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CFTR mutation combinations producing frequent complex alleles with different clinical and functional outcomes

Authors

  • Ayman El-Seedy,

    1. Institut de Physiologie et Biologie Cellulaires, Centre National de la Recherche Scientifique Formation de Recherche en Evolution FRE 3511, Université de Poitiers, Poitiers, France
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  • Emmanuelle Girodon,

    1. AP-HP, Groupe Hospitalier Henri Mondor, Service de Biochimie-Génétique, Créteil, France
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  • Caroline Norez,

    1. Institut de Physiologie et Biologie Cellulaires, Centre National de la Recherche Scientifique Formation de Recherche en Evolution FRE 3511, Université de Poitiers, Poitiers, France
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  • Julie Pajaud,

    1. Institut de Physiologie et Biologie Cellulaires, Centre National de la Recherche Scientifique Formation de Recherche en Evolution FRE 3511, Université de Poitiers, Poitiers, France
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  • Marie-Claude Pasquet,

    1. Institut de Physiologie et Biologie Cellulaires, Centre National de la Recherche Scientifique Formation de Recherche en Evolution FRE 3511, Université de Poitiers, Poitiers, France
    2. CHU de Poitiers, Poitiers; France
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  • Alix de Becdelièvre,

    1. AP-HP, Groupe Hospitalier Henri Mondor, Service de Biochimie-Génétique, Créteil, France
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  • Thierry Bienvenu,

    1. Laboratoire de Biochimie et Génétique Moléculaire, Groupe hospitalier Cochin-Saint Vincent de Paul, AP-HP, Paris, France
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  • Marie des Georges,

    1. Laboratoire de Génétique Moléculaire, IURC, CHU de Montpellier, Montpellier, France
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  • Faïza Cabet,

    1. Service d'Endocrinologie Moléculaire et Maladies rares, Centre de Biologie et Pathologie Est, CHU de Lyon, Bron, France
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  • Guy Lalau,

    1. Pôle de Biochimie et Biologie Moléculaire, Centre de Biologie Pathologie, CHU de Lille, Lille, France
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  • Eric Bieth,

    1. Service de Génétique Médicale, Hôpital Purpan, Toulouse, France
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  • Martine Blayau,

    1. Laboratoire de Génétique Moléculaire, CHU Pontchaillou, Rennes, France
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  • Frédéric Becq,

    1. Institut de Physiologie et Biologie Cellulaires, Centre National de la Recherche Scientifique Formation de Recherche en Evolution FRE 3511, Université de Poitiers, Poitiers, France
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  • Alain Kitzis,

    1. Institut de Physiologie et Biologie Cellulaires, Centre National de la Recherche Scientifique Formation de Recherche en Evolution FRE 3511, Université de Poitiers, Poitiers, France
    2. CHU de Poitiers, Poitiers; France
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  • Pascale Fanen,

    1. AP-HP, Groupe Hospitalier Henri Mondor, Service de Biochimie-Génétique, Créteil, France
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  • Véronique Ladeveze

    Corresponding author
    1. Institut de Physiologie et Biologie Cellulaires, Centre National de la Recherche Scientifique Formation de Recherche en Evolution FRE 3511, Université de Poitiers, Poitiers, France
    • Institut de Physiologie et Biologie Cellulaires, CNRS FRE 3511, Université de Poitiers, 86022 Poitiers, France.
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  • Communicated by Garry R. Cutting

Abstract

Genotype–phenotype correlations in cystic fibrosis (CF) may be difficult to establish because of phenotype variability, which is associated with certain CF transmembrane conductance regulator (CFTR) gene mutations and the existence of complex alleles. To elucidate the clinical significance of complex alleles involving p.Gly149Arg, p.Asp443Tyr, p.Gly576Ala, and p.Arg668Cys, we performed a collaborative genotype–phenotype correlation study, collected epidemiological data, and investigated structure–function relationships for single and natural complex mutants, p.[Gly576Ala;Arg668Cys], p.[Gly149Arg;Gly576Ala;Arg668Cys], and p.[Asp443Tyr;Gly576Ala;Arg668Cys]. Among 153 patients carrying at least one of these mutations, only three had classical CF and all carried p.Gly149Arg in the triple mutant. Sixty-four had isolated infertility and seven were healthy individuals with a severe mutation in trans, but none had p.Gly149Arg. Functional studies performed on all single and natural complex mutants showed that (1) p.Gly149Arg results in a severe misprocessing defect; (2) p.Asp443Tyr moderately alters CFTR maturation; and (3) p.Gly576Ala, a known splicing mutant, and p.Arg668Cys mildly alter CFTR chloride conductance. Overall, the results consistently show the contribution of p.Gly149Arg to the CF phenotype, and suggest that p.[Arg668Cys], p.[Gly576Ala;Arg668Cys], and p.[Asp443Tyr;Gly576Ala;Arg668Cys] are associated with CFTR-related disorders. The present study emphasizes the importance of comprehensive genotype–phenotype and functional studies in elucidating the impact of mutations on clinical phenotype. Hum Mutat 33:1557–1565, 2012. © 2012 Wiley Periodicals, Inc.

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