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General Information
Name
spinocerebellar ataxia 12
FlyBase ID
FBhh0000067
Overview

This report describes spinocerebellar ataxia 12 (SCA12), which is a subtype of spinocerebellar ataxia; SCA12 exhibits autosomal dominant inheritance. The human gene implicated in this disease is PPP2R2B, which encodes a brain-specific regulatory subunit B of protein phosphatase 2 (PP2A), a heterotrimeric serine/threonine phosphatase.There is one high-scoring fly ortholog, tws, for which classical amorphic alleles, RNAi targeting constructs, and alleles caused by insertional mutagenesis have been generated. Dmel\tws is also orthologous to the human genes PPP2R2D, PPP2R2A, and PPP2R2C.

Expanded (CAG)n repeats at the PPP2R2B locus are associated with SCA12, however, SCA12 pathology does not appear to be due to a polyglutamine expansion. The PPP2R2B gene encodes multiple isoforms with different N-termini. The repeat is within the promoter region of some isoforms, within the 5' UTR of several isoforms, and within the translated CDS of at least one isoform, but not in the ORF that would encode polyglutamine. Evidence of polyglutamine aggregates has not been found. Current data suggest that the repeat has an impact on levels of PPP2R2B expression and/or that the repeat-containing RNA is pathogenic.

A UAS construct of the wild-type human Hsap\PPP2R2B gene has been introduced into flies. Pan-neuronal or ubiquitous expression of PPP2R2B results in neurodegeneration, apoptosis, and shortened life span.

Homozygous loss-of-function mutations of Dmel\tws are lethal, typically during larval or pupal stages; homozygous germline clones result in embryos that exhibit patterning defects and fail to hatch (maternal effect lethal). Using GAL4-UAS constructs, pan-neuronal overexpression of tws results in an increase in the number of apoptotic cells in embryos, severe reduction in adult lifespan, and progressive neural degeneration and mitochondrial abnormalities in the adult stage. Genetic and physical interactions of Dmel\tws have been described; see below and in the gene report for tws.

[updated Jul. 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 12
OMIM report

[SPINOCEREBELLAR ATAXIA 12; SCA12](https://omim.org/entry/604326)

Human gene(s) implicated

[PROTEIN PHOSPHATASE 2, REGULATORY SUBUNIT B, BETA; PPP2R2B](https://omim.org/entry/604325)

Symptoms and phenotype
Genetics

This form of autosomal dominant spinocerebellar ataxia, SCA12, is caused by an expanded (CAG)n trinucleotide repeat in PPP2R2B. Normal alleles carry 7 to 32 triplets, whereas disease alleles carry 51 to 78 triplets (Bahl et al., 2005, pubmed:16138911). [From OMIM:604326, 2015.10.30]

Cellular phenotype and pathology

Neuropathological examination of a brain from an SCA12 patient revealed both cerebellar and cerebral cortical atrophy, with a noted loss of Purkinje cells and no evidence of polyglutamine aggregates (Cohen and Margolis, 2016; pubmed:27748686).

Molecular information

The PPP2R2B gene encodes a brain-specific regulatory subunit B of protein phosphatase 2. Protein phosphatase 2A (PP2A), a heterotrimeric serine/threonine phosphatase, has been implicated in a variety of regulatory processes, including cell growth and division, muscle contraction, and gene transcription. PP2A is composed of a 36-kD catalytic subunit (OMIM:176915), a highly homologous 65-kD structural subunit (176915), and any of several different regulatory subunits that control its specificity, including PPP2R2B (Mayer et al., 1991, pubmed:1849734). [From OMIM:604385, 2015.12.14]

PPP2R2B appears to encode at least eight isoforms each with a different N-terminal region. The repeat potentially influences PPP2R2B expression, and is itself included in several splice variants, falling within an open reading frame of at least one of these variants (Cohen and Margolis, 2016; pubmed:27748686).

External links
Disease synonyms
SCA12
spinocerebellar ataxia 12; SCA12
spinocerebellar ataxia type 12
Ortholog Information
Human gene(s) in FlyBase
Human gene (HGNC)
D. melanogaster ortholog (based on DIOPT)
Comments on ortholog(s)

Many to one (4 human to 1 Drosophila). The additional human genes are PPP2R2D, PPP2R2A, and PPP2R2C.

Other mammalian ortholog(s) used
    D. melanogaster Gene Information (1)
    Gene Snapshot
    twins (tws) encodes a regulatory subunit of protein phosphatase 2A (PP2A) and is involved in many developmental processes and signaling pathways. [Date last reviewed: 2018-09-13]
    Gene Groups / Pathways
    Comments on ortholog(s)

    Ortholog of human PPP2R2D, PPP2R2A, PPP2R2B, and PPP2R2C (1 Drosophila to 4 human).

    Dmel\tws shares 78% identity and 90% similarity with human PPP2R2D, 80% identity and 89% similarity with human PPP2R2A, 68% identity and 78% similarity with human PPP2R2B, and 76% identity and 89% similarity to human PPP2R2C.

    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 (15 groups)
    protein-protein
    Interacting group
    Assay
    References
    anti bait coimmunoprecipitation, western blot
    anti tag coimmunoprecipitation, anti tag western blot, proximity ligation assay, fluorescence microscopy
    anti tag coimmunoprecipitation, anti tag western blot
    experimental knowledge based
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, western blot
    pull down, western blot, autoradiography
    anti tag coimmunoprecipitation, peptide massfingerprinting, experimental knowledge based
    proximity ligation assay, fluorescence microscopy, anti tag coimmunoprecipitation, anti tag western blot
    anti tag coimmunoprecipitation, anti tag western blot
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, anti tag western blot, western blot
    anti tag coimmunoprecipitation, anti tag western blot
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, anti tag western blot
    Alleles Reported to Model Human Disease (Disease Ontology) (2 alleles)
    Models Based on Experimental Evidence ( 1 )
    Allele
    Disease
    Evidence
    References
    Modifiers Based on Experimental Evidence ( 1 )
    Allele
    Disease
    Interaction
    References
    Models Based on Experimental Evidence ( 1 )
    Allele
    Disease
    Evidence
    References
    Modifiers Based on Experimental Evidence ( 0 )
    Allele
    Disease
    Interaction
    References
    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
    loss of function allele
    loss of function allele
    ethyl methanesulfonate
    References (6)