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POLRMT mutations impair mitochondrial transcription causing neurological disease.
- Source :
-
Nature communications [Nat Commun] 2021 Feb 18; Vol. 12 (1), pp. 1135. Date of Electronic Publication: 2021 Feb 18. - Publication Year :
- 2021
-
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.
- Subjects :
- Adolescent
Adult
Child
DNA, Mitochondrial genetics
DNA-Directed RNA Polymerases chemistry
Female
Fibroblasts metabolism
Fibroblasts pathology
Humans
Infant
Male
Nervous System Diseases pathology
Oxidative Phosphorylation
Pedigree
Protein Domains
Protein Subunits metabolism
RNA, Messenger genetics
RNA, Messenger metabolism
Young Adult
DNA-Directed RNA Polymerases genetics
Mitochondria genetics
Mutation genetics
Nervous System Diseases genetics
Transcription, Genetic
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 12
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 33602924
- Full Text :
- https://doi.org/10.1038/s41467-021-21279-0