Mutations in GLDN , Encoding Gliomedin, a Critical Component of the Nodes of Ranvier, Are Responsible for Lethal Arthrogryposis
Jérôme Maluenda
(1)
,
Constance Manso
(2)
,
Loic Quevarec
(1)
,
Alexandre Vivanti
(1)
,
Florent Marguet
(3, 4)
,
Marie Gonzales
(5, 6)
,
Fabien Guimiot
(7, 8)
,
Florence Petit
(9, 10)
,
Annick Toutain
(11)
,
Sandra Whalen
(5, 6)
,
Romulus Grigorescu
(5, 6)
,
Anne Dieux Coeslier
(9, 10)
,
Marta Gut
(12, 13)
,
Ivo Gut
(12, 13)
,
Annie Laquerrière
(3, 4)
,
Jérôme Devaux
(2)
,
Judith Melki
(1)
1
U 1169 -
Thérapie génique, Génomique et Epigénomique
2 CRN2M - Centre de recherche en neurobiologie - neurophysiologie de Marseille
3 CHU Rouen
4 NeoVasc - Team 4 NeoVasc - Region Team ERI 28 INSERM
5 CHU Trousseau [APHP]
6 UPMC - Université Pierre et Marie Curie - Paris 6
7 NeuroDiderot (UMR_S_1141 / U1141) - Maladies neurodéveloppementales et neurovasculaires
8 Hôpital Robert Debré
9 Clinique de Génétique médicale Guy Fontaine [CHRU LIlle]
10 Hôpital Jeanne de Flandre [Lille]
11 Hôpital Bretonneau
12 BIST - Barcelona Institute of Science and Technology
13 UPF - Universitat Pompeu Fabra [Barcelona]
2 CRN2M - Centre de recherche en neurobiologie - neurophysiologie de Marseille
3 CHU Rouen
4 NeoVasc - Team 4 NeoVasc - Region Team ERI 28 INSERM
5 CHU Trousseau [APHP]
6 UPMC - Université Pierre et Marie Curie - Paris 6
7 NeuroDiderot (UMR_S_1141 / U1141) - Maladies neurodéveloppementales et neurovasculaires
8 Hôpital Robert Debré
9 Clinique de Génétique médicale Guy Fontaine [CHRU LIlle]
10 Hôpital Jeanne de Flandre [Lille]
11 Hôpital Bretonneau
12 BIST - Barcelona Institute of Science and Technology
13 UPF - Universitat Pompeu Fabra [Barcelona]
Romulus Grigorescu
- Fonction : Auteur
Judith Melki
Connectez-vous pour contacter l'auteur
- Fonction : Auteur correspondant
- PersonId : 931056
Connectez-vous pour contacter l'auteur
Résumé
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.
Format du dépôt | Fichier |
---|---|
Type de dépôt | Article dans une revue |
Titre |
en
Mutations in GLDN , Encoding Gliomedin, a Critical Component of the Nodes of Ranvier, Are Responsible for Lethal Arthrogryposis
|
Résumé |
en
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.
|
Auteur(s) |
Jérôme Maluenda
1
, Constance Manso
2
, Loic Quevarec
1
, Alexandre Vivanti
1
, Florent Marguet
3, 4
, Marie Gonzales
5, 6
, Fabien Guimiot
7, 8
, Florence Petit
9, 10
, Annick Toutain
11
, Sandra Whalen
5, 6
, Romulus Grigorescu
5, 6
, Anne Dieux Coeslier
9, 10
, Marta Gut
12, 13
, Ivo Gut
12, 13
, Annie Laquerrière
3, 4
, Jérôme Devaux
2
, Judith Melki
1
1
U 1169 -
Thérapie génique, Génomique et Epigénomique
( 421312 )
- France
2
CRN2M -
Centre de recherche en neurobiologie - neurophysiologie de Marseille
( 192792 )
- Faculté de Médecine
Secteur Nord
Boulevard Pierre Dramard
13916 MARSEILLE CEDEX 20
- France
3
CHU Rouen
( 300147 )
- 1 rue de Germont 76031 Rouen cedex
- France
4
NeoVasc -
Team 4 NeoVasc - Region Team ERI 28 INSERM
( 1089348 )
- 22 Boulevard Gambetta - 76183 Rouen Cedex
- France
5
CHU Trousseau [APHP]
( 360410 )
- 26 Avenue du Dr Arnold Netter, 75012 Paris
- France
6
UPMC -
Université Pierre et Marie Curie - Paris 6
( 93591 )
- 4 place Jussieu - 75005 Paris
- France
7
NeuroDiderot (UMR_S_1141 / U1141) -
Maladies neurodéveloppementales et neurovasculaires
( 1005068 )
- Hôpital Robert Debré
48 Bd Serurier
75019 Paris
- France
8
Hôpital Robert Debré
( 300089 )
-
- France
9
Clinique de Génétique médicale Guy Fontaine [CHRU LIlle]
( 497291 )
- 59037 Lille Cedex.
- France
10
Hôpital Jeanne de Flandre [Lille]
( 300137 )
- Avenue Eugène Avinée, 59000 Lille
- France
11
Hôpital Bretonneau
( 134720 )
- 2 boulevard Tonnellé, 37044 Tours
- France
12
BIST -
Barcelona Institute of Science and Technology
( 491770 )
- Carrer Comte d'Urgell, 187, 08036 Barcelona, Espagne
- Espagne
13
UPF -
Universitat Pompeu Fabra [Barcelona]
( 128785 )
- Plaça de la Mercè, 10-12 - 08002 Barcelona
- Espagne
|
Vulgarisation |
Non
|
Comité de lecture |
Oui
|
Audience |
Internationale
|
Langue du document |
Anglais
|
Nom de la revue |
|
Date de publication |
2016-09-08
|
Volume |
99
|
Numéro |
4
|
Page/Identifiant |
928 - 933
|
Domaine(s) |
|
DOI | 10.1016/j.ajhg.2016.07.021 |
Pubmed Id | 27616481 |
PubMed Central | PMC5065655 |
Origine :
Publication financée par une institution
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