PXD030427-1

PXD030427 is an original dataset announced via ProteomeXchange.

Title	TEFM variants impair mitochondrial transcription elongation causing childhood-onset neurological disease
Description	Mutations in either the mitochondrial or nuclear genomes are associated with a diverse group of human disorders characterized by impaired mitochondrial respiration. Within this group, an increasing number of mutations have been identified in nuclear genes involved in mitochondrial RNA biology. The TEFM gene codes for the mitochondrial transcription elongation factor responsible for enhancing the processivity of mitochondrial RNA polymerase, POLRMT. Here, we report for the first time that TEFM variants are associated with mitochondrial respiratory chain deficiency and a wide range of clinical presentations including neonatal lactic acidosis, epileptic encephalopathy, developmental delay, intellectual disability or mitochondrial myopathy with a treatable neuromuscular transmission defect. Mechanistically, we show that muscle samples and primary fibroblasts from the affected individuals have reduced levels of promoter distal mitochondrial RNA transcripts, consistent with decreased processivity of POLRMT when TEFM is dysfunctional. We provide further evidence for the pathogenicity of these variants by investigating mitochondrial transcription and proteomic changes in patient cells and muscle and by studying TEFM activity in an in vitro system. Finally, tefm knock-down in zebrafish embryos resulted in neuromuscular junction abnormalities and abnormal mitochondrial function, strengthening the genotype-phenotype correlation. In conclusion, our study highlights that TEFM regulates mitochondrial transcription elongation in human tissues and its defect results in variable, tissue specific neurological and neuromuscular symptoms.
HostingRepository	PRIDE
AnnounceDate	2022-11-07
AnnouncementXML	Submission_2022-11-07_15:28:05.178.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	DavidStroud
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2021-12-15 08:20:41	ID requested
⏵ 1	2022-11-07 15:28:05	announced

Dataset with its publication pending

submitter keyword: Mitochondria, transcription, mitochondrial disease, RNA

DavidStroud
contact affiliation	Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, 30 Flemington Road, Parkville, Victoria 3052 Australia
contact email	david.stroud@unimelb.edu.au
lab head
DavidStroud
contact affiliation	The University of Melbourne
contact email	david.stroud@unimelb.edu.au
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD030427
     1. Label: PRIDE project
     2. Name: TEFM variants impair mitochondrial transcription elongation causing childhood-onset neurological disease