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General Information
Name
amyotrophic lateral sclerosis (postulated), EWSR1-related
FlyBase ID
FBhh0000408
Disease Ontology Term
Parent Disease
OMIM
Overview

The human gene EWSR1 may be implicated in amyotrophic lateral sclerosis. EWSR1 is related to several human genes carrying RNA recognition motifs and prion-like domains that have been implicated in ALS; missense variants of EWSR1 were detected in ALS patients (FBrf0218546). EWSR1 is one of multiple human genes orthologous to the Drosophila gene caz; the others are FUS (implicated in ALS6, FBhh0000018) and TAF15 (see FBhh0000407). A second orthologous gene in flies, CG14718, appears to be expressed exclusively in testis.

Translocations involving the EWSR1 gene are involved in Ewing sarcoma and related neuroectodermal tumors.

Multiple different UAS constructs of the human Hsap\EWSR1 gene have been introduced into flies, including wild-type and genes carrying putative mutational lesions found in ALS patients. Expression of the wild-type human gene in neural tissues results in neurodegeneration phenotypes; pan-neuronal expression results in decreased lifespan and progressive loss of motility. Expression of ALS-linked Hsap\EWSR1 variants results in similar phenotypes; no increase in severity of phenotypes is observed with the ALS-linked variants.

Variant(s) implicated in human disease tested (as transgenic human gene, EWSR1): G511A and P552L variant forms of the human gene have been introduced.

For loss-of-function mutations in the Dmel\caz gene, observed phenotypes include aspects similar to ALS, including locomotor defects, defects in synaptic transmission, and reduced lifespan. Physical and genetic interactions of Dmel\caz have been described; see below and in the caz gene report.

[updated Jul. 2017 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 (postulated), EWSR1-related
OMIM report
Human gene(s) implicated
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). [from OMIM:105400, 2016.10.11]
Genetics
Translocations involving the EWSR1 gene (Ewing sarcoma breakpoint region 1) are involved in Ewing sarcoma and related neuroectodermal tumors. [from OMIM:133450; 2016.10.11]
Cellular phenotype and pathology
Molecular information
The protein encoded by EWSR1 includes an N-terminal transcriptional activation domain and a C-terminal RNA-binding domain. Fusion proteins involving EWSR1 are produced by a number of different translocations implicated in tumorigenesis; such chimeric proteins usually consist of the N-terminal transcriptional activation domain of EWSR1 and the C-terminal DNA-binding domain of a transcription factor protein. [from Gene Cards, EWSR1; 2016.10.11]
External links
Disease synonyms
Ortholog Information
Human gene(s) in FlyBase
Human gene (HGNC)
D. melanogaster ortholog (based on DIOPT)
Comments on ortholog(s)
Many to many (3 human to 2 Drosophila); additional human orthologs are FUS and TAF15.
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)
    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.
    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) (18 alleles)
    Models Based on Experimental Evidence ( 3 )
    Modifiers Based on Experimental Evidence ( 0 )
    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 (4)