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Master Thesis

Mécanisme physiopathologique et spectre clinique liés aux mutations d’ECEL1, un gène majeur d’arthrogrypose

Abstract : Arthrogryposis multiplex congenita is a large family of disorders characterized by multiple congenital joint limitations due to reduced fetal movements. The prevalence is estimated between 1/3000 and 1/12000 births. Molecular investigations by Dieterich et al. at the university Hospital of Grenoble/France and at Grenoble Institute of Neurosciences INSERM U836 revealed mutations of ECEL1 (endothelin-converting enzyme like 1) associated with a new and recognizable phenotype of distal arthrogryposis (Dieterich et al., 2013). In this study, we tested the enzymatic activity of missense mutations. We performed experiments to test their expression and their cellular localization. We developed a new enzymatic peptidase assay for ECEL1. A decrease of the activity was found for one mutation p. C760R, located inside the catalytic domain (p<0,001, n=4), confirming loss of function mechanism. All other missense mutations, located outside the catalytic domain, did not diminish the enzymatic activity of ECEL1 in vitro heralding a different pathological mechanism. Furthermore, we analyzed the phenotype-genotype correlation, using a severity score specifically designed for ECEL1 related arthrogryposis. We found that missense mutations yielded higher severity scores than non-sense and splice site mutations.
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Master Thesis
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https://dumas.ccsd.cnrs.fr/dumas-01254570
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Submitted on : Tuesday, January 12, 2016 - 2:22:24 PM
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  • HAL Id : dumas-01254570, version 1

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Brice Poreau. Mécanisme physiopathologique et spectre clinique liés aux mutations d’ECEL1, un gène majeur d’arthrogrypose . Médecine humaine et pathologie. 2014. ⟨dumas-01254570⟩

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