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General Information
Name
spinocerebellar ataxia 2
FlyBase ID
FBhh0000062
Overview

This report describes spinocerebellar ataxia 2 (SCA2 or SCA2/ALS13), which is a subtype of spinocerebellar ataxia; SCA2 is inherited as an autosomal dominant. The human gene implicated in this disease is ATXN2. SCA2 is one of a number spinocerebellar ataxias caused by expansion of CAG repeats within the coding region of the causative gene, resulting in an expanded run of glutamine (Q) residues in the encoded protein. Expanded (CAG)n repeats in ATXN2 are also associated with a susceptibility to amyotrophic lateral sclerosis 13 (OMIM:183090), and with a susceptibility to late-onset Parkinson disease (OMIM:168600); ALS13 is now treated as a form of SCA2 by OMIM. There is one high-scoring fly ortholog, Atx2, for which multiple genetic reagents have been generated including classical amorphic alleles, overexpression and RNAi targeting constructs, and alleles caused by insertional mutagenesis. Dmel\Atx2 is orthologous to a second human gene, ATXN2L.

Multiple UAS constructs of the human Hsap\ATXN2 gene have been introduced into flies, including ATXN2 genes with expanded (CAG)n repeats, and genes containing deletions of protein domains. Assaying eye phenotypes, expression of the Hsap\ATXN2 gene with the pathogenic polyQ expansion enhances phenotypes observed for a model of ALS10 (FBhh0000017).

Variants implicated in this human disease have been assessed using transgenic constructs of the human gene; see the 'Disease-Implicated Variants' table below. Variant described as (CAG)n EXPANSION, INTERMEDIATE are in the range associated with ALS13. A construct with a LONG (CAG)n repeat expansion has been introduced into flies and has been made available, but it has not been characterized. (Longer expansions (>33) are described as associated with SCA2, and intermediate expansions (27-33) with symptoms of ALS13). Some resources describe ALS13 as a form of SCA2 (OMIM:183090).

Animals homozygous for loss-of-function alleles of Dmel\Atx2 die, usually during the larval stage; germline clones result in female sterility; somatic clones result in visible phenotypes and tissue loss. RNAi experiments implicate Atx2 in maintenance of circadian rhythms. Experiments using Atx2 constructs in which the polyQ or other intrinsically disordered regions have been deleted suggest that these regions are dispensable for the essential functions of the Atx2 protein, but are necessary for long-term memory formation/consolidation; they appear to support RNP-granule assembly in neurons. Physical and genetic interactions have been described for Dmel\Atx2; see below and in the gene report for Atx2.

Extensive studies have also been done with polyglutamine-only models in flies; see the disease report for polyglutamine diseases, polyQ models (FBhh0000001).

[updated Jul. 2021 by FlyBase; FBrf0222196]

Disease Summary Information
Parent Disease Summary: spinocerebellar ataxia, autosomal dominant
Symptoms and phenotype

The autosomal dominant cerebellar degenerative disorders are generally referred to as 'spinocerebellar ataxias,' (SCAs) even though 'spinocerebellar' is a hybrid term, referring to both clinical signs and neuroanatomical regions (Margolis, 2003, pubmed:14628900). Neuropathologists have defined SCAs as cerebellar ataxias with variable involvement of the brainstem and spinal cord, and the clinical features of the disorders are caused by degeneration of the cerebellum and its afferent and efferent connections, which involve the brainstem and spinal cord (Schols et al., 2004 pubmed:15099544; Taroni and DiDonato, 2004, pubmed:15263894). [From OMIM:164400, 2015.10.27]

The autosomal dominant cerebellar degenerative disorders are generally referred to as 'spinocerebellar ataxias' (SCAs). Neuropathologists have defined SCAs as cerebellar ataxias with variable involvement of the brainstem and spinal cord; the clinical features of the disorders are caused by degeneration of the cerebellum and its afferent and efferent connections, which involve the brainstem and spinal cord (Schols et al., 2004 pubmed:15099544; Taroni and DiDonato, 2004, pubmed:15263894). [From OMIM:164400, 2015.10.27]

Specific Disease Summary: spinocerebellar ataxia 2
OMIM report

[SPINOCEREBELLAR ATAXIA 2; SCA2](https://omim.org/entry/183090)

Human gene(s) implicated

[ATAXIN 2; ATXN2](https://omim.org/entry/601517)

Symptoms and phenotype

Spinocerebellar ataxia type 2 (SCA2) is characterized by progressive cerebellar ataxia, including nystagmus, slow saccadic eye movements and, in some individuals, ophthalmoparesis or parkinsonism. Pyramidal findings are present; deep tendon reflexes are brisk early on and absent later in the course. Age of onset is typically in the fourth decade with a ten- to 15-year disease duration. [From GeneReviews, Spinocerebellar Ataxia Type 2, pubmed:20301452 2015.12.14]

Genetics

This form of autosomal dominant spinocerebellar ataxia, SCA2, is caused by an expanded (CAG)n trinucleotide repeat in ATXN2, the gene encoding ataxin-2. Unaffected individuals have 13 to 31 CAG repeats, whereas affected individuals have 32 to 79 repeats, with some in the range of 500 repeats (summary by Almaguer-Mederosa et al., 2010, pubmed:20095980). There is also an association between 29 or more CAG repeats and the development of amyotrophic lateral sclerosis-13 (ALS13). For a phenotypic description and a discussion of genetic heterogeneity of amyotrophic lateral sclerosis, see ALS1 (OMIM:105400). [From OMIM:183090, 2015.10.27]

