Mutations in CNTNAP1 and ADCY6 are responsible for severe arthrogryposis multiplex congenita with axoglial defects. J. Melki1, J. Maluenda1, A. Camus1, L. Fontenas2, K. Dieterich3, F. Nolent1, N. Monnier4, P. Latour5, J. Lunardi4, M. Bayes6, PS. Jouk3, S. Sternberg7, J. Warszawski8, I. Gut6, M. Gonzales9, M. Tawk2, A. Laquérriere10 1) Unité Mixte de recherche (UMR)-986, Inserm and University Paris 11, 94276 Le Kremlin Bicêtre, France; 2) Unité Mixte de recherche (UMR)-788, Inserm and University Paris 11, 94276 Le Kremlin Bicêtre, France; 3) Département de Génétique, CHU Grenoble, Inserm U-836, Institut des Neurosciences, 38043 Grenoble, France; 4) Laboratoire de Biochimie et Génétique Moléculaire, CHU Grenoble, 38043 Grenoble, France; 5) Service de Neurobiologie, CHU de Lyon, 69677 Bron, France; 6) Centro Nacional de Análisis Genómico, Barcelona, 080028, Spain; 7) Assistance Publique Hôpitaux de Paris, Hôpitaux Universitaires Pitié-Salpêtrière, Service de Biochimie Métabolique, 75651 Paris, France; 8) UMR-1018, Inserm et Université Paris 11, Service dEpidémiologie-Santé Publique, CHU Bicetre, 94276 Le Kremlin-Bicêtre, France; 9) Service de Génétique et d'Embryologie Médicales, Université Paris VI, Hopital Trousseau, 75571 Paris, France; 10) Pathology Laboratory and NeoVasc Region-Inserm Team ERI28, Institute of Research for Innovation in Biomedicine, University of Rouen, 76031 Rouen, France.

   Non-syndromic arthrogryposis multiplex congenita (AMC) is characterized by multiple congenital contractures resulting from reduced fetal mobility. Genetic mapping and whole exome sequencing were performed in 31 multiplex and/or consanguineous undiagnosed AMC families. We report pathogenic mutations in two new genes. Homozygous frameshift mutations in CNTNAP1 were found in four unrelated families. Patients showed a marked reduction in motor nerve conduction velocity (less than 10m/sec) and transmission electron microscopy (TEM) of sciatic nerve in the index cases revealed severe abnormalities of both nodes of Ranvier width and myelinated axons. CNTNAP1 encodes CASPR, an essential component of node of Ranvier domains which underly saltatory conduction of action potentials along myelinated axons, an important process for neuronal function. A homozygous missense mutation in Adenylate Cyclase 6 gene (ADCY6) was found in another family characterized by a lack of myelin in the Peripheral Nervous System (PNS) as determined by TEM. Morpholino knockdown of the zebrafish orthologs led to severe and specific defects in peripheral myelin in spite of the presence of Schwann cells. ADCY6 encodes a protein that belongs to adenylate cyclase family responsible for the synthesis of cAMP. Our data indicate an essential and so far unknown role of ADCY6 in PNS myelination likely through the cAMP pathway. Additional AMC families have been included and using the same approach, two new genes involved in the development of the neuromuscular system have been identified and will be presented.

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