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Lookup NU author(s): Dr Yi NgORCiD, Dr Kyle Thompson, Daniela Loher, Sila Hopton, Gavin Falkous, Dr Steven Hardy, Dr Andrew Schaefer, Professor Robert Taylor
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© Copyright © 2020 Ng, Thompson, Loher, Hopton, Falkous, Hardy, Schaefer, Shaunak, Roberts, Lilleker and Taylor. Mitochondrial complex I deficiency is associated with a diverse range of clinical phenotypes and can arise due to either mitochondrial DNA (mtDNA) or nuclear gene defects. We investigated two adult patients who exhibited non-syndromic neurological features and evidence of isolated mitochondrial complex I deficiency in skeletal muscle biopsies. The first presented with indolent myopathy, progressive since age 17, while the second developed deafness around age 20 and other relapsing-remitting neurological symptoms since. A novel, likely de novo, frameshift variant in MT-ND6 (m.14512_14513del) and a novel maternally-inherited transversion mutation in MT-ND1 were identified, respectively. Skewed tissue segregation of mutant heteroplasmy level was observed; the mutant heteroplasmy levels of both variants were greater than 70% in muscle homogenate, however, in blood the MT-ND6 variant was undetectable while the mutant heteroplasmy level of the MT-ND1 variant was low (12%). Assessment of complex I assembly by Blue-Native PAGE demonstrated a decrease in fully assembled complex I in the muscle of both cases. SDS-PAGE and immunoblotting showed decreased levels of mtDNA-encoded ND1 and several nuclear encoded complex I subunits in both cases, consistent with functional pathogenic consequences of the identified variants. Pathogenicity of the m.14512_14513del was further corroborated by single-fiber segregation studies.
Author(s): Ng YS, Thompson K, Loher D, Hopton S, Falkous G, Hardy SA, Schaefer AM, Shaunak S, Roberts ME, Lilleker JB, Taylor RW
Publication type: Article
Publication status: Published
Journal: Frontiers in Genetics
Year: 2020
Volume: 11
Online publication date: 25/02/2020
Acceptance date: 08/01/2020
Date deposited: 02/04/2020
ISSN (electronic): 1664-8021
Publisher: Frontiers Research Foundation
URL: https://doi.org/10.3389/fgene.2020.00024
DOI: 10.3389/fgene.2020.00024
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