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Novel mutations in NLGN3 causing autism spectrum disorder and cognitive impairment
Author(s) -
Quartier Angélique,
Courraud Jérémie,
Thi Ha Thuong,
McGillivray George,
Isidor Bertrand,
Rose Katherine,
Drouot Nathalie,
Savidan MarieArmel,
Feger Claire,
Jagline Hélène,
Chelly Jamel,
Shaw Marie,
Laumonnier Frédéric,
Gecz Jozef,
Mandel JeanLouis,
Piton Amélie
Publication year - 2019
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.23836
Subject(s) - missense mutation , biology , autism spectrum disorder , hek 293 cells , genetics , neurodevelopmental disorder , mutation , gene , endoplasmic reticulum , autism , medicine , psychiatry
Abstract The X‐linked NLGN3 gene, encoding a postsynaptic cell adhesion molecule, was involved in a nonsyndromic 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, 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.