Identification and Characterization of New RNASEH1 Mutations Associated With PEO Syndrome and Multiple Mitochondrial DNA Deletions
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...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-06-01
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| Series: | Frontiers in Genetics |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fgene.2019.00576/full |
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| author | Lidia Carreño-Gago Lidia Carreño-Gago Cora Blázquez-Bermejo Cora Blázquez-Bermejo Jordi Díaz-Manera Jordi Díaz-Manera Yolanda Cámara Yolanda Cámara Eduard Gallardo Eduard Gallardo Ramon Martí Ramon Martí Javier Torres-Torronteras Javier Torres-Torronteras Elena García-Arumí Elena García-Arumí Elena García-Arumí |
| author_facet | Lidia Carreño-Gago Lidia Carreño-Gago Cora Blázquez-Bermejo Cora Blázquez-Bermejo Jordi Díaz-Manera Jordi Díaz-Manera Yolanda Cámara Yolanda Cámara Eduard Gallardo Eduard Gallardo Ramon Martí Ramon Martí Javier Torres-Torronteras Javier Torres-Torronteras Elena García-Arumí Elena García-Arumí Elena García-Arumí |
| author_sort | Lidia Carreño-Gago |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-20T13:11:33Z |
| format | Article |
| id | doaj.art-cd58f1af7be14c018f24419717dfc6ed |
| institution | Directory Open Access Journal |
| issn | 1664-8021 |
| language | English |
| last_indexed | 2024-12-20T13:11:33Z |
| publishDate | 2019-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Genetics |
| spelling | doaj.art-cd58f1af7be14c018f24419717dfc6ed2022-12-21T19:39:39ZengFrontiers Media S.A.Frontiers in Genetics1664-80212019-06-011010.3389/fgene.2019.00576452641Identification and Characterization of New RNASEH1 Mutations Associated With PEO Syndrome and Multiple Mitochondrial DNA DeletionsLidia Carreño-Gago0Lidia Carreño-Gago1Cora Blázquez-Bermejo2Cora Blázquez-Bermejo3Jordi Díaz-Manera4Jordi Díaz-Manera5Yolanda Cámara6Yolanda Cámara7Eduard Gallardo8Eduard Gallardo9Ramon Martí10Ramon Martí11Javier Torres-Torronteras12Javier Torres-Torronteras13Elena García-Arumí14Elena García-Arumí15Elena García-Arumí16Departament de Patologia Mitocondrial i Neuromuscular, Hospital Universitari Vall d’Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, SpainCentro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Barcelona, SpainDepartament de Patologia Mitocondrial i Neuromuscular, Hospital Universitari Vall d’Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, SpainCentro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Barcelona, SpainCentro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Barcelona, SpainServei de Neurologia, Malalties Neuromusculars, Hospital de la Santa Creu i Sant Pau i Institut de Recerca de HSCSP, Universitat Autònoma de Barcelona, Barcelona, SpainDepartament de Patologia Mitocondrial i Neuromuscular, Hospital Universitari Vall d’Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, SpainCentro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Barcelona, SpainCentro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Barcelona, SpainServei de Neurologia, Malalties Neuromusculars, Hospital de la Santa Creu i Sant Pau i Institut de Recerca de HSCSP, Universitat Autònoma de Barcelona, Barcelona, SpainDepartament de Patologia Mitocondrial i Neuromuscular, Hospital Universitari Vall d’Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, SpainCentro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Barcelona, SpainDepartament de Patologia Mitocondrial i Neuromuscular, Hospital Universitari Vall d’Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, SpainCentro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Barcelona, SpainDepartament de Patologia Mitocondrial i Neuromuscular, Hospital Universitari Vall d’Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, SpainCentro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Barcelona, SpainÀrea de Genètica Clínica i Molecular, Hospital Universitari Vall d’Hebron, Barcelona, SpainMitochondrial 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.https://www.frontiersin.org/article/10.3389/fgene.2019.00576/fullmtDNAmitochondrial diseasePEOmultiple mtDNA deletionsRNASEH1 |
| spellingShingle | Lidia Carreño-Gago Lidia Carreño-Gago Cora Blázquez-Bermejo Cora Blázquez-Bermejo Jordi Díaz-Manera Jordi Díaz-Manera Yolanda Cámara Yolanda Cámara Eduard Gallardo Eduard Gallardo Ramon Martí Ramon Martí Javier Torres-Torronteras Javier Torres-Torronteras Elena García-Arumí Elena García-Arumí Elena García-Arumí Identification and Characterization of New RNASEH1 Mutations Associated With PEO Syndrome and Multiple Mitochondrial DNA Deletions Frontiers in Genetics mtDNA mitochondrial disease PEO multiple mtDNA deletions RNASEH1 |
| title | Identification and Characterization of New RNASEH1 Mutations Associated With PEO Syndrome and Multiple Mitochondrial DNA Deletions |
| title_full | Identification and Characterization of New RNASEH1 Mutations Associated With PEO Syndrome and Multiple Mitochondrial DNA Deletions |
| title_fullStr | Identification and Characterization of New RNASEH1 Mutations Associated With PEO Syndrome and Multiple Mitochondrial DNA Deletions |
| title_full_unstemmed | Identification and Characterization of New RNASEH1 Mutations Associated With PEO Syndrome and Multiple Mitochondrial DNA Deletions |
| title_short | Identification and Characterization of New RNASEH1 Mutations Associated With PEO Syndrome and Multiple Mitochondrial DNA Deletions |
| title_sort | identification and characterization of new rnaseh1 mutations associated with peo syndrome and multiple mitochondrial dna deletions |
| topic | mtDNA mitochondrial disease PEO multiple mtDNA deletions RNASEH1 |
| url | https://www.frontiersin.org/article/10.3389/fgene.2019.00576/full |
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