RT Journal Article
T1 SEMA6B variants cause intellectual disability and alter dendritic spine density and axon guidance.
A1 Cordovado, Amelie
A1 Schaettin, Martina
A1 Jeanne, Mederic
A1 Panasenkava, Veranika
A1 Denomme-Pichon, Anne-Sophie
A1 Keren, Boris
A1 Mignot, Cyril
A1 Doco-Fenzy, Martine
A1 Rodan, Lance
A1 Ramsey, Keri
A1 Narayanan, Vinodh
A1 Jones, Julie R
A1 Prijoles, Eloise J
A1 Mitchell, Wendy G
A1 Ozmore, Jillian R
A1 Juliette, Kali
A1 Torti, Erin
A1 Normand, Elizabeth A
A1 Granger, Leslie
A1 Petersen, Andrea K
A1 Au, Margaret G
A1 Matheny, Juliann P
A1 Phornphutkul, Chanika
A1 Chambers, Mary-Kathryn
A1 Fernandez-Ramos, Joaquin-Alejandro
A1 Lopez-Laso, Eduardo
A1 Kruer, Michael C
A1 Bakhtiari, Somayeh
A1 Zollino, Marcella
A1 Morleo, Manuela
A1 Marangi, Giuseppe
A1 Mei, Davide
A1 Pisano, Tiziana
A1 Guerrini, Renzo
A1 Louie, Raymond J
A1 Childers, Anna
A1 Everman, David B
A1 Isidor, Betrand
A1 Audebert-Bellanger, Severine
A1 Odent, Sylvie
A1 Bonneau, Dominique
A1 Gilbert-Dussardier, Brigitte
A1 Redon, Richard
A1 Bezieau, Stephane
A1 Laumonnier, Frederic
A1 Stoeckli, Esther T
A1 Toutain, Annick
A1 Vuillaume, Marie-Laure
K1 Animals
K1 Axon guidance
K1 Chick embryo
K1 Dendritic spines
AB 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.
PB Oxford University Press
YR 2022
FD 2022-05-12
LK http://hdl.handle.net/10668/19787
UL http://hdl.handle.net/10668/19787
LA en
NO Cordovado A, Schaettin M, Jeanne M, Panasenkava V, Denommé-Pichon AS, Keren B, et al. SEMA6B variants cause intellectual disability and alter dendritic spine density and axon guidance. Hum Mol Genet. 2022 Sep 29;31(19):3325-3340
NO Funding for HUGODIMS (Western France exomebased trio approach project to identify genes involved in ID) was supported by a grant from the French Ministry of Health and from the Health Regional Agency from Poitou-Charentes (HUGODIMS, 2013, RC14_0107). A.C. is a research student recipient of a grant from the University of Tours
DS RISalud
RD Apr 7, 2025