Abstract
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.
Abbreviations
- HR1
- Heptad Repeat 1
- HR2
- Heptad Repeat 2
- MFN
- Mitofusin
- CMT2A
- Charcot-Marie Tooth type 2A
- OPA1
- Optic Atrophy 1
- IMS
- Inter Membrane Space
- mtDNA
- Mitochondrial Dexoyribo Nucleic Acid
- ER
- Endoplasmic Reticulum
- MERCs
- Mitochondria – Endoplasmic Reticulum Contact sites
- CAPOS
- Cerebellar ataxia, Areflexia, Pes cavus, Optic atrophy, and Sensorineural hearing loss
- GAD
- Glutamic Acid Decarboxylase
- MRI
- Magnetic Resonance Imaging
- NGS
- Next Generation Sequencing
- PLA
- Proximity Ligation Assay
- BDLP
- Bacterial Dynamin Like Protein
- OCR
- Oxygen Consumption Rate
- EDTA
- Ethylenediaminetetraacetic acid
- VCFs
- Velocardiofacial syndrome
- CADD
- Combined Annotation Dependent Depletion
- OMIM
- Online Mendelian Inheritance in Man
- VEP
- Variant Effect Predictor
- CO2
- Carbon dioxide
- MEM
- Minimum Essential Media
- FBS
- Fetal Bovine Serum
- PBS
- Phosphate Buffered Saline
- DSHB
- Developmental Studies Hybridoma Bank
- DAPI
- 4′,6-diamidino-2-phenylindole
- PFA
- Paraformaldehyde
- SD
- Standard Deviation
- qPCR
- Quantitative Polymerase Chain Reaction