Dataset Information

Case Report: Rare Homozygous RNASEH1 Mutations Associated With Adult-Onset Mitochondrial Encephalomyopathy and Multiple Mitochondrial DNA Deletions.

ABSTRACT: Mitochondrial DNA (mtDNA) maintenance disorders embrace a broad range of clinical syndromes distinguished by the evidence of mtDNA depletion and/or deletions in affected tissues. Among the nuclear genes associated with mtDNA maintenance disorders, RNASEH1 mutations produce a homogeneous phenotype, with progressive external ophthalmoplegia (PEO), ptosis, limb weakness, cerebellar ataxia, and dysphagia. The encoded enzyme, ribonuclease H1, is involved in mtDNA replication, whose impairment leads to an increase in replication intermediates resulting from mtDNA replication slowdown. Here, we describe two unrelated Italian probands (Patient 1 and Patient 2) affected by chronic PEO, ptosis, and muscle weakness. Cerebellar features and severe dysphagia requiring enteral feeding were observed in one patient. In both cases, muscle biopsy revealed diffuse mitochondrial abnormalities and multiple mtDNA deletions. A targeted next-generation sequencing analysis revealed the homozygous RNASEH1 mutations c.129-3C>G and c.424G>A in patients 1 and 2, respectively. The c.129-3C>G substitution has never been described as disease-related and resulted in the loss of exon 2 in Patient 1 muscle RNASEH1 transcript. Overall, we recommend implementing the use of high-throughput sequencing approaches in the clinical setting to reach genetic diagnosis in case of suspected presentations with impaired mtDNA homeostasis.

SUBMITTER: Manini A

PROVIDER: S-EPMC9194440 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Case Report: Rare Homozygous <i>RNASEH1</i> Mutations Associated With Adult-Onset Mitochondrial Encephalomyopathy and Multiple Mitochondrial DNA Deletions.

Manini Arianna A Caporali Leonardo L Meneri Megi M Zanotti Simona S Piga Daniela D Arena Ignazio Giuseppe IG Corti Stefania S Toscano Antonio A Comi Giacomo Pietro GP Musumeci Olimpia O Carelli Valerio V Ronchi Dario D

Frontiers in genetics 20220531

Mitochondrial DNA (mtDNA) maintenance disorders embrace a broad range of clinical syndromes distinguished by the evidence of mtDNA depletion and/or deletions in affected tissues. Among the nuclear genes associated with mtDNA maintenance disorders, <i>RNASEH1</i> mutations produce a homogeneous phenotype, with progressive external ophthalmoplegia (PEO), ptosis, limb weakness, cerebellar ataxia, and dysphagia. The encoded enzyme, ribonuclease H1, is involved in mtDNA replication, whose impairment ...[more]

PMID: 35711919

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Project description:BackgroundInfantile-onset encephalopathy and hypertrophic cardiomyopathy caused by mitochondrial oxidative phosphorylation defects are genetically heterogeneous with defects involving both the mitochondrial and nuclear genomes.ObjectiveTo identify the causative genetic defect in two sisters presenting with lethal infantile encephalopathy, hypertrophic cardiomyopathy and optic atrophy.MethodsWe describe a comprehensive clinical, biochemical and molecular genetic investigation of two affected siblings from a consanguineous family. Molecular genetic analysis was done by a combined approach involving genome-wide autozygosity mapping and next-generation exome sequencing. Biochemical analysis was done by enzymatic analysis and Western blot. Evidence for mitochondrial DNA (mtDNA) instability was investigated using long-range and real-time PCR assays. Mitochondrial cristae morphology was assessed with transmission electron microscopy.ResultsBoth affected sisters presented with a similar cluster of neurodevelopmental deficits marked by failure to thrive, generalised neuromuscular weakness and optic atrophy. The disease progression was ultimately fatal with severe encephalopathy and hypertrophic cardiomyopathy. Mitochondrial respiratory chain complex activities were globally decreased in skeletal muscle biopsies. They were found to be homozygous for a novel c.1601T>G (p.Leu534Arg) mutation in the OPA1 gene, which resulted in a marked loss of steady-state levels of the native OPA1 protein. We observed severe mtDNA depletion in DNA extracted from the patients' muscle biopsies. Mitochondrial morphology was consistent with abnormal mitochondrial membrane fusion.ConclusionsWe have established, for the first time, a causal link between a pathogenic homozygous OPA1 mutation and human disease. The fatal multisystemic manifestations observed further extend the complex phenotype associated with pathogenic OPA1 mutations, in particular the previously unreported association with hypertrophic cardiomyopathy. Our findings further emphasise the vital role played by OPA1 in mitochondrial biogenesis and mtDNA maintenance.

Dataset Information

Case Report: Rare Homozygous RNASEH1 Mutations Associated With Adult-Onset Mitochondrial Encephalomyopathy and Multiple Mitochondrial DNA Deletions.

Publications

Case Report: Rare Homozygous <i>RNASEH1</i> Mutations Associated With Adult-Onset Mitochondrial Encephalomyopathy and Multiple Mitochondrial DNA Deletions.

Similar Datasets

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