Identification and Characterization of New RNASEH1 Mutations Associated With PEO Syndrome and Multiple Mitochondrial DNA Deletions.

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

doi:10.3389/fgene.2019.00576

Abstract

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.

Highlights

The mitochondrion is a cellular organelle crucial for cell metabolism that integrates various metabolic pathways, including oxidative phosphorylation (OXPHOS), fatty acid oxidation, Krebs cycle, urea cycle, gluconeogenesis, and ketogenesis (Gorman et al, 2016)
A group of nuclear genes are involved in several mitochondrial processes, such as mitochondrial DNA (mtDNA) maintenance, transcription and translation, and control of mitochondrial dynamics, which are essential for proper OXPHOS function
Mitochondrial depletion and deletion syndromes are a group of mitochondrial disorders caused by mutations in nuclear genes associated with mtDNA instability

Summary

Introduction

The mitochondrion is a cellular organelle crucial for cell metabolism that integrates various metabolic pathways, including oxidative phosphorylation (OXPHOS), fatty acid oxidation, Krebs cycle, urea cycle, gluconeogenesis, and ketogenesis (Gorman et al, 2016). Mitochondrial function is under the control of two genomes, nuclear DNA (nDNA) and mitochondrial DNA (mtDNA). Most mitochondrial proteins are encoded by nDNA genes (Anderson et al, 1981). A large number of these mitochondrial proteins are OXPHOS complex subunits or complex assembly factors and they are directly involved in the electron transport chain and energy production in the form of ATP. A group of nuclear genes are involved in several mitochondrial processes, such as mtDNA maintenance, transcription and translation, and control of mitochondrial dynamics, which are essential for proper OXPHOS function. Mitochondrial diseases are caused by mutations in mtDNA genes and in a very long list of nuclear mitochondrial-related genes (Cerritelli et al, 2003; Ruhanen et al, 2011; Uhler and Falkenberg, 2015)

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