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POLRMT mutations impair mitochondrial transcription causing neurological disease

  1. 1.
    0541626 - FGÚ 2022 RIV GB eng J - Článek v odborném periodiku
    Oláhová, M. - Peter, B. - Szilagyi, Z. - Diaz-Maldonado, H. - Singh, M. - Sommerville, E. W. - Blakely, E. L. - Collier, J. J. - Hoberg, E. - Stránecký, V. - Hartmannová, H. - Bleyer, A. J. - McBride, K. L. - Bowden, S. A. - Korandová, Zuzana - Pecinová, Alena - Ropers, H.-H. - Kahrizi, K. - Najmabadi, H. - Tarnopolsky, M. A. - Brady, L. I. - Weaver, K. N. - Prada, C. E. - Ounap, K. - Wojcik, M. H. - Pajusalu, S. - Syeda, S. B. - Pais, L. - Estrella, E. A. - Bruels, Ch. C. - Kunkel, L. M. - Kang, P. B. - Bonnen, P. E. - Mráček, Tomáš - Kmoch, S. - Gorman, G. S. - Falkenberg, M. - Gustafsson, C. M. - Taylor, R. W.
    POLRMT mutations impair mitochondrial transcription causing neurological disease.
    Nature Communications. Roč. 12, č. 1 (2021), č. článku 1135. E-ISSN 2041-1723
    Grant CEP: GA MZd(CZ) NV19-07-00149; GA MŠk(CZ) LQ1604
    Výzkumná infrastruktura: NCMG II - 90132
    Institucionální podpora: RVO:67985823
    Klíčová slova: POLRMT * mitochondrial RNA polymerase * mitochondrial transcription * neurological disease
    Obor OECD: Biochemistry and molecular biology
    Impakt faktor: 17.694, rok: 2021
    Způsob publikování: Open access
    https://www.nature.com/articles/s41467-021-21279-0

    While >300 disease-causing variants have been identified in the mitochondrial DNA (mtDNA) polymerase gamma, 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. POLRMT is key for transcription of the mitochondrial genome, yet has not been implicated in mitochondrial disease to date. Here, the authors identify mutations in POLRMT in individuals with mitochondrial disease-related phenotypes and characterise underlying defects in mitochondrial transcription.
    Trvalý link: http://hdl.handle.net/11104/0319159

     
     
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