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J Cell Mol Med. 2019 Jun 18. doi: 10.1111/jcmm.14397. [Epub ahead of print]

Potentiation of ABCA3 lipid transport function by ivacaftor and genistein.

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Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, Munich, Germany.
Member of the German Center for Lung Research (DZL), Munich, Germany.
Institute of Structural Biology, Helmholtz Zentrum M√ľnchen, Neuherberg, Germany.
Center for Integrated Protein Science Munich at Department Chemie, Technical University of Munich, Garching, Germany.


ABCA3 is a phospholipid transporter implicated in pulmonary surfactant homoeostasis and localized at the limiting membrane of lamellar bodies, the storage compartment for surfactant in alveolar type II cells. Mutations in ABCA3 display a common genetic cause for diseases caused by surfactant deficiency like respiratory distress in neonates and interstitial lung disease in children and adults, for which currently no causal therapy exists. In this study, we investigated the effects of ivacaftor and genistein, two potentiators of the cystic fibrosis transmembrane conductance regulator (CFTR), on ABCA3-specific lipid transport function. Wild-type (WT) and functional ABCA3 mutations N568D, F629L, G667R, T1114M and L1580P were stably expressed in A549 cells. Three-dimensional modelling predicted functional impairment for all five mutants that was confirmed by in vitro experiments (all <14% of WT functional activity). Treatment with potentiators rescued the mutants N568D (up to 114% of WT), F629L (up to 47% of WT), and G667R (up to 60% of WT), the latter variation needing higher concentrations of genistein, showing reduced affinity of the potentiator to the mutant protein. Our results present a first proof that functional ABCA3 mutations are rescued by CFTR potentiators, making them a potential therapeutical option for patients suffering from surfactant deficiency due to ABCA3 mutations.


ABCA3; CFTR potentiators; genistein; interstitial lung disease; ivacaftor

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