- Tools
- Downloads
- Links
- Community
- About
- Help
FB2026_01
,
released March 12, 2026
This report describes Charcot-Marie-Tooth disease, dominant intermediate C (CMTDIC), which is a subtype of Charcot-Marie-Tooth disease; CMTDIC exhibits autosomal dominant inheritance. The human gene implicated in this disease is YARS1, which encodes tyrosyl-tRNA synthetase. There is a single fly ortholog, TyrRS, for which transgenic alleles equivalent to missense mutations associated with CMTDIC, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated.
Multiple different UAS constructs of the human gene, Hsap\YARS1, have been introduced into flies, both wild-type and with mutational lesions; results support a gain-of-function model for YARS1-associated CMT. Classes of phenotypes observed include neurophysiology defective and locomotor behavior defective. Heterologous rescue (functional complementation) has been demonstrated for a cell-type-specific RNAi-induced phenotype. Phenotypic assays using the human gene have allowed characterization of genetic interactions.
Variant(s) implicated in human disease tested (as transgenic human gene, YARS1): the variant forms G41R, E196K, and the 12-bp deletion variant (aa153-156del) of the human gene have been introduced into flies. Variant(s) implicated in human disease tested (as analogous mutation in fly gene): G40R in the fly TyrRS gene (corresponds to G41R in the human YARS1 gene); E195K in the fly TyrRS gene (corresponds to E196K in the human YARS1 gene); aa152-155del in the fly TyrRS gene (corresponds to aa153-156del in the human YARS1 gene).
Transgenic UAS constructs carrying mutations in Dmel\TyrRS analogous to disease-associated mutation in the human YARS1 gene produce semi-lethality and locomotor behavior defective phenotypes; results vary with different GAL4 drivers. A small number of genetic and physical interactions been reported for Dmel\TyrRS; see below and in the TyrRS gene report.
[updated Nov. 2019 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, DOMINANT INTERMEDIATE C; CMTDIC](https://omim.org/entry/608323)
[TYROSYL-tRNA SYNTHETASE 1; YARS1](https://omim.org/entry/603623)
CMTDIC is characterized by intermediate nerve conduction velocities and histologic evidence of both axonal and demyelinating features. [from MIM:603623; 2015.12.16] See description of different CMT classification types, above.
CMTDIC is inherited as an autosomal dominant and is caused by heterozygous mutation in the YARS gene. Age of onset ranges from childhood to late adulthood. [from MIM:608323; 2015.12.16]
The YARS gene encodes tyrosyl-tRNA synthetase, an essential enzyme that is responsible for charging tRNA molecules with tyrosine via an aminoacylation reaction. [from MIM:603623; 2015.12.16]
One to one: 1 human to 1 Drosophila.
Ortholog of human YARS (1 Drosophila to 1 human). Dmel\TyrRS shares 68% identity and 80% similarity with human YARS.