Identification and characterization of new RNASEH1 mutations associated with PEO syndrome and multiple mitochondrial DNA deletions

Lidia Carreño-Gago, Cora Blázquez-Bermejo, Jordi Díaz-Manera, Yolanda Cámara, Eduard Gallardo, Ramon Martí, Javier Torres-Torronteras, Elena García-Arumí

    Research output: Contribution to journalArticleResearch

    5 Citations (Scopus)

    Abstract

    © 2019 Frontiers Media S.A. All Rights Reserved. Mitochondrial DNA (mtDNA) depletion and deletion syndrome encompasses a group of disorders caused by mutations in genes involved in mtDNA replication and maintenance. The clinical phenotype ranges from fatal infantile hepatocerebral forms to mild adult onset progressive external ophthalmoplegia (PEO). We report the case of a patient with PEO and multiple mtDNA deletions, with two new homozygous mutations in RNASEH1. The first mutation (c.487T>C) is located in the same catalytic domain as the four previously reported mutations, and the second (c.258-260del) is located in the connection domain, where no mutations have been reported. In silico study of the mutations predicted only the first mutation as pathogenic, but functional studies showed that both mutations cause loss of ribonuclease H1 activity. mtDNA replication dysfunction was demonstrated in patient fibroblasts, which were unable to recover normal mtDNA copy number after ethidium bromide-induced mtDNA depletion. Our results demonstrate the pathogenicity of two new RNASEH1 variants found in a patient with PEO syndrome, multiple deletions, and mild mitochondrial myopathy.
    Original languageEnglish
    Article number576
    JournalFrontiers in Genetics
    Volume10
    DOIs
    Publication statusPublished - 1 Jan 2019

    Keywords

    • Mitochondrial disease
    • MtDNA
    • Multiple mtDNA deletions
    • PEO
    • RNASEH1

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