TEFM variants impair mitochondrial transcription causing childhood-onset neurological disease.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
23 02 2023
23 02 2023
Historique:
received:
30
09
2021
accepted:
20
01
2023
entrez:
23
2
2023
pubmed:
24
2
2023
medline:
3
3
2023
Statut:
epublish
Résumé
Mutations in 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 encodes the mitochondrial transcription elongation factor responsible for enhancing the processivity of mitochondrial RNA polymerase, POLRMT. We report for the first time that TEFM variants are associated with mitochondrial respiratory chain deficiency and a wide range of clinical presentations including mitochondrial myopathy with a treatable neuromuscular transmission defect. Mechanistically, we show muscle and primary fibroblasts from the affected individuals have reduced levels of promoter distal mitochondrial RNA transcripts. Finally, tefm knockdown in zebrafish embryos resulted in neuromuscular junction abnormalities and abnormal mitochondrial function, strengthening the genotype-phenotype correlation. Our study highlights that TEFM regulates mitochondrial transcription elongation and its defect results in variable, tissue-specific neurological and neuromuscular symptoms.
Identifiants
pubmed: 36823193
doi: 10.1038/s41467-023-36277-7
pii: 10.1038/s41467-023-36277-7
pmc: PMC9950373
doi:
Substances chimiques
Transcription Factors
0
RNA, Mitochondrial
0
DNA, Mitochondrial
0
Mitochondrial Proteins
0
TEFM protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1009Subventions
Organisme : Medical Research Council
ID : MC_UU_00015/4
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/V009346/1
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Informations de copyright
© 2023. The Author(s).
Références
Genet Med. 2020 Jul;22(7):1254-1261
pubmed: 32313153
Nat Genet. 2002 Jul;31(3):289-94
pubmed: 12068295
Genome Biol. 2016 Jun 06;17(1):122
pubmed: 27268795
PLoS Comput Biol. 2018 Aug 17;14(8):e1006360
pubmed: 30118475
Nucleic Acids Res. 2019 May 7;47(8):e47
pubmed: 30783653
Mol Genet Metab. 2016 Sep;119(1-2):91-9
pubmed: 27448789
Bioinformatics. 2013 Jan 1;29(1):15-21
pubmed: 23104886
Nat Methods. 2016 Sep;13(9):731-40
pubmed: 27348712
FEBS Lett. 2021 Apr;595(8):1132-1158
pubmed: 33655490
Essays Biochem. 2018 Jul 20;62(3):309-320
pubmed: 30030363
Bioinformatics. 2012 Jun 1;28(11):1525-6
pubmed: 22500002
Nat Genet. 2010 Oct;42(10):851-8
pubmed: 20818383
Science. 2015 Jan 30;347(6221):548-51
pubmed: 25635099
Cell. 2017 Nov 16;171(5):1082-1093.e13
pubmed: 29033127
Am J Hum Genet. 1995 Oct;57(4):772-80
pubmed: 7573035
Neurotoxicology. 2009 Jan;30(1):52-8
pubmed: 18952124
J Biol Chem. 2017 Feb 17;292(7):2637-2645
pubmed: 28028173
J Neuromuscul Dis. 2016 Aug 30;3(3):363-379
pubmed: 27854233
