Abstract
While >300 disease-causing variants have been identified in the mitochondrial DNA (mtDNA) polymerase γ, no mitochondrial phenotypes have been associated with POLRMT, the RNA polymerase responsible for transcription of the mitochondrial genome. Here, we characterise the clinical and molecular nature of POLRMT variants in eight individuals from seven unrelated families. Patients present with global developmental delay, hypotonia, short stature, and speech/intellectual disability in childhood; one subject displayed an indolent progressive external ophthalmoplegia phenotype. Massive parallel sequencing of all subjects identifies recessive and dominant variants in the POLRMT gene. Patient fibroblasts have a defect in mitochondrial mRNA synthesis, but no mtDNA deletions or copy number abnormalities. The in vitro characterisation of the recombinant POLRMT mutants reveals variable, but deleterious effects on mitochondrial transcription. Together, our in vivo and in vitro functional studies of POLRMT variants establish defective mitochondrial transcription as an important disease mechanism.
Original language | English (US) |
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Article number | 1135 |
Pages (from-to) | 1135 |
Journal | Nature communications |
Volume | 12 |
Issue number | 1 |
DOIs | |
State | Published - Feb 18 2021 |
Externally published | Yes |
Bibliographical note
Funding Information:R.W.T. is supported by the Wellcome Centre for Mitochondrial Research (203105/Z/16/Z), Mitochondrial Disease Patient Cohort (UK) (G0800674), the Lily Foundation, the UK NIHR Biomedical Research Centre for Ageing and Age-related disease award to the Newcastle upon Tyne Foundation Hospitals NHS Trust, the MRC/EPSRC Molecular Pathology Node and the UK NHS Highly Specialised Service for Rare Mitochondrial Disorders of Adults and Children. E.W.S. was in receipt of a Medical Research Council (MRC) PhD studentship. C.M.G. and M.F. are supported by the Swedish Research Council (2013–3621 to M.F., 2012–2583 to C.M.G.), Swedish Cancer Foundation, the Knut and Alice Wallenberg foundation and grants from the Swedish state under the agreement between the Swedish government and the county councils, the ALF agreement to M.F. (ALFGBG-727491) and C.M.G. (ALFGBG-728151). S.K. was supported by the grant NV19-07-00136 from the Ministry of Health of the Czech Republic, acknowledge institutional program UNCE/MED/007 of the Charles University, the project LQ1604 NPU II from the Ministry of Education, Youth and Sports of the Czech Republic, and thanks to The National Center for Medical Genomics (LM2018132) for instrumental and metho-dologic support with the WES analyses. T.M. was supported by the grant NV19-07-00149 from the Ministry of Health of the Czech Republic and RVO:67985823 (to Institute of Physiology CAS); Z.K. was in receipt of Charles University PhD project GA UK 772119. K.Õ. and S.P. were supported by the Estonian Research Council grants PRG471 and PUTJD827. The Broad Center for Mendelian Genomics (UM1 HG008900) is funded by the National Human Genome Research Institute with supplemental funding provided by the National Heart, Lung, and Blood Institute under the Trans-Omics for Precision Medicine (TOPMed) program and the National Eye Institute. M.H.W. is supported by T32GM007748. P.B.K. is supported by NIH R01 NS080929 and the Children’s Miracle Network. Exome sequencing and analysis were provided by the Broad Institute of Harvard and MIT Center for Mendelian Genomics (Broad CMG) and was funded by the National Human Genome Research Institute, the National Eye Institute, and the National Heart, Lung and Blood Institute grant NIH UM1 HG008900 to Daniel MacArthur and Heidi Rehm. We thank Daniel MacArthur and Anne O’Donnell-Luria at the Center for Mendelian Genetics of the Broad Institute for their contributions to exome sequencing and analysis. P.E.B. is supported by NIH NINDS RO1 NS08372. We thank Doug Turnbull and Andrew Schaefer for their long-term support and care of patient 3 described in this manuscript and Laura Bone for technical support. We would like to thank Dan Wright and family and Warren Lammert and Kathy Corkins for donations to the McMaster Neuromuscular Clinic which has supported the care of patient 2 described in this manuscript.
Publisher Copyright:
© 2021, The Author(s).
Keywords
- Adolescent
- Adult
- Child
- DNA, Mitochondrial/genetics
- DNA-Directed RNA Polymerases/chemistry
- Female
- Fibroblasts/metabolism
- Humans
- Infant
- Male
- Mitochondria/genetics
- Mutation/genetics
- Nervous System Diseases/genetics
- Oxidative Phosphorylation
- Pedigree
- Protein Domains
- Protein Subunits/metabolism
- RNA, Messenger/genetics
- Transcription, Genetic
- Young Adult
PubMed: MeSH publication types
- Journal Article
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't