Repository logo
 

TMEM63C mutations cause mitochondrial morphology defects and underlie hereditary spastic paraplegia.

Accepted version
Peer-reviewed

Type

Article

Change log

Authors

Tábara, Luis Carlos  ORCID logo  https://orcid.org/0000-0001-7684-3811
Al-Salmi, Fatema 
Maroofian, Reza 
Al-Futaisi, Amna Mohammed 
Al-Murshedi, Fathiya 

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.

Description

Keywords

TMEM63C, endoplasmic reticulum/ER, hereditary spastic paraplegia/HSP, mitochondria, mitochondria-ER contact sites/MERCs, Calcium Channels, Endoplasmic Reticulum, Humans, Mitochondria, Mutation, Spastic Paraplegia, Hereditary

Journal Title

Brain

Conference Name

Journal ISSN

0006-8950
1460-2156

Volume Title

Publisher

Oxford University Press (OUP)
Sponsorship
MRC (MC_UU_00015/7)
Medical Research Council (MC_UU_00015/7)
MRC (MC_UU_00028/2)
MRC (MC_UU_00028/5)