Bioinformatics. 2014 Aug 1;30(15):2114-20
pubmed: 24695404
Genome Biol. 2014;15(12):550
pubmed: 25516281
Elife. 2017 Jul 26;6:
pubmed: 28745585
Eur J Hum Genet. 2018 Jun;26(6):778-785
pubmed: 29487416
Hum Mol Genet. 2010 May 1;19(9):1726-40
pubmed: 20147321
Nat Biotechnol. 2019 Aug;37(8):907-915
pubmed: 31375807
Essays Biochem. 2018 Jul 20;62(3):297-308
pubmed: 29950321
Nucleic Acids Res. 2016 Sep 19;44(16):7817-29
pubmed: 27436287
Nat Commun. 2016 Jun 30;7:12039
pubmed: 27356879
Genet Med. 2015 Oct;17(10):774-81
pubmed: 25590979
Nat Biotechnol. 2008 Dec;26(12):1367-72
pubmed: 19029910
Nat Commun. 2021 Feb 18;12(1):1135
pubmed: 33602924
Nat Rev Genet. 2001 May;2(5):342-52
pubmed: 11331900
J Biol Chem. 2006 Aug 25;281(34):24647-52
pubmed: 16790426
Nat Methods. 2012 Jun 28;9(7):676-82
pubmed: 22743772
Nucleic Acids Res. 2010 Sep;38(16):e164
pubmed: 20601685
Cell. 2009 Nov 25;139(5):934-44
pubmed: 19945377
Eur J Hum Genet. 2018 Mar;26(3):330-339
pubmed: 29343805
Hum Mol Genet. 2019 Jul 15;28(14):2339-2351
pubmed: 31220253
J Biol Chem. 2003 Jan 17;278(3):1879-85
pubmed: 12433926
Nat Genet. 2011 May;43(5):491-8
pubmed: 21478889
Dev Dyn. 1995 Jul;203(3):253-310
pubmed: 8589427
Cells. 2019 Aug 07;8(8):
pubmed: 31394789
J Vis Exp. 2018 Aug 28;(138):
pubmed: 30222157
EMBO Rep. 2019 Jun;20(6):
pubmed: 31036713
J Neurobiol. 1998 Dec;37(4):622-32
pubmed: 9858263
Nat Methods. 2010 Apr;7(4):248-9
pubmed: 20354512
Neurol Clin Pract. 2021 Apr;11(2):97-104
pubmed: 33842062
Hum Mutat. 2019 Oct;40(10):1731-1748
pubmed: 31045291
Hum Mutat. 2015 Oct;36(10):928-30
pubmed: 26220891
Annu Rev Biochem. 2016 Jun 2;85:133-60
pubmed: 27023847
Am J Med Genet A. 2018 May;176(5):1216-1221
pubmed: 29681102
Bioinformatics. 2019 Jan 1;35(1):122-125
pubmed: 30561546
Cell Rep. 2016 Aug 16;16(7):1874-90
pubmed: 27498866
Nature. 2011 Sep 25;478(7368):269-73
pubmed: 21947009
Mol Biol Cell. 2008 Jan;19(1):150-8
pubmed: 17942598
Essays Biochem. 2018 Jul 20;62(3):321-340
pubmed: 29980628
Cell. 2017 Nov 16;171(5):1072-1081.e10
pubmed: 29149603
J Microsc. 2006 Dec;224(Pt 3):213-32
pubmed: 17210054
Elife. 2021 Jan 08;10:
pubmed: 33416493
Nucleic Acids Res. 2011 May;39(10):4284-99
pubmed: 21278163
Hum Mol Genet. 2017 Nov 1;26(21):4257-4266
pubmed: 28973171
Eur J Hum Genet. 2016 Jan;25(1):79-84
pubmed: 27759031
Hum Mol Genet. 1997 Apr;6(4):615-25
pubmed: 9097968
Nat Methods. 2017 Apr;14(4):417-419
pubmed: 28263959
Proc Natl Acad Sci U S A. 2010 Sep 14;107(37):16072-7
pubmed: 20798345
Nucleic Acids Res. 2015 Mar 11;43(5):2615-24
pubmed: 25690892
Nature. 2013 Apr 25;496(7446):498-503
pubmed: 23594743
Bioinformatics. 2010 Mar 15;26(6):841-2
pubmed: 20110278
PLoS Comput Biol. 2013;9(7):e1003153
pubmed: 23874191
Proc Natl Acad Sci U S A. 1982 Dec;79(23):7195-9
pubmed: 6185947
BMC Bioinformatics. 2018 Dec 12;19(1):477
pubmed: 30541431