The epilepsy-associated protein TBC1D24 is required for normal development, survival and vesicle trafficking in mammalian neurons
Open accessAbstract
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.
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Autosomal recessive LOF variants in TBC1D24 lead to DEEs with myoclonic seizures and EIMFS, with dystonia.
“Autosomal recessive LOF variants in TBC1D24, encoding a GTPase-activating protein essential for synaptic vesicle trafficking 105 , lead to DEEs with myoclonic seizures and EIMFS, with dystonia 106 .”
From Developmental and epileptic encephalopathies (2024) · cites this paper as [105]
The Introduction and Results (page numbers unavailable) link predominantly recessive TBC1D24 mutations and likely loss-of-function alleles to myoclonic epilepsy and early-onset epileptic encephalopathy. The paper does not identify EIMFS or dystonia as associated phenotypes, so those specifics are not supported. (LLM, conf=0.88)
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Developmental and epileptic encephalopathies: from genetic heterogeneity to phenotypic continuum
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- Authors
- Finelli, M. J., Aprile, D., Castroflorio, E., Jeans, A., Moschetta, M., Chessum, L., Degiacomi, M. T., Grasegger, J., Lupien-Meilleur, A., Bassett, A., Rossignol, E., Campeau, P. M., Bowl, M. R., Benfenati, F., Fassio, A., & Oliver, P. L.
- Affiliations
- University of Oxford (GB)
- University of Genoa (IT)
- Italian Institute of Technology (IT)
- Mary Lyon Centre at MRC Harwell (GB)
- Durham University (GB)
- CHU Ste-Justine, Departments of Neurosciences and Pediatrics, Université de Montréal, Montreal, QC, Canada
- Wellcome Sanger Institute (GB)
- Centre Hospitalier Universitaire Sainte-Justine (CA)
- Ospedale Policlinico San Martino (IT)
- Corresponding author
- Fassio, Anna
- Oliver, Peter L
- ORCID
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2018-10-17
- Volume
- 28
- Issue
- 4
- Pages
- 584-597
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- PMC
- PMC6360273
- OpenAlex
- W2896326568
- Cited by
- 62
- References
- 47
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 14 · 2023: 3 · 2022: 8 · 2021: 7 · 2020: 11 · 2019: 6 · 2018: 2
- FWCI
- 3.99
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Human Molecular Genetics (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Repository@Nottingham (University of Nottingham) (publishedVersion, cc-by)
- Durham Research Online (Durham University) (acceptedVersion, other-oa)
- UCL Discovery (University College London) (submittedVersion)
- Durham Research Online (Durham University) (submittedVersion, cc-by)
- Repository@Nottingham (University of Nottingham) (submittedVersion, cc-by)
- CINECA IRIS Institutial Research Information System (University of Genoa) (submittedVersion, other-oa)
- Funders
- European Research Council Consolidator Award ‘PAROSIN’ (311394)
- Medical Research Council Programme Grant (MR/P502005/1)
- University of Genoa
- Compagnia di San Paolo (2015.0546)
- EU FP7 Integrating Project ‘Desire’ (602531)
- Fondazione CARIGE
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Keywords
- TBC1D24, haploinsufficiency, epilepsy, brain development, neuronal survival, vesicle trafficking, endocytosis, endosomes, presynaptic function, spontaneous neurotransmission, loss-of-function mutations, mouse model, synapses
- MeSH terms
- Amino Acid Sequence, Animals, Carrier Proteins, Disease Models, Animal, Endocytosis, Epilepsy, Gene Expression Regulation, Hand Deformities, Congenital, Hearing Loss, Sensorineural, Humans, Membrane Proteins, Intellectual Disability, Mutation, Nails, Malformed, Nerve Tissue Proteins, Neuronal Plasticity, Neurons, Pedigree, Seizures, Craniofacial Abnormalities, GTPase-Activating Proteins, Mice, Haploinsufficiency, Exome
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