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Lookup NU author(s): Professor Rita HorvathORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© The Author(s) 2019. Published by Oxford University Press.Charcot-Marie-Tooth disease (CMT) type 2A is a form of peripheral neuropathy, due almost exclusively to dominant mutations in the nuclear gene encoding the mitochondrial protein mitofusin-2 (MFN2). However, there is no understanding of the relationship of clinical phenotype to genotype. MFN2 has two functions: it promotes inter-mitochondrial fusion and mediates endoplasmic reticulum (ER)-mitochondrial tethering at mitochondria-associated ER membranes (MAM). MAM regulates a number of key cellular functions, including lipid and calcium homeostasis, and mitochondrial behavior. To date, no studies have been performed to address whether mutations in MFN2 in CMT2A patient cells affect MAM function, which might provide insight into pathogenesis. Using fibroblasts from three CMT2AMFN2 patients with different mutations in MFN2, we found that some, but not all, examined aspects of ER-mitochondrial connectivity and of MAM function were indeed altered, and correlated with disease severity. Notably, however, respiratory chain function in those cells was unimpaired. Our results suggest that CMT2AMFN2 is a MAM-related disorder but is not a respiratory chain-deficiency disease. The alterations in MAM function described here could also provide insight into the pathogenesis of other forms of CMT.
Author(s): Larrea D, Pera M, Gonnelli A, Quintana-Cabrera R, Akman HO, Guardia-Laguarta C, Velasco KR, Area-Gomez E, Dal Bello F, De Stefani D, Horvath R, Shy ME, Schon EA, Giacomello M
Publication type: Article
Publication status: Published
Journal: Human molecular genetics
Year: 2019
Volume: 28
Issue: 11
Pages: 1782-1800
Print publication date: 01/06/2019
Online publication date: 11/01/2019
Acceptance date: 31/12/2018
Date deposited: 07/08/2019
ISSN (print): 0964-6906
ISSN (electronic): 1460-2083
Publisher: NLM (Medline)
URL: https://doi.org/10.1093/hmg/ddz008
DOI: 10.1093/hmg/ddz008
PubMed id: 30649465
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