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Am J Hum Genet. 2016 Oct 6;99(4):928-933. doi: 10.1016/j.ajhg.2016.07.021. Epub 2016 Sep 8.

Mutations in GLDN, Encoding Gliomedin, a Critical Component of the Nodes of Ranvier, Are Responsible for Lethal Arthrogryposis.

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INSERM UMR-1169, Université Paris Saclay, Le Kremlin Bicêtre 94276, France.
UMR-7286, Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille, Aix-Marseille Université, Centre National de la Recherche Scientifique, Marseille 13444, France.
Pathology Laboratory, Rouen University Hospital, Rouen 76000, France; INSERM, NéoVasc Laboratory, University of Rouen, Rouen 76000, France.
Département de Génétique Médicale, Hôpital Trousseau and Université Pierre et Marie Curie, Paris 75571, France.
INSERM U-1141, Service de Biologie du Développement, Hôpital Robert Debré, Paris 75019, France.
Clinique de Génétique Guy Fontaine, Hôpital Jeanne de Flandre, Centre Hospitalier Régional Universitaire, Lille 59037, France.
Service de Génétique, Hôpital Bretonneau, Centre Hospitalier Universitaire de Tours, Tours 37044, France.
CNAG-CRG, Barcelona Institute of Science and Technology, Universitat Pompeu Fabra, Baldiri i Reixac 4, Barcelona 08028, Spain.
INSERM UMR-1169, Université Paris Saclay, Le Kremlin Bicêtre 94276, France. Electronic address:


Arthrogryposis multiplex congenita (AMC) is a developmental condition characterized by multiple joint contractures resulting from reduced or absent fetal movements. Through linkage analysis, homozygosity mapping, and exome sequencing in four unrelated families affected by lethal AMC, we identified biallelic mutations in GLDN in the affected individuals. GLDN encodes gliomedin, a secreted cell adhesion molecule involved in the formation of the nodes of Ranvier. Transmission electron microscopy of the sciatic nerve from one of the affected individuals showed a marked lengthening defect of the nodes. The GLDN mutations found in the affected individuals abolish the cell surface localization of gliomedin and its interaction with its axonal partner, neurofascin-186 (NF186), in a cell-based assay. The axoglial contact between gliomedin and NF186 is essential for the initial clustering of Na+ channels at developing nodes. These results indicate a major role of gliomedin in node formation and the development of the peripheral nervous system in humans. These data indicate that mutations of GLDN or CNTNAP1 (MIM: 616286), encoding essential components of the nodes of Ranvier and paranodes, respectively, lead to inherited nodopathies, a distinct disease entity among peripheral neuropathies.

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