Cellular phenotype and pathology
Molecular information

Genetic, biochemical, and neuropathologic interactions between TDP43 (OMIM:605078), a protein involved in amyotrophic lateral sclerosis (ALS10; OMIM:612069), and ATXN2, which raised the possibility that mutations in ATXN2 may have a causative role in ALS. The ATXN2 polyQ tract length, although variable, is most frequently 22-23, with expansions of greater than 34 causing SCA2. However, the variable nature of the polyQ repeat indicated a mechanism by which such mutations in ATXN2 could be linked to ALS. Elden et al. (2010, pubmed:20740007) proposed that intermediate-length expansions greater than 23 but below the threshold for SCA2 may be associated with ALS. PolyQ expansions in ATXN2 enhance its interaction with TDP43. Both ATXN2 and TDP43 relocalize to stress granules, sites of RNA processing, under various stress situations such as heat shock and oxidative stress. Under normal conditions TDP43 localized to the nucleus and ATXN2 to the cytoplasm in both control cells and cells harboring polyQ repeat expansions. It has been proposed that intermediate-length ATXN2 polyQ repeats might confer genetic risk for ALS by making TDP43 more prone to mislocalize from the nucleus to the cytoplasm under situations of stress (Elden et al., 2010, pubmed:20740007). [From OMIM:183090, 2015.12.14]

External links
Disease synonyms
ALS13
amyotrophic lateral sclerosis 13
autosomal dominant hereditary ataxia
cerebellar degeneration with slow eye movements
olivopontocerebellar atrophy, Holguin type
olivopontocerebellar atrophy II
OPCA2
SCA2/ALS13
SDSEM
spinocerebellar ataxia 2; SCA2
spinocerebellar ataxia, Cuban type
spinocerebellar ataxia type 2
spinocerebellar atrophy II
spinocerebellar degeneration with slow eye movements
susceptibility to amyotrophic lateral sclerosis 13
Wadia-Swami syndrome
Ortholog Information
Human gene(s) in FlyBase
Human gene (HGNC)
Symbol / Name
D. melanogaster ortholog (based on DIOPT)
Comments on ortholog(s)

Many to one: 2 human to 1 Drosophila (See DIOPT, link below).

Other mammalian ortholog(s) used
    D. melanogaster Gene Information (1)
    Gene Snapshot
    Ataxin-2 (Atx2) encodes the ortholog of human gene ATXN2, which is implicated in spinocerebellar ataxia 2. It contributes to eye development, circadian behaviour, and microRNA function. [Date last reviewed: 2019-03-07]
    Molecular function (GO)
    Gene Groups / Pathways
      Comments on ortholog(s)

      Ortholog of human ATXN2 and ATXN2L (1 Drosophila to 2 human).

      Dmel\Atx2 shares 24% identity and 36% similarity with human ATXN2, and 25% identity and 36% similarity to human ATXN2L.

      Orthologs and Alignments from DRSC
      DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
      Other Genes Used: Viral, Bacterial, Synthetic (0)
        Summary of Physical Interactions (35 groups)
        protein-protein
        Interacting group
        Assay
        References
        aggregation assay, molecular weight estimation by staining
        experimental knowledge based
        experimental knowledge based
        experimental knowledge based
        experimental knowledge based
        experimental knowledge based
        anti tag coimmunoprecipitation, western blot
        proximity-dependent biotin identification, Identification by mass spectrometry
        experimental knowledge based
        anti bait coimmunoprecipitation, western blot, two hybrid, anti tag coimmunoprecipitation
        experimental knowledge based
        anti tag coimmunoprecipitation, western blot, anti bait coimmunoprecipitation
        experimental knowledge based
        anti bait coimmunoprecipitation, western blot
        anti tag coimmunoprecipitation, western blot, anti bait coimmunoprecipitation, cosedimentation through density gradient
        experimental knowledge based
        experimental knowledge based
        anti tag coimmunoprecipitation, Identification by mass spectrometry
        experimental knowledge based
        experimental knowledge based
        anti tag coimmunoprecipitation, anti tag western blot, western blot, anti bait coimmunoprecipitation, experimental knowledge based, peptide massfingerprinting
        RNA-protein
        Interacting group
        Assay
        References
        proximity labelling technology, nucleotide sequence identification
        proximity labelling technology, nucleotide sequence identification
        anti tag coimmunoprecipitation, primer specific pcr
        anti tag coimmunoprecipitation, primer specific pcr, quantitative reverse transcription pcr
        anti bait coimmunoprecipitation, primer specific pcr
        anti tag coimmunoprecipitation, primer specific pcr
        anti tag coimmunoprecipitation, primer specific pcr, quantitative reverse transcription pcr
        anti bait coimmunoprecipitation, primer specific pcr
        anti tag coimmunoprecipitation, primer specific pcr, quantitative reverse transcription pcr
        anti tag coimmunoprecipitation, quantitative reverse transcription pcr, anti bait coimmunoprecipitation, primer specific pcr
        anti bait coimmunoprecipitation, primer specific pcr
        anti bait coimmunoprecipitation, primer specific pcr
        anti tag coimmunoprecipitation, quantitative reverse transcription pcr, primer specific pcr, anti bait coimmunoprecipitation
        anti tag coimmunoprecipitation, primer specific pcr, quantitative reverse transcription pcr
        Alleles Reported to Model Human Disease (Disease Ontology) (14 alleles)
        Models Based on Experimental Evidence ( 2 )
        Modifiers Based on Experimental Evidence ( 12 )
        Allele
        Disease
        Interaction
        References
        Models Based on Experimental Evidence ( 1 )
        Allele
        Disease
        Evidence
        References
        Modifiers Based on Experimental Evidence ( 1 )
        Allele
        Disease
        Interaction
        References
        Alleles Representing Disease-Implicated Variants
        Genetic Tools, Stocks and Reagents
        References (33)