Clinicopathologic and molecular spectrum of RNASEH1 -related mitochondrial disease

Neurology. Genetics
Enrico BugiardiniRobert D S Pitceathly

Abstract

Pathologic ribonuclease H1 (RNase H1) causes aberrant mitochondrial DNA (mtDNA) segregation and is associated with multiple mtDNA deletions. We aimed to determine the prevalence of RNase H1 gene (RNASEH1) mutations among patients with mitochondrial disease and establish clinically meaningful genotype-phenotype correlations. RNASEH1 was analyzed in patients with (1) multiple deletions/depletion of muscle mtDNA and (2) mendelian progressive external ophthalmoplegia (PEO) with neuropathologic evidence of mitochondrial dysfunction, but no detectable multiple deletions/depletion of muscle mtDNA. Clinicopathologic and molecular evaluation of the newly identified and previously reported patients harboring RNASEH1 mutations was subsequently undertaken. Pathogenic c.424G>A p.Val142Ile RNASEH1 mutations were detected in 3 pedigrees among the 74 probands screened. Given that all 3 families had Indian ancestry, RNASEH1 genetic analysis was undertaken in 50 additional Indian probands with variable clinical presentations associated with multiple mtDNA deletions, but no further RNASEH1 mutations were confirmed. RNASEH1-related mitochondrial disease was characterized by PEO (100%), cerebellar ataxia (57%), and dysphagia (50%). The ataxia neuro...Continue Reading

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Citations

Nov 20, 2018·Nature Reviews. Neurology·Shamima Rahman, William C Copeland
Mar 20, 2018·Neurology. Genetics·Stefan M PulstJeffery M Vance
Aug 23, 2019·Current Opinion in Ophthalmology·Eloise WatsonClare L Fraser
Feb 23, 2020·Frontiers in Genetics·Aurelio ReyesMassimo Zeviani
Dec 19, 2020·Neuromuscular Disorders : NMD·Zohar Argov, Marianne de Visser
Apr 20, 2021·American Journal of Ophthalmology Case Reports·Elizabeth M McElneaAlan A McNab

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Methods Mentioned

BETA
electron microscopy
PCR
exome-sequencing
biopsy

Software Mentioned

GCTA
plink

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