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General Information
Name
Charcot-Marie-Tooth disease, MFN2-related
FlyBase ID
FBhh0000087
OMIM
Overview

This report describes Charcot-Marie-Tooth disease, MFN2-related, which encompasses a group of three Charcot-Marie-Tooth subtypes. The human gene implicated in these diseases is mitofusin 2 (MFN2), a transmembrane GTPase that mediates mitochondrial fusion. MFN2 is implicated in three similar diseases: Charcot-Marie-Tooth disease, type 2A2A, CMT2A2A (OMIM:609260, FBhh0001192) which is inherited as an autosomal dominant; CMT2A2B (OMIM:617087, FBhh0001193) which is inherited as an autosomal recessive and is a more severe disorder with earlier onset; and hereditary motor and sensory neuropathy VIA, HMSN6A (OMIM:601152, FBhh0001194) which is inherited as an autosomal dominant. There is a single fly ortholog of MFN2, Dmel\Marf, for which classical amorphic and loss-of-function alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated. Dmel\Marf is also orthologous to a second human mitofusin gene, MFN1.

Multiple different UAS constructs of the human gene, Hsap\MFN2, have been introduced into flies, both wild-type and with mutational lesions. Phenotypes affecting various tissues and behavior have been described; mitochondrial defects at the cellular level have been observed. Heterologous rescue (functional complementation) of some aspects of the null Dmel\Marf phenotype and of RNAi-induced phenotypes has been demonstrated.

Variant(s) implicated in human disease tested (as transgenic human gene, MFN2): the variant form R94Q of the human gene has been introduced into flies; this variant is implicated in CMT2A2A. Mutational lesions outside regions implicated in CMT2A2 or HMSN6A have also been characterized (as variants of transgenic human genes). Variant(s) implicated in human disease tested (as analogous mutation in fly gene): R135Q in the fly Marf gene (corresponds to R94Q in the human MFN2 gene); R404W in the fly Marf gene (corresponds to R364W in the human MFN2 gene); L118P in the fly Marf gene (corresponds to L76P in the human MFN2 gene); T146M in the fly Marf gene (corresponds to T105M in the human MFN2 gene). Based on work using the transgenic human gene in Drosophila, the rare human variants M393I and R400Q are postulated to be implicated in CMT2A2; R400Q exhibits more severe cardiac phenotypes in flies.

Most loss-of-function mutations in the Dmel\Marf gene are lethal during the third larval instar. Phenotypes observed in larvae, in somatic clones, or for GAL4-UAS targeted expression include locomotor behavior defective, neurophysiology defective and stress response defective; cellular phenotypes include mitochondrial defects. Physical interactions of the Dmel\Marf protein product have been described; see below and in the FlyBase gene report for Marf.

[updated Feb. 2020 by FlyBase; FBrf0222196]

Disease Summary Information
Parent Disease Summary: Charcot-Marie-Tooth disease
Symptoms and phenotype

Charcot-Marie-Tooth disease (CMT) constitutes a clinically and genetically heterogeneous group of hereditary motor and sensory peripheral neuropathies. CMT is divided into several major types: Type 1 is characterized by demyelination and by a significantly slowed motor median nerve conduction velocity (NCV). Type 2 is characterized by axonal abnormalities and a normal or slightly reduced NCV. "Intermediate" types describe CMT families with nerve conduction velocities, in different affected individuals, that overlap the division between Type 1 and Type 2. Additional types are defined on the basis inheritance patterns. [from OMIM:609260 and OMIM:606482; 2015.12.15]

Symptoms typically include progressive distal muscle weakness and atrophy, often associated with mild to moderate sensory loss, depressed tendon reflexes, and high-arched feet. [from Gene Reviews, http://www.ncbi.nlm.nih.gov/books/NBK1358 2015.12.15]

Specific Disease Summary: Charcot-Marie-Tooth disease, MFN2-related
OMIM report
Human gene(s) implicated
Symptoms and phenotype

See description of different CMT classification types, above.

Genetics
Cellular phenotype and pathology
Molecular information

MFN2 encodes a mitochondrial outer membrane GTPase that participates in mitochondrial fusion and contributes to the maintenance and operation of the mitochondrial network. [Gene Cards, MFN2; 2020.02.19]

External links
Disease synonyms
CMT2A2
Charcot-Marie-Tooth disease, axonal, type 2A2
Charcot-Marie-Tooth neurophathy, type 2A2
hereditary motor and sensory neuropathy IIA2
HMSN2A2
HMSN IIA2
Charcot-Marie-Tooth disease, type 2A2
Charcot-Marie-Tooth disease
Charcot-Marie-Tooth disease, type 2
CMT2A
Charcot-Marie-Tooth disease type 2A
Ortholog Information
Human gene(s) in FlyBase
Human gene (HGNC)
Symbol / Name
D. melanogaster ortholog (based on DIOPT)
Comments on ortholog(s)

Many to one: 2 human to 1 Drosophila; the second orthologous human gene is MFN1. There is, in addition, a lower-scoring fly ortholog (Dmel\fzo).

Other mammalian ortholog(s) used
    D. melanogaster Gene Information (1)
    Gene Snapshot
    Mitochondrial assembly regulatory factor (Marf) encodes a dynamin-family GTPase that mediates outer mitochondrial membrane tethering and fusion. Marf loss causes mitochondrial fragmentation and endoplasmic reticular stress that evoke skeletal muscle, retinal and heart tube dysfunction. [Date last reviewed: 2019-03-14]
    Molecular function (GO)
    Gene Groups / Pathways
    Comments on ortholog(s)

    Ortholog of human MFN2 and MFN1 (1 Drosphila to 2 human). Dmel\Marf shares 46% identity and 66% similarity with human MFN2; it shares 46% identity and 63% similarity with human MFN1.

    Orthologs and Alignments from DRSC
    DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
    Synthetic Gene(s) Used (0)
    Summary of Physical Interactions (8 groups)
    RNA-protein
    Interacting group
    Assay
    References
    anti tag coimmunoprecipitation, quantitative reverse transcription pcr
    protein-protein
    Interacting group
    Assay
    References
    anti tag coimmunoprecipitation, western blot
    anti tag coimmunoprecipitation, anti tag western blot
    anti bait coimmunoprecipitation, peptide massfingerprinting, western blot
    anti bait coimmunoprecipitation, western blot, anti tag coimmunoprecipitation, anti tag western blot
    anti tag coimmunoprecipitation, anti tag western blot
    anti bait coimmunoprecipitation, western blot
    anti bait coimmunoprecipitation, western blot
    Alleles Reported to Model Human Disease (Disease Ontology) (13 alleles)
    Models Based on Experimental Evidence ( 9 )
    Modifiers Based on Experimental Evidence ( 10 )
    Allele
    Disease
    Interaction
    References
    Genetic Tools, Stocks and Reagents
    Sources of Stocks
    Contact lab of origin for a reagent not available from a public stock center.
    Bloomington Stock Center Disease Page
    Selected mammalian transgenes
    Allele
    Transgene
    Publicly Available Stocks
    Selected Drosophila transgenes
    Allele
    Transgene
    Publicly Available Stocks
    RNAi constructs available
    Allele
    Transgene
    Publicly Available Stocks
    Selected Drosophila classical alleles
    Allele
    Allele class
    Mutagen
    Publicly Available Stocks
    ends-out gene targeting
    amorphic allele - genetic evidence
    ethyl methanesulfonate
    amorphic allele - molecular evidence
    gene targeting by homologous recombination
    References (24)