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Two mutations in human BICC1 resulting in Wnt pathway hyperactivity associated with cystic renal dysplasia

Authors

  • Marine R.-C. Kraus,

    1. Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Station 19, Lausanne, Switzerland
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  • Séverine Clauin,

    1. Département de Génétique, Université Pierre et Marie Curie, AP-HP, Groupe Hospitalier Pitié Salpêtrière, 47-83 bd de l'Hôpital, Paris, France
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  • Yvan Pfister,

    1. Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Station 19, Lausanne, Switzerland
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  • Massimo Di Maïo,

    1. Département de Pédiatrie, CHU Poitiers, Poitiers, France
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  • Tim Ulinski,

    1. Département de Néphrologie Pédiatrique, Université Pierre et Marie Curie, AP-HP, Hôpital Armand Trousseau, Paris, France
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  • Daniel Constam,

    1. Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Station 19, Lausanne, Switzerland
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  • Christine Bellanné-Chantelot,

    Corresponding author
    1. Département de Génétique, Université Pierre et Marie Curie, AP-HP, Groupe Hospitalier Pitié Salpêtrière, 47-83 bd de l'Hôpital, Paris, France
    • Département de Génétique, Université Pierre et Marie Curie, AP-HP, Groupe Hospitalier Pitié Salpêtrière, 47-83 bd de l'Hôpital, 75651 Paris Cedex 13, France
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  • Anne Grapin-Botton

    Corresponding author
    1. Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Station 19, Lausanne, Switzerland
    • Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Station 19, CH-1015 Lausanne, Switzerland
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    • Both authors contributed equally to this work.


  • Communicated by Michel Goossens

Abstract

Bicaudal C homologue 1 (Bicc1) knockout in mice causes polycystic kidney disease and pancreas development defects, including a reduction in insulin-producing β-cells and ensuing diabetes. We therefore screened 137 patients with renal abnormalities or association of early-onset diabetes and renal disease for genetic alterations in BICC1. We identified two heterozygous mutations, one nonsense in the first K Homology (KH) domain and one missense in the sterile alpha motif (SAM) domain. In mice, Bicc1 blocks canonical Wnt signaling, mostly via its SAM domain. We show that the human BICC1, similar to its mouse counterpart, blocks canonical Wnt signaling. The nonsense mutation identified results in a complete loss of Wnt inhibitory activity. The point mutation in the SAM domain has a similar effect to a complete SAM domain deletion, resulting in a 22% loss of activity. Hum Mutat 33:86–90, 2012. © 2011 Wiley Periodicals, Inc.

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