affiliation: Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama, Birmingham, Alabama, USA.
authors.forename: W Joon
authors.initials: WJ
authors.lastname: Chung
authors.affiliation: Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama, Birmingham, Alabama, USA.
authors.forename: Lianwu
authors.initials: L
authors.lastname: Fu
authors.affiliation: Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama, Birmingham, Alabama, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Wen
authors.affiliation: Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama, Birmingham, Alabama, USA.
authors.forename: Marina
authors.initials: M
authors.lastname: Mazur
authors.affiliation: Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama, Birmingham, Alabama, USA.
authors.forename: Kevin L
authors.initials: KL
authors.lastname: Kirk
authors.affiliation: Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama, Birmingham, Alabama, USA.
authors.forename: James F
authors.initials: JF
authors.lastname: Collawn
authors.affiliation: Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama, Birmingham, Alabama, USA.
authors.forename: Jeong S
authors.initials: JS
authors.lastname: Hong
authors.affiliation: Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama, Birmingham, Alabama, USA.; Emory University, Atlanta, Georgia, USA.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Sorscher