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]
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]
[SPINOCEREBELLAR ATAXIA 12; SCA12](https://omim.org/entry/604326)
[PROTEIN PHOSPHATASE 2, REGULATORY SUBUNIT B, BETA; PPP2R2B](https://omim.org/entry/604325)
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).
Many to one (4 human to 1 Drosophila). The additional human genes are PPP2R2D, PPP2R2A, and PPP2R2C.
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.