PMID- 27132592
OWN - NLM
STAT- MEDLINE
DCOM- 20170515
LR  - 20221111
IS  - 1537-6605 (Electronic)
IS  - 0002-9297 (Print)
IS  - 0002-9297 (Linking)
VI  - 98
IP  - 5
DP  - 2016 May 5
TI  - Recessive Mutations in TRMT10C Cause Defects in Mitochondrial RNA Processing and 
      Multiple Respiratory Chain Deficiencies.
PG  - 993-1000
LID - S0002-9297(16)30045-3 [pii]
LID - 10.1016/j.ajhg.2016.03.010 [doi]
AB  - 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.
CI  - Copyright (c) 2016 The Authors. Published by Elsevier Inc. All rights reserved.
FAU - Metodiev, Metodi D
AU  - Metodiev MD
AD  - INSERM U1163, Universite Paris Descartes-Sorbonne Paris Cite, Institut Imagine, 
      75015 Paris, France.
FAU - Thompson, Kyle
AU  - Thompson K
AD  - Institute of Neuroscience, Wellcome Trust Centre for Mitochondrial Research, 
      Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
FAU - Alston, Charlotte L
AU  - Alston CL
AD  - Institute of Neuroscience, Wellcome Trust Centre for Mitochondrial Research, 
      Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
FAU - Morris, Andrew A M
AU  - Morris AAM
AD  - 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.
FAU - He, Langping
AU  - He L
AD  - Institute of Neuroscience, Wellcome Trust Centre for Mitochondrial Research, 
      Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
FAU - Assouline, Zarah
AU  - Assouline Z
AD  - Departments of Pediatric, Neurology and Genetics, Hopital Necker-Enfants-Malades, 
      75015 Paris, France.
FAU - Rio, Marlene
AU  - Rio M
AD  - Departments of Pediatric, Neurology and Genetics, Hopital Necker-Enfants-Malades, 
      75015 Paris, France.
FAU - Bahi-Buisson, Nadia
AU  - Bahi-Buisson N
AD  - Departments of Pediatric, Neurology and Genetics, Hopital Necker-Enfants-Malades, 
      75015 Paris, France.
FAU - Pyle, Angela
AU  - Pyle A
AD  - Institute of Genetic Medicine, Wellcome Trust Centre for Mitochondrial Research, 
      Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
FAU - Griffin, Helen
AU  - Griffin H
AD  - Institute of Genetic Medicine, Wellcome Trust Centre for Mitochondrial Research, 
      Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
FAU - Siira, Stefan
AU  - Siira S
AD  - 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.
FAU - Filipovska, Aleksandra
AU  - Filipovska A
AD  - 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.
FAU - Munnich, Arnold
AU  - Munnich A
AD  - INSERM U1163, Universite Paris Descartes-Sorbonne Paris Cite, Institut Imagine, 
      75015 Paris, France; Departments of Pediatric, Neurology and Genetics, Hopital 
      Necker-Enfants-Malades, 75015 Paris, France.
FAU - Chinnery, Patrick F
AU  - Chinnery PF
AD  - 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.
FAU - McFarland, Robert
AU  - McFarland R
AD  - Institute of Neuroscience, Wellcome Trust Centre for Mitochondrial Research, 
      Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
FAU - Rotig, Agnes
AU  - Rotig A
AD  - INSERM U1163, Universite Paris Descartes-Sorbonne Paris Cite, Institut Imagine, 
      75015 Paris, France. Electronic address: agnes.rotig@inserm.fr.
FAU - Taylor, Robert W
AU  - Taylor RW
AD  - Institute of Neuroscience, Wellcome Trust Centre for Mitochondrial Research, 
      Newcastle University, Newcastle upon Tyne NE2 4HH, UK. Electronic address: 
      robert.taylor@ncl.ac.uk.
LA  - eng
GR  - MC_UP_1501/2/MRC_/Medical Research Council/United Kingdom
GR  - G0601943/MRC_/Medical Research Council/United Kingdom
GR  - MC_PC_13047/MRC_/Medical Research Council/United Kingdom
GR  - WT_/Wellcome Trust/United Kingdom
GR  - NIHR-HCS-D12-03-04/DH_/Department of Health/United Kingdom
PT  - Case Reports
PT  - Journal Article
DEP - 20160428
PL  - United States
TA  - Am J Hum Genet
JT  - American journal of human genetics
JID - 0370475
RN  - 0 (RNA, Mitochondrial)
RN  - 63231-63-0 (RNA)
RN  - 9014-25-9 (RNA, Transfer)
RN  - EC 2.1.1.- (Methyltransferases)
RN  - EC 2.1.1.- (TRMT10c protein, human)
RN  - EC 3.1.26.5 (PRORP protein, human)
RN  - EC 3.1.26.5 (Ribonuclease P)
SB  - IM
EIN - Am J Hum Genet. 2016 Jul 7;99(1):246. PMID: 27392079
MH  - Amino Acid Sequence
MH  - Electron Transport/genetics
MH  - Female
MH  - Genes, Recessive/*genetics
MH  - Humans
MH  - Infant, Newborn
MH  - Male
MH  - Methyltransferases/*genetics
MH  - Mitochondria/metabolism
MH  - Mitochondrial Diseases/*etiology/pathology
MH  - Mutation/*genetics
MH  - Pedigree
MH  - Protein Biosynthesis/physiology
MH  - RNA/*genetics/metabolism
MH  - RNA Processing, Post-Transcriptional/*genetics
MH  - RNA, Mitochondrial
MH  - RNA, Transfer/genetics
MH  - Ribonuclease P/*genetics
MH  - Sequence Homology, Amino Acid
PMC - PMC4863561
EDAT- 2016/05/03 06:00
MHDA- 2017/05/16 06:00
PMCR- 2016/04/28
CRDT- 2016/05/03 06:00
PHST- 2016/01/26 00:00 [received]
PHST- 2016/03/14 00:00 [accepted]
PHST- 2016/05/03 06:00 [entrez]
PHST- 2016/05/03 06:00 [pubmed]
PHST- 2017/05/16 06:00 [medline]
PHST- 2016/04/28 00:00 [pmc-release]
AID - S0002-9297(16)30045-3 [pii]
AID - 10.1016/j.ajhg.2016.03.010 [doi]
PST - ppublish
SO  - Am J Hum Genet. 2016 May 5;98(5):993-1000. doi: 10.1016/j.ajhg.2016.03.010. Epub 
      2016 Apr 28.