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FB2026_01
,
released March 12, 2026
This report describes Charcot-Marie-Tooth disease, axonal, type 2A2A (CMT2A2A), which is a subtype of Charcot-Marie-Tooth disease. CMT2A2A exhibits autosomal recessive inheritance. The human gene implicated in this is mitofusin 2 (MFN2), a transmembrane GTPase that mediates mitochondrial fusion. 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. The human gene implicated in this disease, MFN2, is implicated in several related diseases. See the report for 'Charcot-Marie-Tooth disease, MFN2-related' (FBhh0000087) for additional information on experimental results using Drosophila models of this and related diseases.
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.
A number of variants of MFN2 implicated in disease have been assessed in flies. Variants specific to this disease include MFN2:p.Arg94Gln , MFN2:p.Leu76Pro , and MFN2:p.Arg364Trp . 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. 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).
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]
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 MIM:609260 and MIM: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]
[CHARCOT-MARIE-TOOTH DISEASE, AXONAL, AUTOSOMAL DOMINANT, TYPE 2A2A; CMT2A2A](https://omim.org/entry/609260)
[MITOFUSIN 2; MFN2](https://omim.org/entry/608507)
Autosomal dominant Charcot-Marie-Tooth (CMT) disease type 2A2A (CMT2A2A) is caused by heterozygous mutation in the MFN2 gene. [from MIM:609260; 2020.02.19]
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]
Many to one: 2 human to 1 Drosophila; the second orthologous human gene is MFN1.
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.