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The CFTR Mutation c.3453G > C (D1152H) Confers an Anion Selectivity Defect in Primary Airway Tissue that Can be Rescued by Ivacaftor

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Programme in Molecular Medicine, Research Institute, Hospital for Sick Children, Toronto, ON M5G 8X4, Canada
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Department of Physiology, University of Toronto, Toronto, ON M5G 8X4, Canada
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Programme in Translational Medicine, Research Institute, Hospital for Sick Children, 555 University Avenue, room 8415, Toronto, ON M5G 8X4, Canada
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Department of Paediatrics, University of Toronto, Toronto, ON M5G 8X4, Canada
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Programme in Genetics and Genome Biology, Research Institute, Hospital for Sick Children, Toronto, ON M5G 8X4, Canada
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The Centre for Applied Genomics, Hospital for Sick Children, Toronto, ON M5G 8X4, Canada
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Department of Statistical Sciences and Division of Biostatistics, University of Toronto, Toronto, ON M5G 8X4, Canada
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Department of Biochemistry, University of Toronto, Toronto, ON M5G 8X4, Canada
*
Author to whom correspondence should be addressed.
J. Pers. Med. 2020, 10(2), 40; https://doi.org/10.3390/jpm10020040
Received: 9 April 2020 / Revised: 29 April 2020 / Accepted: 8 May 2020 / Published: 13 May 2020
The Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene variant, c.3453G > C (D1152H), is associated with mild Cystic Fibrosis (CF) disease, though there is considerable clinical variability ranging from no detectable symptoms to lung disease with early acquisition of Pseudomonas aeruginosa. The approval extension of ivacaftor, the first CFTR modulator drug approved, to include D1152H was based on a positive drug response of defective CFTR-D1152H chloride channel function when expressed in FRT cells. Functional analyses of primary human nasal epithelial cells (HNE) from an individual homozygous for D1152H now revealed that while CFTR-D1152H demonstrated normal, wild-type level chloride conductance, its bicarbonate-selective conductance was impaired. Treatment with ivacaftor increased this bicarbonate-selective conductance. Extensive genetic, protein and functional analysis of the nasal cells of this D1152H/D1152H patient revealed a 90% reduction of CFTR transcripts due to the homozygous presence of the 5T polymorphism in the poly-T tract forming a complex allele with D1152H. Thus, we confirm previous observation in patient-derived tissue that 10% normal CFTR transcripts confer normal, wild-type level chloride channel activity. Together, this study highlights the benefit of patient-derived tissues to study the functional expression and pharmacological modulation of CF-causing mutations, in order to understand pathogenesis and therapeutic responses. View Full-Text
Keywords: cystic fibrosis; personalized medicine; D1152H; CFTR; VX-770; rare mutation cystic fibrosis; personalized medicine; D1152H; CFTR; VX-770; rare mutation
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Laselva, O.; Moraes, T.J.; He, G.; Bartlett, C.; Szàrics, I.; Ouyang, H.; Gunawardena, T.N.A.; Strug, L.; Bear, C.E.; Gonska, T. The CFTR Mutation c.3453G > C (D1152H) Confers an Anion Selectivity Defect in Primary Airway Tissue that Can be Rescued by Ivacaftor. J. Pers. Med. 2020, 10, 40.

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