Fiche publication
Date publication
mars 2025
Journal
Human mutation
Auteurs
Membres identifiés du Cancéropôle Est :
Pr FAIVRE Laurence
Tous les auteurs :
Cordovado A, Hérenger Y, Cormier C, López-Martín E, Stamberger H, Faivre L, Denommé-Pichon AS, Vitobello A, Abdallah HH, Barcia G, Courtin T, Martínez-Delgado B, Bermejo-Sánchez E, Barrero MJ, Gasser B, Bezieau S, Küry S, Weckhuysen S, Laumonnier F, Toutain A, Vuillaume ML
Lien Pubmed
Résumé
Intellectual disability is a neurodevelopmental disorder, affecting 2%-3% of the population, with a genetic cause in the majority of cases. (Online Mendelian Inheritance in Man (OMIM)609126, NM_006045.3) has recently been added to the list of candidate genes involved in this disorder with the identification of biallelic truncating variants in patients with a neurodevelopmental disorder. In this study, we propose a novel mode of inheritance for -related disorders with the identification of five de novo heterozygous missense variants (p.(Thr393Arg), p.(Glu400Gln), p.(Lys461Glu), p.(Gly552Ala), and p.(His713Asp)), in patients with intellectual disability. In a patient with a similar phenotype, we also identified two truncating variants in (p.(Arg145), p.(Glu901)), adding a novel family to the six already described in the literature with the recessive mode of inheritance. Functional studies were performed to assess the pathogenicity of these variants. Overexpression of four selected missense mutant forms of in HeLa cells and in primary neuronal cultures led to a loss of mature dendritic spines. In HeLa cells, the endosomal localization of the protein encoded by three of these missense variants was preserved whereas the fourth remained blocked in the endoplasmic reticulum. To mimic the effect on neuronal morphology and spine density of nonsense variants, small hairpin RNAs (shRNAs) were used. They induced a decreased expression of , affecting the neuronal arborization by decreasing the number of dendrites per neuron. Our results therefore demonstrate the pathogenicity of heterozygous missense variants and confirm the role of in neuronal maturation and in brain wiring during development. They strengthen the association of with neurodevelopmental disorders and demonstrate that a double mode of inheritance should be considered for -related disorders.
Mots clés
Humans, Mutation, Missense, Intellectual Disability, genetics, Heterozygote, Male, Dendritic Spines, metabolism, Female, Pedigree, HeLa Cells, Sodium-Potassium-Exchanging ATPase, genetics, Phenotype, Genetic Predisposition to Disease, Genetic Association Studies
Référence
Hum Mutat. 2025 03 5;2025:7085599
