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Clinicopathologic and molecular spectrum of RNASEH1-related mitochondrial disease.

Bugiardini, E; Poole, OV; Manole, A; Pittman, AM; Horga, A; Hargreaves, I; Woodward, CE; Sweeney, MG; Holton, JL; Taanman, J-W; et al. Bugiardini, E; Poole, OV; Manole, A; Pittman, AM; Horga, A; Hargreaves, I; Woodward, CE; Sweeney, MG; Holton, JL; Taanman, J-W; Plant, GT; Poulton, J; Zeviani, M; Ghezzi, D; Taylor, J; Smith, C; Fratter, C; Kanikannan, MA; Paramasivam, A; Thangaraj, K; Spinazzola, A; Holt, IJ; Houlden, H; Hanna, MG; Pitceathly, RDS (2017) Clinicopathologic and molecular spectrum of RNASEH1-related mitochondrial disease. Neurol Genet, 3 (3). e149. ISSN 2376-7839 https://doi.org/10.1212/NXG.0000000000000149
SGUL Authors: Pittman, Alan Michael

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Abstract

OBJECTIVE: 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. METHODS: 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. RESULTS: 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 neuropathy spectrum phenotype was observed in 1 patient. Although the c.424G>A p.Val142Ile mutation underpins all reported RNASEH1-related mitochondrial disease, haplotype analysis suggested an independent origin, rather than a founder event, for the variant in our families. CONCLUSIONS: In our cohort, RNASEH1 mutations represent the fourth most common cause of adult mendelian PEO associated with multiple mtDNA deletions, following mutations in POLG, RRM2B, and TWNK. RNASEH1 genetic analysis should also be considered in all patients with POLG-negative ataxia neuropathy spectrum. The pathophysiologic mechanisms by which the c.424G>A p.Val142Ile mutation impairs human RNase H1 warrant further investigation.

Item Type: Article
Additional Information: Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. This is an open access article distributed under the terms of the Creative Commons Attribution License 4.0 (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Journal or Publication Title: Neurol Genet
ISSN: 2376-7839
Language: eng
Dates:
DateEvent
June 2017Published
2 May 2017Published Online
13 March 2017Accepted
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
G0800674Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
MC_UP_1002/1Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
MC_U105663140Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
MR/K000608/1Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
G1001253Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
G108/638Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
MC_PC_13029Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
MR/J004758/1Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
MC_UP_1202/14Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
G0802760Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
FP7/2007-2013Seventh Framework Programmehttp://dx.doi.org/10.13039/501100004963
G0601943Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
SG/14-15/11NewLifeUNSPECIFIED
MR/J010448/1Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
0948685/Z/10/ZWellcome Trusthttp://dx.doi.org/10.13039/100004440
BSC0118BioAgeUNSPECIFIED
PDF/2016/000881Science and Engineering Research Boardhttp://dx.doi.org/10.13039/501100001843
PubMed ID: 28508084
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/111063
Publisher's version: https://doi.org/10.1212/NXG.0000000000000149

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