Missense mutations of conserved glycine residues in fibrillin-1 highlight a potential subtype of cb-EGF-like domains

Authors

  • Philippe Khau Van Kien,

    Corresponding author
    1. CHU Montpellier, Hôpital Arnaud de Villeneuve, Laboratoire de Génétique Moléculaire, Montpellier, F-34000 France
    • CHU Montpellier, Laboratoire de Génétique Moléculaire, UFR Médecine site Nord UPM/IURC, 640 Avenue du doyen Gaston GIRAUD, 34295 Montpellier Cedex 5, France
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  • David Baux,

    1. CHU Montpellier, Hôpital Arnaud de Villeneuve, Laboratoire de Génétique Moléculaire, Montpellier, F-34000 France
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  • Nathalie Pallares-Ruiz,

    1. CHU Montpellier, Hôpital Arnaud de Villeneuve, Laboratoire de Génétique Moléculaire, Montpellier, F-34000 France
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  • Corinne Baudoin,

    1. CHU Montpellier, Hôpital Arnaud de Villeneuve, Laboratoire de Génétique Moléculaire, Montpellier, F-34000 France
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  • Aurélie Plancke,

    1. CHU Montpellier, Hôpital Arnaud de Villeneuve, Laboratoire de Génétique Moléculaire, Montpellier, F-34000 France
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  • Nicolas Chassaing,

    1. CHU Toulouse, Hôpital Purpan, Service de Génétique Médicale, Toulouse, F-31300, France
    2. INSERM, U563, Centre de Physiopathologie de Toulouse Purpan, Toulouse, F-31300, France
    3. Université Toulouse III Paul-Sabatier, Toulouse, F-31400, France
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  • Patrick Collignon,

    1. CHU Marseille, Hôpital d'Enfants de la Timone, Département de Génétique Médicale, Marseille F-13000, France
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  • Valérie Drouin-Garraud,

    1. CHU Rouen, Département de Génétique, Rouen, France
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  • Alain Hovnanian,

    1. CHU Toulouse, Hôpital Purpan, Service de Génétique Médicale, Toulouse, F-31300, France
    2. INSERM, U563, Centre de Physiopathologie de Toulouse Purpan, Toulouse, F-31300, France
    3. Université Toulouse III Paul-Sabatier, Toulouse, F-31400, France
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  • Dominique Martin-Coignard,

    1. CH le Mans, Service de Génétique Médicale, le Mans, F-72000, France
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  • Gwenaëlle Collod-Béroud,

    1. INSERM, U827, Montpellier, F-34000 France
    2. Université Montpellier1, UFR Médecine, Montpellier, F-34000 France
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  • Christophe Béroud,

    1. CHU Montpellier, Hôpital Arnaud de Villeneuve, Laboratoire de Génétique Moléculaire, Montpellier, F-34000 France
    2. INSERM, U827, Montpellier, F-34000 France
    3. Université Montpellier1, UFR Médecine, Montpellier, F-34000 France
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  • Anne-Françoise Roux,

    1. CHU Montpellier, Hôpital Arnaud de Villeneuve, Laboratoire de Génétique Moléculaire, Montpellier, F-34000 France
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  • Mireille Claustres

    1. CHU Montpellier, Hôpital Arnaud de Villeneuve, Laboratoire de Génétique Moléculaire, Montpellier, F-34000 France
    2. INSERM, U827, Montpellier, F-34000 France
    3. Université Montpellier1, UFR Médecine, Montpellier, F-34000 France
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  • Communicated by Reed E. Pyeritz

Abstract

In six index cases/families referred for Marfan syndrome (MFS) molecular diagnosis, we identified six novel mutations in the FBN1 gene: c.1753G>C (p.Gly585Arg), c.2456G>A (p.Gly819Glu), c.4981G>A (p.Gly1661Arg), c.5339G>A (p.Gly1780Glu), c.6418G>A (p.Gly2140Arg) and c.6419G>A (p.Gly2140Glu). These variants, predicted to result in Glycine substitutions are located at the third position of a 4 amino acids loop-region of calcium-binding Epidermal Growth Factor-like (cb-EGF) fibrillin-1 domains 5, 9, 24, 25 and 32. Familial segregation studies showing cosegregation with MFS manifestations or de novo inheritance in addition to in silico analyses (conservation, 3D modeling) suggest evidence for a crucial role of the respective Glycine positions. Extending these analyses to all Glycine residue at position 3 of this 4 residues loop in fibrillin-1 cb-EGF with the UMD predictor tool and alignment of 2038 available related sequences strongly support a steric strain that only allows Glycine or even Alanine residues for domain structure maintenance and for the fibrillin functions. Our data compared with those of the literature strongly suggest the existence of a cb-EGF domain subtype with implications for related diseases. © 2009 Wiley-Liss, Inc.

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