Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Cordovado A

PROVIDER: S-EPMC9764436 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Cordovado Amélie A Schaettin Martina M Jeanne Médéric M Panasenkava Veranika V Denommé-Pichon Anne-Sophie AS Keren Boris B Mignot Cyril C Doco-Fenzy Martine M Rodan Lance L Ramsey Keri K Narayanan Vinodh V Jones Julie R JR Prijoles Eloise J EJ Mitchell Wendy G WG Ozmore Jillian R JR Juliette Kali K Torti Erin E Normand Elizabeth A EA Granger Leslie L Petersen Andrea K AK Au Margaret G MG Matheny Juliann P JP Phornphutkul Chanika C Chambers Mary-Kathryn MK Fernández-Ramos Joaquín-Alejandro JA López-Laso Eduardo E Kruer Michael C MC Bakhtiari Somayeh S Zollino Marcella M Morleo Manuela M Marangi Giuseppe G Mei Davide D Pisano Tiziana T Guerrini Renzo R Louie Raymond J RJ Childers Anna A Everman David B DB Isidor Betrand B Audebert-Bellanger Séverine S Odent Sylvie S Bonneau Dominique D Gilbert-Dussardier Brigitte B Redon Richard R Bézieau Stéphane S Laumonnier Frédéric F Stoeckli Esther T ET Toutain Annick A Vuillaume Marie-Laure ML

Human molecular genetics 20220901 19

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 varia ...[more]

PMID: 35604360

Similar Datasets

Project description:There is considerable genetic and phenotypic heterogeneity associated with intellectual disability (ID), specific learning disabilities, attention-deficit hyperactivity disorder, autism and epilepsy. The intelligence quotient (IQ) motif and SEC7 domain containing protein 2 gene (IQSEC2) is located on the X-chromosome and harbors mutations that contribute to non-syndromic ID with and without early-onset seizure phenotypes in both sexes. Although IQ and Sec7 domain mutations lead to partial loss of IQSEC2 enzymatic activity, the in vivo pathogenesis resulting from these mutations is not known. Here we reveal that IQSEC2 has a key role in dendritic spine morphology. Partial loss-of-function mutations were modeled using a lentiviral short hairpin RNA (shRNA) approach, which achieved a 57% knockdown of Iqsec2 expression in primary hippocampal cell cultures from mice. Investigating gross morphological parameters after 8 days of in vitro culture (8DIV) identified a 32% reduction in primary axon length, in contrast to a 27% and 31% increase in the number and complexity of dendrites protruding from the cell body, respectively. This increase in dendritic complexity and spread was carried through dendritic spine development, with a 34% increase in the number of protrusions per dendritic segment compared with controls at 15DIV. Although the number of dendritic spines had normalized by 21DIV, a reduction was noted in the number of immature spines. In contrast, when modeling increased dosage, overexpression of wild-type IQSEC2 led to neurons with shorter axons that were more compact and displayed simpler dendritic branching. Disturbances to dendritic morphology due to knockdown of Iqsec2 were recapitulated in neurons from Iqsec2 knockout mice generated in our laboratory using CRISPR/Cas9 technology. These observations provide evidence of dosage sensitivity for IQSEC2, which normally escapes X-inactivation in females, and links these disturbances in expression to alterations in the morphology of developing neurons.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets