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Redefining Hypo- and Hyper-Responding Phenotypes of CFTR Mutants for Understanding and Therapy.

ABSTRACT: Mutations in CFTR cause misfolding and decreased or absent ion-channel function, resulting in the disease Cystic Fibrosis. Fortunately, a triple-modulator combination therapy (Trikafta) has been FDA-approved for 178 mutations, including all patients who have F508del on one allele. That so many CFTR mutants respond well to modulators developed for a single mutation is due to the nature of the folding process of this multidomain protein. We have addressed the question 'What characterizes the exceptions: the mutants that functionally respond either not or extremely well'. A functional response is the product of the number of CFTR molecules on the cell surface, open probability, and conductivity of the CFTR chloride channel. By combining biosynthetic radiolabeling with protease-susceptibility assays, we have followed CF-causing mutants during the early and late stages of folding in the presence and absence of modulators. Most CFTR mutants showed typical biochemical responses for each modulator, such as a TMD1 conformational change or an increase in (cell-surface) stability, regardless of a functional response. These modulators thus should still be considered for hypo-responder genotypes. Understanding both biochemical and functional phenotypes of outlier mutations will boost our insights into CFTR folding and misfolding, and lead to improved therapeutic strategies.

SUBMITTER: Hillenaar T

PROVIDER: S-EPMC9735543 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Redefining Hypo- and Hyper-Responding Phenotypes of CFTR Mutants for Understanding and Therapy.

Hillenaar Tamara T Beekman Jeffrey J van der Sluijs Peter P Braakman Ineke I

International journal of molecular sciences 20221202 23

Mutations in CFTR cause misfolding and decreased or absent ion-channel function, resulting in the disease Cystic Fibrosis. Fortunately, a triple-modulator combination therapy (Trikafta) has been FDA-approved for 178 mutations, including all patients who have F508del on one allele. That so many CFTR mutants respond well to modulators developed for a single mutation is due to the nature of the folding process of this multidomain protein. We have addressed the question 'What characterizes the excep ...[more]

PMID: 36499495

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Redefining Hypo- and Hyper-Responding Phenotypes of CFTR Mutants for Understanding and Therapy.

Publications

Redefining Hypo- and Hyper-Responding Phenotypes of CFTR Mutants for Understanding and Therapy.

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