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Lookup NU author(s): Marina Bartsakoulia, Dr Angela Pyle, Dr Jennifer Duff, Dr Helen GriffinORCiD, Dr Veronika Boczonadi, Professor Hanns Lochmuller, Professor Patrick Chinnery, Professor Rita HorvathORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© The Author(s) 2018. Published by Oxford University Press. All rights reserved. Mitochondrial dynamics play an important role in cellular homeostasis and a variety of human diseases are linked to its dysregulated function. Here, we describe a 15-year-old boy with a novel disease caused by altered mitochondrial dynamics. The patient was the second child of consanguineous Jewish parents. He developed progressive muscle weakness and exercise intolerance at 6 years of age. His muscle biopsy revealed mitochondrial myopathy with numerous ragged red and cytochrome c oxidase (COX) negative fibers and combined respiratory chain complex I and IV deficiency. MtDNA copy number was elevated and no deletions of the mtDNA were detected in muscle DNA. Whole exome sequencing identified a homozygous nonsense mutation (p.Q92*) in the MIEF2 gene encoding the mitochondrial dynamics protein of 49 kDa (MID49). Immunoblotting revealed increased levels of proteins promoting mitochondrial fusion (MFN2, OPA1) and decreased levels of the fission protein DRP1. Fibroblasts of the patient showed elongated mitochondria, and significantly higher frequency of fusion events, mtDNA abundance and aberrant mitochondrial cristae ultrastructure, compared with controls. Thus, our data suggest that mutations in MIEF2 result in imbalanced mitochondrial dynamics and a combined respiratory chain enzyme defect in skeletal muscle, leading to mitochondrial myopathy.
Author(s): Bartsakoulia M, Pyle A, Troncoso-Chandia D, Vial-Brizzi J, Paz-Fiblas MV, Duff J, Griffin H, Boczonadi V, Lochmuller H, Kleinle S, Chinnery PF, Grunert S, Kirschner J, Eisner V, Horvath R
Publication type: Article
Publication status: Published
Journal: Human Molecular Genetics
Year: 2018
Volume: 27
Issue: 7
Pages: 1186-1195
Print publication date: 01/04/2018
Online publication date: 19/01/2018
Acceptance date: 16/01/2018
Date deposited: 16/04/2018
ISSN (print): 0964-6906
ISSN (electronic): 1460-2083
Publisher: Oxford University Press
URL: https://doi.org/10.1093/hmg/ddy033
DOI: 10.1093/hmg/ddy033
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