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Recessive Mutations in TRMT10C Cause Defects in Mitochondrial RNA Processing and Multiple Respiratory Chain Deficiencies

Lookup NU author(s): Dr Kyle Thompson, Dr Charlotte Alston, Dr Langping He, Dr Angela Pyle, Dr Helen GriffinORCiD, Professor Patrick Chinnery, Professor Bobby McFarlandORCiD, Professor Robert Taylor



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Mitochondrial disorders are clinically and genetically diverse, with mutations in mitochondrial or nuclear genes able to cause defects in mitochondrial gene expression. Recently, mutations in several genes encoding factors involved in mt-tRNA processing have been identified to cause mitochondrial disease. Using whole-exome sequencing, we identified mutations in TRMT10C (encoding the mitochondrial RNase P protein 1 [MRPP1]) in two unrelated individuals who presented at birth with lactic acidosis, hypotonia, feeding difficulties, and deafness. Both individuals died at 5 months after respiratory failure. MRPP1, along with MRPP2 and MRPP3, form the mitochondrial ribonuclease P (mt-RNase P) complex that cleaves the 50 ends of mt-tRNAs from polycistronic precursor transcripts. Additionally, a stable complex of MRPP1 and MRPP2 has m(1)R9 methyltransferase activity, which methylates mt-tRNAs at position 9 and is vital for folding mt-tRNAs into their correct tertiary structures. Analyses of fibroblasts from affected individuals harboring TRMT10C missense variants revealed decreased protein levels of MRPP1 and an increase in mt-RNA precursors indicative of impaired mt-RNA processing and defective mitochondrial protein synthesis. The pathogenicity of the detected variants-compound heterozygous c.542G>T (p.Arg181Leu) and c.814A>G (p.Thr272Ala) changes in subject 1 and a homozygous c.542G>T (p.Arg181Leu) variant in subject 2-was validated by the functional rescue of mt-RNA processing and mitochondrial protein synthesis defects after lentiviral transduction of wild-type TRMT10C. Our study suggests that these variants affect MRPP1 protein stability and mt-tRNA processing without affecting m(1)R9 methyltransferase activity, identifying mutations in TRMT10C as a cause of mitochondrial disease and highlighting the importance of RNA processing for correct mitochondrial function.

Publication metadata

Author(s): Metodiev MD, Thompson K, Alston CL, Morris AAM, He LP, Assouline Z, Rio M, Bahi-Buisson N, Pyle A, Griffin H, Siira S, Filipovska A, Munnich A, Chinnery PF, McFarland R, Rotig A, Taylor RW

Publication type: Article

Publication status: Published

Journal: American Journal of Human Genetics

Year: 2016

Volume: 98

Issue: 5

Pages: 993-1000

Print publication date: 05/05/2016

Online publication date: 28/04/2016

Acceptance date: 14/03/2016

Date deposited: 05/07/2016

ISSN (print): 0002-9297

ISSN (electronic): 1537-6605

Publisher: Cell Press


DOI: 10.1016/j.ajhg.2016.03.010

PubMed id: 27132592


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Funder referenceFunder name
National Institute for Health Research (NIHR) Biomedical Research Centre based at Cambridge University Hospitals NHS Foundation Trust
UK NHS Highly Specialised "Rare Mitochondrial Disorders of Adults and Children" Service
University of Cambridge
Alexander von Humboldt Fellowship for experienced researchers
Association Francaise contre les Myopathies
Lily Foundation
01GM1207E-Rare project GENOMIT
096919/Z/11/ZWellcome Trust
G0601943MRC Centre for Neuromuscular Diseases
MC_UP_1501/2Medical Research Council Mitochondrial Biology Unit
NIHR-HCS-D12-03-04UK National Institute for Health Research (NIHR)