TMEM63C mutations cause mitochondrial morphology defects and underlie hereditary spastic paraplegia

Author:

Tábara Luis Carlos1ORCID,Al-Salmi Fatema2,Maroofian Reza3,Al-Futaisi Amna Mohammed4,Al-Murshedi Fathiya4,Kennedy Joanna25,Day Jacob O26,Courtin Thomas7ORCID,Al-Khayat Aisha8,Galedari Hamid9,Mazaheri Neda9,Protasoni Margherita1,Johnson Mark1,Leslie Joseph S2ORCID,Salter Claire G2,Rawlins Lettie E210ORCID,Fasham James210,Al-Maawali Almundher4,Voutsina Nikol2,Charles Perrine7,Harrold Laura2,Keren Boris7,Kunji Edmund R S1ORCID,Vona Barbara11ORCID,Jelodar Gholamreza12,Sedaghat Alireza13,Shariati Gholamreza14,Houlden Henry3ORCID,Crosby Andrew H2ORCID,Prudent Julien1ORCID,Baple Emma L210

Affiliation:

1. Medical Research Council Mitochondrial Biology Unit, University of Cambridge , Cambridge CB2 0XY , UK

2. Level 4, RILD Wellcome Wolfson Medical Research Centre, RD&E (Wonford) NHS Foundation Trust, University of Exeter Medical School , Exeter EX2 5DW , UK

3. UCL Queen Square Institute of Neurology, University College London , London WC1E 6BT , UK

4. Genetic and Developmental Medicine Clinic, Department of Genetics, College of Medicine and Health Sciences, Sultan Qaboos University Hospital , Muscat 123 , Oman

5. Clinical Genetics, University Hospitals Bristol , Bristol BS2 8EG , UK

6. Faculty of Health, University of Plymouth , Plymouth PL4 8AA , UK

7. Département de génétique, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris , 75019 Paris, Sorbonne Université , France

8. Department of Biology, College of Science, Sultan Qaboos University , Muscat , Oman

9. Department of Genetics, Faculty of Science, Shahid Chamran University of Ahvaz , Ahvaz , Iran

10. Peninsula Clinical Genetics Service, Royal Devon and Exeter Hospital (Heavitree) , Exeter EX1 2ED , UK

11. Department of Otolaryngology-Head and Neck Surgery, Tübingen Hearing Research Centre, Eberhard Karls University Tübingen , Tübingen , Germany

12. Pediatric Neurology, Ahvaz Jundishapur University of Medical Sciences , Ahvaz , Iran

13. Health Research Institute, Diabetes Research Center, Ahvaz Jundishapur University of Medical Sciences , Ahvaz , Iran

14. Department of Medical Genetic, Faculty of Medicine, Ahvaz Jundishapur, University of Medical Sciences , Ahvaz , Iran

Abstract

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.

Funder

Halpin Trust

Hereditary Spastic Paraplegia Support Group

Medical Research Council UK

University of Exeter

Newlife Foundation for Disabled Children

Oman Ministry of Higher Education

Sultanate of Oman

Publisher

Oxford University Press (OUP)

Subject

Neurology (clinical)

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