This report describes essential tremor, hereditary, 4 (ETM4), which is a subtype of essential tremor, hereditary. ETM4 exhibits autosomal dominant inheritance. The human gene implicated in this disease is FUS, which encodes an RNA-binding protein. FUS is more commonly implicated in the disease amyotrophic lateral sclerosis 6 (MIM:608030; see FBhh0000018). There is one high-scoring fly ortholog of FUS, caz, for which RNAi targeting constructs, alleles caused by insertional mutagenesis, and classical amorphic alleles have been generated. FUS is one of multiple human genes orthologous to the Dmel\caz; the others are EWSR1 (see FBhh0000408) and TAF15 (see FBhh0000407). A second orthologous gene in flies, CG14718, appears to be expressed exclusively (or predominantly) in testis.
Multiple UAS constructs of the human Hsap\FUS gene have been introduced into flies, including wild-type FUS and genes carrying mutational lesions implicated in ETM4 or ALS6. Heterologous rescue (functional complementation) of some phenotypes of Dmel\caz null mutants has been demonstrated. The reverse experiment has also been performed: a phenotype observed when the wild-type Hsap\FUS is overexpressed is almost completely rescued by knockdown of endogenous Dmel\caz by RNAi.
Variant(s) implicated in human disease tested (as transgenic human gene, FUS): the Q290* variant form of the human gene (implicated specifically in ETM4) has been introduced into flies. See the human disease model report 'amyotrophic lateral sclerosis 6' (FBhh0000018) for information on additional pathogenic FUS variants introduced into flies. Using the Q290* variant form of Hsap\FUS, targeted expression in the dopaminergic and the serotonergic neurons resulted in motor dysfunction, which was accompanied by impairment in the GABAergic pathway. Neuronal degeneration was not detected. Involvement of the GABAergic pathway was supported by rescue of motor symptoms with gabapentin.
[updated Feb. 2018 by FlyBase; FBrf0222196]
Essential tremor may be the most common human movement disorder. The main feature of essential tremor is postural tremor of the arms, but the head, legs, trunk, voice, jaw, and facial muscles also may be involved. Aggravated by emotions, hunger, fatigue, and temperature extremes, the condition may cause a functional disability or even incapacitation (summary by Higgins et al., 1997; pubmed:9399207). [from MIM:190300; 2018.02.12]
[TREMOR, HEREDITARY ESSENTIAL, 4; ETM4](https://omim.org/entry/614782)
[FUS RNA-BINDING PROTEIN; FUS](https://omim.org/entry/137070)
In a large multigenerational family with essential tremor, hereditary, 4 (ETM4), the age at onset was variable, ranging from the first to the fifth decade. [from MIM:614782; 2018.02.12]
Hereditary essential tremor-4 (ETM4) is caused by heterozygous mutation in the FUS gene. [from MIM:614782; 2018.02.12]
Many to many (3 human to 2 Drosophila); additional human orthologs are EWSR1 and TAF15.
High-to moderate-scoring ortholog of human genes FUS and EWSR1; lower-scoring ortholog of TAF15 (2 Drosophila to 3 human). Dmel\caz shares 40-42% identity and 50-51% similarity with the human genes FUS and EWSR1; TAF15 is less similar.
