TY - JOUR T1 - Characterization of a novel variant in the HR1 domain of <em>MFN2</em> in a patient with ataxia, optic atrophy and sensorineural hearing loss JF - bioRxiv DO - 10.1101/2021.01.11.426268 SP - 2021.01.11.426268 AU - Govinda Sharma AU - Rasha Saubouny AU - Matthew M Joel AU - Kristina Martens AU - Davide Martino AU - A.P. Jason de Koning AU - Gerald Pfeffer AU - Timothy E. Shutt Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/01/11/2021.01.11.426268.abstract N2 - Pathogenic variants in MFN2 cause Charcot-Marie-Tooth disease (CMT) type 2A (CMT2A) and are the leading cause of the axonal subtypes of CMT. CMT2A is characterized by predominantly distal motor weakness and muscle atrophy, with highly variable severity and onset age. Notably, some MFN2 variants can also lead to other phenotypes such as optic atrophy, hearing loss and lipodystrophy. Despite the clear link between MFN2 and CMT2A, our mechanistic understanding of how dysfunction of the MFN2 protein causes human disease pathologies remains incomplete. This lack of understanding is due in part to the multiple cellular roles of MFN2. Though initially characterized for its role in mediating mitochondrial fusion, MFN2 also plays important roles in mediating interactions between mitochondria and other organelles, such as the endoplasmic reticulum and lipid droplets. Additionally, MFN2 is also important for mitochondrial transport, mitochondrial autophagy, and has even been implicated in lipid transfer. Though over 100 pathogenic MFN2 variants have been described to date, only a few have been characterized functionally, and even then, often only for one or two functions. Here, we describe a novel homozygous MFN2 variant, D414V, in a patient presenting with cerebellar ataxia, deafness, blindness, and diffuse cerebral and cerebellar atrophy. Characterization of patient fibroblasts reveals phenotypes consistent with impaired MFN2 functions and expands the phenotypic presentation of MFN2 variants to include cerebellar ataxia.HR1Heptad Repeat 1HR2Heptad Repeat 2MFNMitofusinCMT2ACharcot-Marie Tooth type 2AOPA1Optic Atrophy 1IMSInter Membrane SpacemtDNAMitochondrial Dexoyribo Nucleic AcidEREndoplasmic ReticulumMERCsMitochondria – Endoplasmic Reticulum Contact sitesCAPOSCerebellar ataxia, Areflexia, Pes cavus, Optic atrophy, and Sensorineural hearing lossGADGlutamic Acid DecarboxylaseMRIMagnetic Resonance ImagingNGSNext Generation SequencingPLAProximity Ligation AssayBDLPBacterial Dynamin Like ProteinOCROxygen Consumption RateEDTAEthylenediaminetetraacetic acidVCFsVelocardiofacial syndromeCADDCombined Annotation Dependent DepletionOMIMOnline Mendelian Inheritance in ManVEPVariant Effect PredictorCO2Carbon dioxideMEMMinimum Essential MediaFBSFetal Bovine SerumPBSPhosphate Buffered SalineDSHBDevelopmental Studies Hybridoma BankDAPI4′,6-diamidino-2-phenylindolePFAParaformaldehydeSDStandard DeviationqPCRQuantitative Polymerase Chain Reaction ER -