SEMA6B variants cause intellectual disability and alter dendritic spine density and axon guidance - Université de Rennes Accéder directement au contenu
Article Dans Une Revue Human Molecular Genetics Année : 2022

SEMA6B variants cause intellectual disability and alter dendritic spine density and axon guidance

1 iBraiN - Imaging, Brain & Neuropsychiatry
2 UZH - Universität Zürich [Zürich] = University of Zurich
3 FHU TRANSLAD (CHU de Dijon)
4 Equipe GAD (LNC - U1231)
5 CHU Pitié-Salpêtrière [AP-HP]
6 HERVI - EA 3801 - Hémostase et Remodelage Vasculaire Post-Ischémie
7 Boston Children's Hospital
8 TGen - The Translational Genomics Research Institute
9 The Greenwood Genetic Center
10 Keck School of Medicine [Los Angeles]
11 DHMC - Dartmouth Hitchcock Medical Center
12 Gillette Children's Specialty Healthcare [St Paul]
13 GeneDx [Gaithersburg, MD, USA]
14 Randall Children's Hospital [Portland]
15 UK - University of Kentucky
16 Warren Alpert Medical School of Brown University
17 Rhode Island Hospital [Providence, RI, États-Unis]
18 IMIBIC - Instituto Maimonides de Investigación Biomédica de Cordoba
19 Barrow Neurological Institute
20 IRCCS - Istituti di Ricovero e Cura a Carattere Scientifico
21 TIGEM - Telethon Institute of Genetics and Medicine = Istituto Telethon di Genetica e Medicina
22 UniFI - Università degli Studi di Firenze = University of Florence
23 CHU Nantes - Centre Hospitalier Universitaire de Nantes
24 CHU - BREST - Hôpital Morvan - CHRU de Brest
25 IGDR - Institut de Génétique et Développement de Rennes
26 Centre Hospitalier Universitaire de Rennes [CHU Rennes] = Rennes University Hospital [Ponchaillou]
27 MITOVASC - MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale
28 ITX-lab - ITX-lab unité de recherche de l'institut du thorax UMR1087 UMR6291
Boris Keren
  • Fonction : Auteur
  • PersonId : 1100999
Lance Rodan
Bertrand Isidor
  • Fonction : Auteur
  • PersonId : 886372
Brigitte Gilbert-Dussardier
  • Fonction : Auteur
  • PersonId : 1027055

Résumé

Intellectual disability (ID) is a neurodevelopmental disorder frequently caused by monogenic defects. In this study, we collected 14 SEMA6B heterozygous variants in 16 unrelated patients referred for ID to different centers. Whereas, until now, SEMA6B variants have mainly been reported in patients with progressive myoclonic epilepsy, our study indicates that the clinical spectrum is wider and also includes non-syndromic ID without epilepsy or myoclonus. To assess the pathogenicity of these variants, selected mutated forms of Sema6b were overexpressed in Human Embryonic Kidney 293T (HEK293T) cells and in primary neuronal cultures. shRNAs targeting Sema6b were also used in neuronal cultures to measure the impact of the decreased Sema6b expression on morphogenesis and synaptogenesis. The overexpression of some variants leads to a subcellular mislocalization of SEMA6B protein in HEK293T cells and to a reduced spine density owing to loss of mature spines in neuronal cultures. Sema6b knockdown also impairs spine density and spine maturation. In addition, we conducted in vivo rescue experiments in chicken embryos with the selected mutated forms of Sema6b expressed in commissural neurons after knockdown of endogenous SEMA6B. We observed that expression of these variants in commissural neurons fails to rescue the normal axon pathway. In conclusion, identification of SEMA6B variants in patients presenting with an overlapping phenotype with ID and functional studies highlight the important role of SEMA6B in neuronal development, notably in spine formation and maturation and in axon guidance. This study adds SEMA6B to the list of ID-related genes.
Fichier principal
Vignette du fichier
Cordovado et al - 2022 - SEMA6B variants cause intellectual disability.pdf (2.39 Mo) Télécharger le fichier
Supplemental Data.pdf (487.38 Ko) Télécharger le fichier
Origine : Fichiers produits par l'(les) auteur(s)

Dates et versions

hal-03719616 , version 1 (21-07-2022)

Identifiants

Citer

Amélie Cordovado, Martina Schaettin, Mederic Jeanne, Veranika Panasenkava, Anne‐sophie Denommé‐pichon, et al.. SEMA6B variants cause intellectual disability and alter dendritic spine density and axon guidance. Human Molecular Genetics, 2022, 31 (19), pp.3325-3340. ⟨10.1093/hmg/ddac114⟩. ⟨hal-03719616⟩
216 Consultations
101 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More