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General Information
Name
amyotrophic lateral sclerosis 6
FlyBase ID
FBhh0000018
Overview

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]

Disease Summary Information
Parent Disease Summary: amyotrophic lateral sclerosis
Symptoms and phenotype

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]

Specific Disease Summary: amyotrophic lateral sclerosis 6
OMIM report

[AMYOTROPHIC LATERAL SCLEROSIS 6 WITH OR WITHOUT FRONTOTEMPORAL DEMENTIA; ALS6](https://omim.org/entry/608030)

Human gene(s) implicated

[FUSED IN SARCOMA; FUS](https://omim.org/entry/137070)

Symptoms and phenotype

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]

Genetics

This form of autosomal dominant amyotrophic lateral sclerosis, ALS6, is caused by heterozygous mutation in the FUS gene. [from OMIM:608030, 2015.02.12]

Cellular phenotype and pathology

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]

Molecular information

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.

External links
Disease synonyms
amyotrophic lateral sclerosis 6, autosomal recessive, included
FTLD-FUS
amyotrophic lateral sclerosis 6, with or without frontotemporal dementia
ALS6
Fus-mediated ALS
amyotrophic lateral sclerosis
FUS-ALS
FUS-related ALS
ALS
Amyotrophic lateral sclerosis
motor neurone disease
amyotrophic lateral sclerosis type 6
ALS-FUS
Ortholog Information
Human gene(s) in FlyBase
Human gene (HGNC)
D. melanogaster ortholog (based on DIOPT)
Comments on ortholog(s)

Many to one: 3 human to 1 Drosophila (See DIOPT, link below).

Other mammalian ortholog(s) used
    D. melanogaster Gene Information (1)
    Gene Snapshot
    cabeza (caz) encodes a chromatin binding protein involved in locomotion, synaptic growth at the neuromuscular junction and eye development. [Date last reviewed: 2019-03-28]
    Gene Groups / Pathways
    Comments on ortholog(s)

    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.

    Orthologs and Alignments from DRSC
    DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
    Synthetic Gene(s) Used (0)
    Summary of Physical Interactions (9 groups)
    protein-protein
    Interacting group
    Assay
    References
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti bait coimmunoprecipitation, western blot
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, anti tag western blot
    anti tag coimmunoprecipitation, peptide massfingerprinting
    RNA-protein
    Interacting group
    Assay
    References
    anti tag coimmunoprecipitation, quantitative reverse transcription pcr
    anti tag coimmunoprecipitation, quantitative reverse transcription pcr
    Alleles Reported to Model Human Disease (Disease Ontology) (36 alleles)
    Models Based on Experimental Evidence ( 21 )
    Allele
    Disease
    Evidence
    References
    Modifiers Based on Experimental Evidence ( 13 )
    Allele
    Disease
    Interaction
    References
    Models Based on Experimental Evidence ( 13 )
    Modifiers Based on Experimental Evidence ( 7 )
    Genetic Tools, Stocks and Reagents
    Sources of Stocks
    Contact lab of origin for a reagent not available from a public stock center.
    Bloomington Stock Center Disease Page
    Selected mammalian transgenes
    Allele
    Transgene
    Publicly Available Stocks
    Selected Drosophila transgenes
    Allele
    Transgene
    Publicly Available Stocks
    RNAi constructs available
    Allele
    Transgene
    Publicly Available Stocks
    Selected Drosophila classical alleles
    Allele
    Allele class
    Mutagen
    Publicly Available Stocks
    P-element activity
    amorphic allele - molecular evidence
    Delta2-3 transposase
    amorphic allele - molecular evidence
    ends-out gene targeting
    phiC31 integrase
    phiC31 integrase
    P-element activity
    amorphic allele - molecular evidence
    Delta2-3 transposase
    amorphic allele - molecular evidence
    ends-out gene targeting
    phiC31 integrase
    phiC31 integrase
    References (77)