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]
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 MIM:105400, 2015.02.11]
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 MIM:105400, 2016.10.11]
Translocations involving the EWSR1 gene (Ewing sarcoma breakpoint region 1) are involved in Ewing sarcoma and related neuroectodermal tumors. [from MIM:133450; 2016.10.11]
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]
Many to many (3 human to 2 Drosophila); additional human orthologs are FUS 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.
