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Front Genet. 2019 Jun 14;10:576. doi: 10.3389/fgene.2019.00576. eCollection 2019.

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

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Departament de Patologia Mitocondrial i Neuromuscular, Hospital Universitari Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Barcelona, Spain.
Servei de Neurologia, Malalties Neuromusculars, Hospital de la Santa Creu i Sant Pau i Institut de Recerca de HSCSP, Universitat Autònoma de Barcelona, Barcelona, Spain.
Àrea de Genètica Clínica i Molecular, Hospital Universitari Vall d'Hebron, Barcelona, Spain.


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.


PEO; RNASEH1; mitochondrial disease; mtDNA; multiple mtDNA deletions

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