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]
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]
See description of different CMT classification types, above.
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]