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Am J Hum Genet. 2016 May 5;98(5):993-1000. doi: 10.1016/j.ajhg.2016.03.010. Epub 2016 Apr 28.

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

Author information

1
INSERM U1163, Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, 75015 Paris, France.
2
Institute of Neuroscience, Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
3
Institute of Human Development, University of Manchester, Manchester M13 9WL, UK; Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester M13 9WL, UK.
4
Departments of Pediatric, Neurology and Genetics, Hôpital Necker-Enfants-Malades, 75015 Paris, France.
5
Institute of Genetic Medicine, Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
6
Harry Perkins Institute of Medical Research, Centre for Medical Research and School of Chemistry and Biochemistry, The University of Western Australia, Nedlands, WA 6009, Australia.
7
INSERM U1163, Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, 75015 Paris, France; Departments of Pediatric, Neurology and Genetics, Hôpital Necker-Enfants-Malades, 75015 Paris, France.
8
Institute of Genetic Medicine, Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK; Medical Research Council Mitochondrial Biology Unit, Cambridge CB2 0XY, UK; Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge CB2 0SP, UK.
9
INSERM U1163, Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, 75015 Paris, France. Electronic address: agnes.rotig@inserm.fr.
10
Institute of Neuroscience, Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne NE2 4HH, UK. Electronic address: robert.taylor@ncl.ac.uk.

Abstract

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 5' 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.

PMID:
27132592
PMCID:
PMC4863561
DOI:
10.1016/j.ajhg.2016.03.010
[Indexed for MEDLINE]
Free PMC Article

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