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The epilepsy-associated protein TBC1D24 is required for normal development, survival and vesicle trafficking in mammalian neurons.

Finelli, Mattéa J. and Aprile, Davide and Castroflorio, Enrico and Jeans, Alexander and Moschetta, Matteo and Chessum, Lauren and Degiacomi, Matteo T. and Grasegger, Julia and Lupien-Meilleur, Alexis and Bassett, Andrew and Rossignol, Elsa and Campeau, Philippe M. and Bowl, Michael R. and Benfenati, Fabio and Fassio, Anna and Oliver, Peter L. (2019) 'The epilepsy-associated protein TBC1D24 is required for normal development, survival and vesicle trafficking in mammalian neurons.', Human molecular genetics., 28 (4). pp. 584-597.

Abstract

Mutations in the Tre2/Bub2/Cdc16 (TBC)1 domain family member 24 (TBC1D24) gene are associated with a range of inherited neurological disorders, from drug-refractory lethal epileptic encephalopathy and DOORS syndrome (deafness, onychodystrophy, osteodystrophy, mental retardation, seizures) to non-syndromic hearing loss. TBC1D24 has been implicated in neuronal transmission and maturation, although the molecular function of the gene and the cause of the apparently complex disease spectrum remain unclear. Importantly, heterozygous TBC1D24 mutation carriers have also been reported with seizures, suggesting that haploinsufficiency for TBC1D24 is significant clinically. Here we have systematically investigated an allelic series of disease-associated mutations in neurons alongside a new mouse model to investigate the consequences of TBC1D24 haploinsufficiency to mammalian neurodevelopment and synaptic physiology. The cellular studies reveal that disease-causing mutations that disrupt either of the conserved protein domains in TBC1D24 are implicated in neuronal development and survival and are likely acting as loss-of-function alleles. We then further investigated TBC1D24 haploinsufficiency in vivo and demonstrate that TBC1D24 is also crucial for normal presynaptic function: genetic disruption of Tbc1d24 expression in the mouse leads to an impairment of endocytosis and an enlarged endosomal compartment in neurons with a decrease in spontaneous neurotransmission. These data reveal the essential role for TBC1D24 at the mammalian synapse and help to define common synaptic mechanisms that could underlie the varied effects of TBC1D24 mutations in neurological disease.

Item Type:Article
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Full text:(VoR) Version of Record
Available under License - Creative Commons Attribution.
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Status:Peer-reviewed
Publisher Web site:https://doi.org/10.1093/hmg/ddy370
Publisher statement:© The Author(s) 2018. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
Date accepted:09 October 2018
Date deposited:04 December 2018
Date of first online publication:17 October 2018
Date first made open access:No date available

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