POLRMT mutations impair mitochondrial transcription causing neurological disease

• DOI: 10.1038/s41467-021-21279-0
• Publication Date: 2021-02-20T09:14:59Z
• Authors: Monika Oláhová; Bradley Peter; Zsolt Szilagyi; Hector Diaz-Maldo...; Meenakshi Singh; Ewen W. Sommerville; Emma L. Blakely; Jack J. Collier; Emily Hoberg; Viktor Stránecký; Hana Hartmannová; Anthony J. Bleyer; Kim L. McBride; Sasigarn A. Bowden; Zuzana Korandová; Alena Pecinová; Hans-Hilger Ropers; Kimia Kahrizi; Hossein Najmabadi; Mark A. Tarnopolsky; Lauren I. Brady; K. Nicole Weaver; Carlos E. Prada; Katrin Õunap; Monica H. Wojcik; Sander Pajusalu; Safoora B. Syeda; Lynn Pais; Elicia A. Estrella; Christine C. Bruels; Louis M. Kunkel; Peter B. Kang; Penelope E. Bonnen; Tomáš Mráček; Stanislav Kmoch; Gráinne S. Gorman; Maria Falkenberg; Claes M. Gustafsson; Robert W. Taylor
• Keywords: Male; Transcription, Genetic; mitochondrial RNA polymerase; Clinical Biochemistry; Gene; Oxidative Phosphorylation; mitochondrial transcription; neurological disease; Child; 0303 health sciences; mRNA modification; Q; Life Sciences; Human mitochondrial genetics; DNA-Directed RNA Polymerases; POLRMT; Mitochondrial DNA; Mitochondria; Pedigree; FOS: Philosophy, ethics and religion; 3. Good health; Phenotype; RNA Methylation and Modification in Gene Expression; Mitochondrial Dysfunction; Female; RNA polymerase II; Metabolic Disorders and Biochemical Genetics; Polymerase; Adult; Adolescent; Science; Hypotonia; DNA, Mitochondrial; Article; Young Adult; 03 medical and health sciences; Mitochondrial Dynamics and Reactive Oxygen Species Regulation; Protein Domains; Biochemistry, Genetics and Molecular Biology; Genetics; Humans; RNA, Messenger; Mitochondrion; Molecular Biology; Biology; Inborn Errors of Metabolism; Infant; Promoter; Linguistics; Fibroblasts; Transcription (linguistics); Mitochondrial disease; Protein Subunits; Philosophy; FOS: Biological sciences; Mutation; FOS: Languages and literature; Gene expression; Nervous System Diseases; tRNA fragments

AbstractWhile >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.