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Spectrum of HSPG2 (Perlecan) mutations in patients with Schwartz-Jampel syndrome

Authors

  • Morgane Stum,

    1. Inserm, U546, Paris, France
    2. Université Pierre et Marie Curie-Paris6, UMR S546, Paris, France
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  • Claire-Sophie Davoine,

    1. Inserm, U546, Paris, France
    2. Université Pierre et Marie Curie-Paris6, UMR S546, Paris, France
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  • Savine Vicart,

    1. Inserm, U546, Paris, France
    2. Université Pierre et Marie Curie-Paris6, UMR S546, Paris, France
    3. Assitance Publique-Hôpitaux de Paris, Groupe Hospitalier de la Pitié-Salpêtrière, Fédération des Maladies du Système Nerveux et Centre de Référence “Canalopathies Musculaires,” Paris, France
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  • Léna Guillot-Noël,

    1. Inserm, U546, Paris, France
    2. Université Pierre et Marie Curie-Paris6, UMR S546, Paris, France
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  • Haluk Topaloglu,

    1. Hacettepe University, Faculty of Medicine, Ankara, Turkey
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  • Francisco Javier Carod-Artal,

    1. Neurology Department, Sarah Hospital, Brasilia, Brazil
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  • Hülya Kayserili,

    1. Medical Genetics Department, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey
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  • Fayçal Hentati,

    1. National Institute of Neurology, Tunis, Tunisia
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  • Luciano Merlini,

    1. Muscle Unit, Division of Medical Genetics, Department of Experimental and Diagnostic Medicine, University of Ferrara, Ferrara, Italy
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  • Jon Andoni Urtizberea,

    1. Assistance Publique-Hôpitaux de Paris, Hôpital Marin d'Hendaye, Consultation Neuromusculaire, European Neuromuscular Center (ENMC), Hendaye, France
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  • EL-Hadi Hammouda,

    1. Généthon, AFM, Evry, France
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  • Phuc Canh Quan,

    1. Inserm, U546, Paris, France
    2. Université Pierre et Marie Curie-Paris6, UMR S546, Paris, France
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  • Bertrand Fontaine,

    1. Inserm, U546, Paris, France
    2. Université Pierre et Marie Curie-Paris6, UMR S546, Paris, France
    3. Assitance Publique-Hôpitaux de Paris, Groupe Hospitalier de la Pitié-Salpêtrière, Fédération des Maladies du Système Nerveux et Centre de Référence “Canalopathies Musculaires,” Paris, France
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  • Sophie Nicole

    Corresponding author
    1. Inserm, U546, Paris, France
    2. Université Pierre et Marie Curie-Paris6, UMR S546, Paris, France
    3. Assitance Publique-Hôpitaux de Paris, Groupe Hospitalier de la Pitié-Salpêtrière, Fédération des Maladies du Système Nerveux et Centre de Référence “Canalopathies Musculaires,” Paris, France
    • UMR S546, Faculté de Médecine Pierre et Marie Curie, 105 Boulevard de l'Hôpital, 75634 Paris Cedex 13, France
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  • Communicated by Christine Van Broeckhoven

Abstract

Schwartz-Jampel syndrome (SJS) is a rare autosomal recessive condition defined by the association of myotonia with chondrodysplasia. SJS results from mutations in the HSPG2 gene, which encodes perlecan, a major component of basement membranes. Only eight HSPG2 mutations have been reported in six SJS families. Here, we describe the molecular findings in 23 families (35 patients) with SJS, being one-third of the SJS cases reported in the medical literature. We identified 22 new HSPG2 mutations and unreported polymorphisms. Mutations included nine deletion or insertion (41%), six splice site (27%), five missense (23%), and two nonsense mutations (9%). All but four mutations were private, and we found no evidence for a founder effect. Analyses of HSPG2 messenger RNA (mRNA) and perlecan immunostaining on patients' cells revealed a hypomorphic effect of the studied mutations. They also demonstrated distinct consequences of truncating and missense mutations on perlecan expression as truncating mutations resulted in instability of HSPG2 mRNA through nonsense mRNA-mediated decay, whereas missense mutations involving cysteine residues led to intracellular retention of perlecan, probably due to quality control pathways. Our analyses strengthen the idea that SJS results from hypomorphic mutations of the HSPG2 gene. They also propose tools for its molecular diagnosis and provide new clues for the understanding of its pathophysiology. Hum Mutat 27(11), 1082–1091, 2006. © 2006 Wiley-Liss, Inc.

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