Human Disease Model Report: amyotrophic lateral sclerosis 6
Human Disease Model Report: amyotrophic lateral sclerosis 6
This report describes amyotrophic lateral sclerosis 6 (ALS6), which is a subtype of amyotrophic lateral sclerosis. ALS6 is inherited primarily as an autosomal dominant. The human gene implicated in this disease is FUS, which encodes an RNA-binding protein. 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 Drosophila gene caz; the others are EWSR1 (see FBhh0000408) and TAF15 (see FBhh0000407). A second orthologous gene in flies, CG14718, appears to be expressed exclusively 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 ALS6. UAS constructs of two additional high-scoring human orthologs of caz, TAF15 (OMIM:601574; see FBhh0000407) and EWSR1 (OMIM:133450; see FBhh0000408) have also been introduced into flies. Phenotypic assays using the human gene have allowed characterization of genetic interactions with other transgenically expressed human genes. Transgenic expression of both wild type and mutant human FUS, TAF15, and EWSR1 recapitulate many of the key phenotypes of ALS6, including neurotoxicity, locomotor defects, and decreased lifespan. Heterologous rescue (functional complementation) of some phenotypes of Dmel\caz null mutants has been demonstrated.
Variant(s) implicated in human disease tested (as transgenic human gene, FUS): the R495*, R518K, R521C, R521G, R521H, and R524S, and P525L variant forms of the human gene have been introduced into flies. Variant(s) implicated in human disease tested (as analogous mutation in fly gene): P398L in the fly caz gene (corresponds to P525L in the human FUS gene), Q349* in the fly caz gene (corresponds to R495* in the human FUS gene).
Experiments using modified constructs of the human Hsap\FUS gene in flies have established that two low-complexity domains (LCDs) in FUS play an important role in toxicity. One is the N-terminal QSGY-rich prion-like domain; this domain is not found in the fly caz protein. The second is the C-terminal RGG2 domain. Similar low-complexity domains are found in other RNA-binding proteins implicated in disease; it has been postulated that LCDs play a role in stress granule metabolism and/or the development of pathological aggregates.
For loss-of-function mutations in the Dmel\caz gene, observed phenotypes include aspects similar to the human disease, including locomotor defects, defects in synaptic transmission, and reduced lifespan. Physical interactions of the Dmel\caz protein product have been described; see below and in the caz gene report. Phenotypic assays using the fly genes have allowed characterization of genetic interactions.
[updated Oct. 2018 by FlyBase; FBrf0222196]
Amyotrophic lateral sclerosis is a neurodegenerative disorder characterized by the death of motor neurons in the brain, brainstem, and spinal cord, resulting in fatal paralysis. ALS usually begins with asymmetric involvement of the muscles in middle adult life. Approximately 10% of ALS cases are familial (Siddique and Deng, 1996, pubmed:8875253). ALS is sometimes referred to as 'Lou Gehrig disease' after the famous American baseball player who was diagnosed with the disorder. [from OMIM:105400, 2015.02.11]
[AMYOTROPHIC LATERAL SCLEROSIS 6 WITH OR WITHOUT FRONTOTEMPORAL DEMENTIA; ALS6](https://omim.org/entry/608030)
[FUSED IN SARCOMA; FUS](https://omim.org/entry/137070)
Among 20 affected individuals [with ALS due to mutations in the FUS gene], there was even gender distribution, the average age at onset was 44.5 years, and the average survival was 33 months. The site of onset varied: it was cervical in 10, lumbar in 5, and bulbar in 3. No affected individual developed cognitive deficits. Detailed neuropathologic examination of 3 patients showed severe lower motor neuron loss in the spinal cord, and to a lesser degree in the brain stem, whereas dorsal horn neurons appeared unaffected. There was evidence of mild myelin loss in the dorsal columns, but only 1 case had major pallor of the corticospinal tracts. There was mild to moderate upper motor neuron loss in the motor cortex. FUS immunostaining showed large globular and elongated cytoplasmic inclusions in spinal cord motor neurons and dystrophic neurites in all cases. (Vance, et al., 2009, pubmed:19251628) [from OMIM:608030, 2015.02.12]
This form of autosomal dominant amyotrophic lateral sclerosis, ALS6, is caused by heterozygous mutation in the FUS gene. [from OMIM:608030, 2015.02.12]
In multiple cell lines, wildtype FUS is modified and/or cleaved posttranslationally to produce fragments of various sizes. Immunofluorescent studies showed localization of wildtype FUS to the nucleus, whereas mutant FUS formed inclusion bodies in the cytoplasm and neurites of 5 to 13% of cells. These inclusion bodies did not show evidence of ubiquitination or direct interaction with TARDBP, but did show features of stress granules, which are cellular structures that package mRNA and RNA-binding proteins during cell stress. Deletion constructs indicated that the C-terminal FUS is critical for subcellular distribution and nuclear localization, which is mediated by Ran GTPase-dependent machinery. Lack of the C terminus resulted in the formation of stress granules. The pathogenesis of ALS6 involves disruption of the nuclear transport of FUS and cytoplasmic accumulation of FUS and stress granules, which results in cellular toxicity and neurodegeneration. (Ito, et al., 2011, pubmed:21280085) [from OMIM:608030, 2015.02.12]
FUS is a nucleoprotein that functions in DNA and RNA metabolism, including DNA repair, and the regulation of transcription, RNA splicing, and export to the cytoplasm. Translocation of the FUS transcriptional activation domain results in fusion proteins and has been implicated in tumorigenesis. (summary by Vance, et al., 2009, pubmed:19251628)[from OMIM:137070, 2015.02.12]
A recent emerging theme in ALS research is the hypothesis that some ALS-associated proteins have a key role in the formation and function of cytoplasmic RNP stress granules, a cytosolic component in which non-functional translation initiation products accumulate. Stress granules form in response to a number of environmental stresses known to impede translation of mRNA into protein. Several ALS-associated proteins that have prion-like domains have been identified as accumulating in stress granules, including FUS.
Many to one: 3 human to 1 Drosophila (See DIOPT, link below).
Ortholog of human FUS, human EWSR1, and human TAF15 (1 Drosophila to 3 human; additional more distantly related gene(s) in both species).
Dmel\caz shares 42% identity and 51% similarity with human FUS, 40% identity and 50% similarity with human EWSR1, and 34% identity and 43% similarity with human TAF15.
