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ECEL1 mutations in Distal arthrogryposis – a clinical and biological challenge

le 28 juin 2016
de 13h à 14h

Séminaire de Klaus Dieterich (GIN)

Arthrogryposis multiplex congenita (AMC) is a clinical diagnosis characterized by the presence of joint contractures in at least two joint levels at birth. Causes of AMC are therefore numerous as any dysregulation occurring at the structural or functional level of organs involved in locomotion – CNS, neuromuscular system, connective and bone tissue - can lead to diminished movements in utero and secondary joint contractures. Therefore establish a precise clinical and molecular diagnosis in patients with AMC is still challenging. Distal arthrogryposis is the second most frequent subgroup of AMC. It is characterized by contractures afflicting especially but not exclusively the distal part of the extremities. We identified ECEL1 mutations as the first autosomal recessive form of distal arthrogryposis (Dieterich et al, 2013). Endothelin-converting enzyme like 1 (ECEL1) is a member of the neutral endopeptidase (neprilysine, NEP) family with a critical role in intramuscular axon branching of motor neurons during development. Most of ECEL1 mutations are splice site or non-sense mutations and predicted to lead to loss of protein function by yielding truncated proteins and mRNA decay. Expression and localisation of ECEL1 missense mutants however do not differ from that of wild-type ECEL1 in extra-neural cell models. Furthermore we showed that loss of catalytic activity might not be affected in some missense mutations suggesting a distinct physiopathological mechanism. Functional studies in motor neurons to test this hypothesis are currently undertaken.

Mise à jour le 22 octobre 2016

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