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General Information
Name
spinocerebellar ataxia 7
FlyBase ID
FBhh0000065
Overview

This report describes spinocerebellar ataxia 7 (SCA7), which is a subtype of spinocerebellar ataxia; SCA7 is inherited as an autosomal dominant. The human gene implicated in this disease is ataxin-7 (ATXN7), which encodes a transcription factor important for chromatin remodeling, including histone acetylation and deubiquitination. SCA7 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. Although there is no identified fly ortholog for human ATXN7, Dmel\Atxn7 has been proposed as a potential homolog and as functionally equivalent. RNAi targeting constructs, alleles caused by insertional mutagenesis, and classical hypomorphic alleles have been generated for Dmel\Atxn7.

Multiple UAS constructs of the human Hsap\ATXN7 gene have been introduced into flies, including wild-type ATXN7 and ATXN7 genes with expanded (CAG)n repeats. The truncated ATXN7 with the pathogenic polyQ expansion accumulates neuronal intranuclear inclusions; aggregation is accompanied by a decrease in locomotion and lifespan.

Variant(s) implicated in human disease tested (as transgenic human gene, ATXN7): Q30_Q39 (CAG)n EXPANSION in a truncated protein.

Animals homozygous for loss-of-function mutations of Dmel\Atxn7 exhibit neural and retinal degeneration, impaired movement, and early lethality. Physical and genetic interactions have been described for Dmel\Atxn7; see below and in the gene report for Atxn7.

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

[updated Mar. 2017 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 7
OMIM report

[SPINOCEREBELLAR ATAXIA 7; SCA7](https://omim.org/entry/164500)

Human gene(s) implicated

[ATAXIN 7; ATXN7](https://omim.org/entry/607640)

Symptoms and phenotype

Spinocerebellar ataxia-7 (SCA7) is an autosomal dominant neurodegenerative disorder characterized by adult onset of progressive cerebellar ataxia associated with pigmental macular dystrophy. In her classification of ataxia, Harding (1982, pubmed:7066668) referred to progressive cerebellar ataxia with pigmentary macular degeneration as type II ADCA (autosomal dominant cerebellar ataxia). The age at onset, degree of severity, and rate of progression vary among and within families. Associated neurologic signs, such as ophthalmoplegia, pyramidal or extrapyramidal signs, deep sensory loss, or dementia, are also variable. Genetic anticipation is observed and is greater in paternal than in maternal transmissions (Benomar et al., 1994, pubmed:8154871; summary by David et al., 1996, pubmed:8940279). [From OMIM:164500, 2015.12.14]

Genetics

This form of autosomal dominant spinocerebellar ataxia, SCA7, is caused by an expanded (CAG)n trinucleotide repeat in ATXN7, the gene encoding ataxin-7. [From OMIM:164500, 2015.10.29]

Cellular phenotype and pathology

In a postmortem brain examination of a single patient, neuronal intranuclear inclusions, identified by an antibody directed against the expanded polyglutamine domain, were identified in multiple areas of the brain. Inclusions were most frequent in the inferior olivary complex, a site of severe neuronal loss in SCA7, the lateral geniculate body, and the substantia nigra, but were also present in other brain regions, including the cerebral cortex which is not considered to be affected in the disease. Some cytoplasmic staining was also identified. Some inclusions stained positively for ubiquitin, but the degree was highly variable (Holmberg et al, 1998, pubmed:9536097). [From OMIM:164500, 2015.12.14]

Molecular information

ATXN7 is a transcription factor that appears to be critically important for chromatin remodeling at the level of histone acetylation and deubiquitination. It is a core component of 2 different transcription coactivator complexes: the SPT3 (SUPT3H; OMIM:602947)/TAF9 (OMIM:600822)/GCN5 (KAT2A; OMIM:602301) acetyltransferase (STAGA) complex, which has hi stone acetyltransferase activity, and the USP22 (OMIM:612116) deubiquitination complex (summary by Sopher et al., 2011, pubmed:21689595). [From OMIM:607640, 2015.10.29]

External links
Disease synonyms
SCA7
olivopontocerebellar atrophy III
OPCA3
OPCA III
OPCA with retinal degeneration
OPCA with macular degeneration and external ophthalmoplegia
autosomal dominant cerebellar ataxia, type II
ADCA, type II
spinocerebellar ataxia; SCA7
spinocerebellar ataxia type 7
Ortholog Information
Human gene(s) in FlyBase
Human gene (HGNC)
Symbol / Name
D. melanogaster ortholog (based on DIOPT)
Comments on ortholog(s)

No gene orthologous to human ATXN7 in Drosophila (DIOPT).

Other mammalian ortholog(s) used
    D. melanogaster Gene Information (1)
    Gene Snapshot
    Ataxin 7 (Atxn7) encodes a component of the SAGA chromatin modifying complex, which is responsible for acetylation of histones and deubiquitination of the product of His2B at active promoters. The product of Atxn7 anchors the non-stop containing deubiquitinase module to the remainder of SAGA. Atxn7 is an essential gene for larval survival, neural development, and maintenance of neural tissues. [Date last reviewed: 2019-03-07]
    Molecular function (GO)
      Gene Groups / Pathways
      Comments on ortholog(s)

      Dmel\Atxn7 has proposed as a putative homolog of human ATXN7. Like human ATXN7, Dmel\Atxn7 is a member of the SAGA chromatin-modifying complex. Dmel\Atxn7 shares a high degree of homology with human ATXN7 in 3 ATXN7 signature blocks. However, 0 of 10 orthology prediction algorithms identify Dmel\Atxn7 as an ortholog of human ATXN7 (see DIOPT, below).

      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 (20 groups)
      protein-protein
      Interacting group
      Assay
      References
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, molecular sieving, western blot, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting, experimental knowledge based
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, western blot, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, western blot, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting, anti tag western blot
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      Alleles Reported to Model Human Disease (Disease Ontology) (7 alleles)
      Models Based on Experimental Evidence ( 3 )
      Modifiers Based on Experimental Evidence ( 0 )
      Allele
      Disease
      Interaction
      References
      Models Based on Experimental Evidence ( 4 )
      Modifiers Based on Experimental Evidence ( 1 )
      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
      References (15)