The neuronal endopeptidase ECEL1 is a frequent cause of autosomal recessive distal arthrogryposis associated with limited knee flexion, ptosis, and limb muscle and tongue atrophy. K. Dieterich1,2,3,4, S. Quijano-Roy5, N. Monnier1,13, J. Zhou3, J. Faure1,13, D. Avila-Smirnow5, RY. Carlier6, C. Laroche7, P. Marcorelles8, S. Mercier9, A. Megabarne10, S. Odent9, N. Romero11, D. Sternberg12, I. Marty1, B. Estournet5, PS. Jouk2,4, J. Melki3, J. Lunardi1,13 1) INSERM U836 Grenoble Institut des Neurosciences, Grenoble, France; 2) Département de Génétique et Procréation, Hôpital Couple Enfant, CHU Grenoble, Grenoble, France; 3) INSERM UMR-788, University of Paris 11, Biomedical Institute of Bicêtre, Le Kremlin-Bicêtre, France; 4) Centre de Référence des Anomalies du Développement, Hôpital Couple Enfant, CHU Grenoble, Grenoble, France; 5) AP-HP, Service de Pédiatrie, Hôpital Raymond Poincaré, Garches; Hôpitaux Universitaires Paris-Ile-de-France Ouest, Pôle pédiatrique; Centre de Référence Maladies Neuromusculaires GNMH; CIC-IT - Facult&e; 6) AP-HP, Service dImagerie Médicale, Hôpital R. Poincaré, Garches; Hôpitaux Universitaires Paris-Ile-de-France Ouest, Pôle neuro-locomoteur; GNMH; UVSQ, France; 7) Service de Pédiatrie, CHU Limoges, Limoges, France; 8) Laboratoire dAnatomo-Pathologie, CHU Brest, Brest, France; 9) Service de Génétique Clinique, CHU Rennes, Université Rennes 1, UMR62920, Rennes, France; 10) Unité de Génétique Médicale et Laboratoire Associé INSERM UMR_S910, Pôle Technologie Santé, Université Saint Joseph, Beyrut, Lebanon; 11) Service dAnatomopathologie, Pavillon Riessler, Institut de Myologie, Paris, France; 12) Laboratoire de Cardiogénétique et myogénétique moléculaire et cellulaire, GH Pitié-Salpétrière, AP-HP, Paris; 13) Laboratoire de Biochimie Génétique et Moléculaire, Département de Biochimie, Pharmacologie, Toxicologie, CHU de Grenoble, Grenoble, France.

   Distal arthrogryposis (DA) constitutes a frequent but heterogeneous subgroup among multiple congenital contractures (MCC). Despite its frequency only a limited number of genes have been associated with rare but well characterized types of DA, implicating almost exclusively genes of the contractile apparatus. Our aim was to identify new genes associated with DA. We therefore performed a SNP array based homozygosity mapping approach in two consanguineous African families presenting with an unclassified DA phenotype. We further screened potential candidate genes in 18 familial or sporadic cases with DA that did not show mutations in known genes associated with DA. Combined multipoint linkage analysis of the two families revealed an overlapping locus at 2q37 of 5.7 Mb with a LOD score Zmax = 5.1 at = 0.0 and harboring 77 annotated genes. We excluded pathogenic mutations in the genes encoding the gamma (CHRNG) and delta (CHRND) subunits of the acetylcholine receptor at the neuromuscular junction known to cause MCC. We then searched for candidate genes of the neuromuscular apparatus. The Endothelin Converting Enzyme Like 1 (ECEL1) gene is predominantly expressed during fetal life and encodes a neuronal endopeptidase crucial for intramuscular motoneuron branching during embryogenesis and was therefore highly candidate. Screening for ECEL1 mutations in the total of 20 familial and sporadic cases identified homozygous or compound heterozygous mutations (four non-sense, two splicing and one missense mutation) in six families including the two consanguineous African families. Detailed clinical evaluation showed a recognizable phenotype with limited knee flexion, pes talus or talus valgus, severe muscle atrophy predominant on the lower limbs and the tongue, and ptosis. Muscle MRI evidenced muscle atrophy and frequent fatty replacement, especially in biceps femoris and vastus lateralis. Electrophysiological analyses excluded a neuromuscular transmission defect after birth. Interestingly, ECEL1-deficient mice show acetylcholine receptor deficiency of prenatal onset due to deficient axonal branching of motor neurons. The prenatal expression of ECEL1 and the non-progressive disease state in our patients suggests a developmental defect of the lower motoneuron or neuromuscular junction in patients with ECEL1 mutations. Further work is needed to better understand the role of ECEL1 in human, but our findings already highlight a new mechanism for DA.

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