Mutations in GLDN, Encoding Gliomedin, a Critical Component of the Nodes of Ranvier, Are Responsible for Lethal Arthrogryposis.
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.
INSERM UMR-1169, Université Paris Saclay, Le Kremlin Bicêtre 94276, France.
Jérôme
J
Maluenda
UMR-7286, Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille, Aix-Marseille Université, Centre National de la Recherche Scientifique, Marseille 13444, France.
Constance
C
Manso
INSERM UMR-1169, Université Paris Saclay, Le Kremlin Bicêtre 94276, France.
Loic
L
Quevarec
INSERM UMR-1169, Université Paris Saclay, Le Kremlin Bicêtre 94276, France.
Alexandre
A
Vivanti
Pathology Laboratory, Rouen University Hospital, Rouen 76000, France; INSERM, NéoVasc Laboratory, University of Rouen, Rouen 76000, France.
Florent
F
Marguet
Département de Génétique Médicale, Hôpital Trousseau and Université Pierre et Marie Curie, Paris 75571, France.
Marie
M
Gonzales
INSERM U-1141, Service de Biologie du Développement, Hôpital Robert Debré, Paris 75019, France.
Fabien
F
Guimiot
Clinique de Génétique Guy Fontaine, Hôpital Jeanne de Flandre, Centre Hospitalier Régional Universitaire, Lille 59037, France.
Florence
F
Petit
Service de Génétique, Hôpital Bretonneau, Centre Hospitalier Universitaire de Tours, Tours 37044, France.
Annick
A
Toutain
Département de Génétique Médicale, Hôpital Trousseau and Université Pierre et Marie Curie, Paris 75571, France.
Sandra
S
Whalen
Département de Génétique Médicale, Hôpital Trousseau and Université Pierre et Marie Curie, Paris 75571, France.
Romulus
R
Grigorescu
Clinique de Génétique Guy Fontaine, Hôpital Jeanne de Flandre, Centre Hospitalier Régional Universitaire, Lille 59037, France.
Anne Dieux
AD
Coeslier
CNAG-CRG, Barcelona Institute of Science and Technology, Universitat Pompeu Fabra, Baldiri i Reixac 4, Barcelona 08028, Spain.
Marta
M
Gut
CNAG-CRG, Barcelona Institute of Science and Technology, Universitat Pompeu Fabra, Baldiri i Reixac 4, Barcelona 08028, Spain.
Ivo
I
Gut
Pathology Laboratory, Rouen University Hospital, Rouen 76000, France; INSERM, NéoVasc Laboratory, University of Rouen, Rouen 76000, France.
Annie
A
Laquerrière
UMR-7286, Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille, Aix-Marseille Université, Centre National de la Recherche Scientifique, Marseille 13444, France.
Jérôme
J
Devaux
INSERM UMR-1169, Université Paris Saclay, Le Kremlin Bicêtre 94276, France. Electronic address: judith.melki@inserm.fr.
Judith
J
Melki
D000483:Alleles; D001176:Arthrogryposis / Q000235:genetics*; D001369:Axons / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics; D059472:Exome / Q000235:genetics; D005260:Female; D005313:Fetal Death; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D009414:Nerve Growth Factors / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D011485:Protein Binding / Q000235:genetics; D011901:Ranvier's Nodes / Q000378:metabolism* / Q000648:ultrastructure
C491323:CNTNAP1 protein, human; D015815:Cell Adhesion Molecules; D015816:Cell Adhesion Molecules, Neuronal; C473138:GLDN protein, human; D008565:Membrane Proteins; C054305:NFASC protein, human; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins