TMEM63C mutations cause mitochondrial morphology defects and underlie hereditary spastic paraplegia.
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Authors
Al-Salmi, Fatema
Maroofian, Reza
Al-Futaisi, Amna Mohammed
Al-Murshedi, Fathiya
Kennedy, Joanna
Day, Jacob O
Al-Khayat, Aisha
Galedari, Hamid
Mazaheri, Neda
Protasoni, Margherita
Johnson, Mark
Salter, Claire G
Fasham, James
Al-Maawali, Almundher
Voutsina, Nikol
Charles, Perrine
Harrold, Laura
Keren, Boris
Jelodar, Gholamreza
Sedaghat, Alireza
Shariati, Gholamreza
Baple, Emma L
Publication Date
2022-09-14Journal Title
Brain
ISSN
0006-8950
Publisher
Oxford University Press (OUP)
Type
Article
This Version
AM
Metadata
Show full item recordCitation
Tábara, L. C., Al-Salmi, F., Maroofian, R., Al-Futaisi, A. M., Al-Murshedi, F., Kennedy, J., Day, J. O., et al. (2022). TMEM63C mutations cause mitochondrial morphology defects and underlie hereditary spastic paraplegia.. Brain https://doi.org/10.1093/brain/awac123
Abstract
The hereditary spastic paraplegias (HSP) are among the most genetically diverse of all Mendelian disorders. They comprise a large group of neurodegenerative diseases that may be divided into 'pure HSP' in forms of the disease primarily entailing progressive lower-limb weakness and spasticity, and 'complex HSP' when these features are accompanied by other neurological (or non-neurological) clinical signs. Here, we identified biallelic variants in the transmembrane protein 63C (TMEM63C) gene, encoding a predicted osmosensitive calcium-permeable cation channel, in individuals with hereditary spastic paraplegias associated with mild intellectual disability in some, but not all cases. Biochemical and microscopy analyses revealed that TMEM63C is an endoplasmic reticulum-localized protein, which is particularly enriched at mitochondria-endoplasmic reticulum contact sites. Functional in cellula studies indicate a role for TMEM63C in regulating both endoplasmic reticulum and mitochondrial morphologies. Together, these findings identify autosomal recessive TMEM63C variants as a cause of pure and complex HSP and add to the growing evidence of a fundamental pathomolecular role of perturbed mitochondrial-endoplasmic reticulum dynamics in motor neurone degenerative diseases.
Sponsorship
MRC (MC_UU_00015/7)
Medical Research Council (MC_UU_00015/7)
MRC (MC_UU_00028/2)
Embargo Lift Date
2023-06-20
Identifiers
External DOI: https://doi.org/10.1093/brain/awac123
This record's URL: https://www.repository.cam.ac.uk/handle/1810/335811
Rights
Attribution-NonCommercial-NoDerivatives 4.0 International
Licence URL: https://creativecommons.org/licenses/by-nc-nd/4.0/
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