A Heterozygous Mutation in MFF Associated with a Mild Mitochondrial Phenotype

Article type: Research Article

Authors: Murata, Daisuke^a | Grunseich, Christopher^b | Iijima, Miho^a | Chan, David^c | Corse, Andrea^d | Hoke, Ahmet^d | Schindler, Alice^b | Sesaki, Hiromi^a | Roda, Ricardo H.^{d; *}

Affiliations: [a] Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, USA | [b] National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA | [c] Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA | [d] Neuromuscular Medicine, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

Correspondence: [*] Correspondence to: Ricardo Roda, Meyer 5-119, 601N Caroline St, Baltimore, MD 21287, USA. Tel.: +1 410 955 1961; Fax: +1 410 955 1898/Ext. 3; E-mail: rroda1@jhmi.edu.

Abstract: Background:The number of mutations in nuclear encoded genes causing mitochondrial disease is ever increasing. Identification of these mutations is particularly important in the diagnosis of neuromuscular disorders as their presentation may mimic other acquired disorders.We present a novel heterozygous variant in mitochondrial fission factor (MFF) which mimics myasthenia gravis. Objective:To determine if the MFF c.937G>A, p.E313K variant causes a mild mitochondrial phenotype. Methods:We used whole exome sequencing (WES) to identify a novel heterozygous variant in MFF in a patient with ptosis, fatigue and muscle weakness. Using patient derived fibroblasts, we performed assays to evaluate mitochondrial and peroxisome dynamics. Results:We show that fibroblasts derived from this patient are defective in mitochondrial fission, despite normal recruitment of Drp1 to the mitochondria. Conclusions:The MFF c.937G>A, p.E313K variant leads to a mild mitochondrial phenotype and is associated with defective mitochondrial fission in patient-derived fibroblasts.

Keywords: Mitochondrial myopathies, mitochondrial fission factor, MFF, mitochondrial dynamics

DOI: 10.3233/JND-221532

Journal: Journal of Neuromuscular Diseases, vol. 10, no. 1, pp. 107-118, 2023