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The neuronal endopeptidase ECEL1 is associated with a distinct form of recessive distal arthrogryposis.

Klaus Dieterich 1 Susana Quijano-Roy 2, 3 Nicole Monnier 4 Jie Zhou 5 Julien Fauré 4 Daniela Avila Smirnow 2, 3 Robert Carlier 6 Cécile Laroche 7 Pascale Marcorelles 8 Sandra Mercier 9 André Mégarbané 10 Sylvie Odent 9 Norma Romero 11 Damien Sternberg 12 Isabelle Marty 13 Brigitte Estournet 2, 3 Pierre-Simon Jouk 14, 5 Judith Melki 15 Joël Lunardi 4, *
* Corresponding author
1 INSERM U836, équipe 4, Muscles et pathologies
Stéroides et système nerveux : physiopathologie moléculaire et clinique, GIN - Grenoble Institut des Neurosciences, Département de Génétique et Procréation, Centre de Référence des Anomalies et du Développement
2 Service de Pédiatrie
3 CIC 1429 - Centre d’Investigation Clinique 1429 [Garches]
4 INSERM U836, équipe 4, Muscles et pathologies
GIN - Grenoble Institut des Neurosciences, Laboratoire de Biochimie Génétique et Moléculaire
5 Centre de Référence des Anomalies et du Développement
6 Service d'Imagerie Médicale [Raymond-Poincaré]
7 Service de Pédiatrie médicale [CHU Limoges]
8 CHU - AnaPath - CHRU Brest - Laboratoire d'Anatomo-Pathologie
9 Unité de génétique médicale
10 IGDR - Institut de Génétique et Développement de Rennes
11 Service d'Anatomopathologie
12 CHU Pitié-Salpêtrière [AP-HP]
13 GIN - Grenoble Institut des Neurosciences
14 Département de Génétique et Procréation
15 Stéroides et système nerveux : physiopathologie moléculaire et clinique
Abstract : Distal arthrogryposis (DA) is a heterogeneous subgroup of arthrogryposis multiplex congenita (AMC), a large family of disorders characterized by multiple congenital joint limitations due to reduced fetal movements. DA is mainly characterized by contractures afflicting especially the distal extremities without overt muscular or neurological signs. Although a limited number of genes mostly implicated in the contractile apparatus have been identified in DA, most patients failed to show mutations in currently known genes. Using a pangenomic approach, we demonstrated linkage of DA to chromosome 2q37 in two consanguineous families and the endothelin-converting enzyme like 1 (ECEL1) gene present in this region was associated with DA. Screening of a panel of 20 families with non-specific DA identified seven homozygous or compound heterozygous mutations of ECEL1 in a total of six families. Mutations resulted mostly in the absence of protein. ECEL1 is a neuronal endopeptidase predominantly expressed in the central nervous system and brain structures during fetal life in mice and human. ECEL1 plays a major role in intramuscular axonal branching of motor neurons in skeletal muscle during embryogenesis. A detailed review of clinical findings of DA patients with ECEL1 mutations revealed a homogeneous and recognizable phenotype characterized by limited knee flexion, flexed third to fifth fingers and severe muscle atrophy predominant on lower limbs and tongue that suggested a common pathogenic mechanism. We described a new and homogenous phenotype of DA associated with ECEL1 that resulted in symptoms involving rather the peripheral than the central nervous system and suggesting a developmental dysfunction.
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https://www.hal.inserm.fr/inserm-00904747
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Submitted on : Friday, November 15, 2013 - 10:31:56 AM
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INSERM | CEA | UNIV-RENNES1 | CNRS | U836 | IGDR | BIOSIT | UR1-UFR-SVE | UPMC | UNIV-RENNES | SORBONNE-UNIVERSITE | TIMC-IMAG-DYCTIM | USJB | UGA | SU-TI

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Klaus Dieterich, Susana Quijano-Roy, Nicole Monnier, Jie Zhou, Julien Fauré, et al.. The neuronal endopeptidase ECEL1 is associated with a distinct form of recessive distal arthrogryposis.. Human Molecular Genetics, Oxford University Press (OUP), 2013, 22 (8), pp.1483-92. ⟨10.1093/hmg/dds514⟩. ⟨inserm-00904747⟩

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