Fiche publication
Date publication
juin 2019
Journal
Human mutation
Auteurs
Membres identifiés du Cancéropôle Est :
Pr MANDEL Jean-Louis
Tous les auteurs :
Quartier A, Courraud J, Thi Ha T, McGillivray G, Isidor B, Rose K, Drouot N, Savidan MA, Feger C, Jagline H, Chelly J, Shaw M, Laumonnier F, Gecz J, Mandel JL, Piton A
Lien Pubmed
Résumé
The X-linked NLGN3 gene, encoding a postsynaptic cell adhesion molecule, was involved in a non-syndromic monogenic form of Autism Spectrum Disorder (ASD) by the description of one unique missense variant, p.Arg451Cys (Jamain et al. 2003). We investigated here the pathogenicity of additional missense variants identified in two multiplex families with intellectual disability (ID) and ASD: c.1789C>T, p.Arg597Trp, previously reported by our group (Redin et al. 2014) and present in three affected cousins and c.1540C>T, p.Pro514Ser, identified in two affected brothers. Overexpression experiments in HEK293 and HeLa cell lines revealed that both variants affect the level of the mature NLGN3 protein, its localization at the plasma membrane and its presence as a cleaved form in the extracellular environment, even more drastically than what was reported for the initial p.Arg451Cys mutation. The variants also induced an Unfolded Protein Response (UPR), probably due to the retention of immature NLGN3 proteins in the endoplasmic reticulum. In comparison, the c.1894A>G, p.Ala632Thr and c.1022T>C, p.Val341Ala variants, present in males from the general population, have no effect. Our report of two missense variants affecting the normal localization of NLGN3 in a total of five affected individuals reinforces the involvement of the NLGN3 gene in a neurodevelopmental disorder characterized by ID and ASD. This article is protected by copyright. All rights reserved.
Mots clés
Autism Spectrum Disorder, Intellectual disability, Missense variants, Neuroligin 3, Unfolded Protein Response
Référence
Hum. Mutat.. 2019 Jun 10;:
