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General Information
Name
spinocerebellar ataxia 6
FlyBase ID
FBhh0000428
Overview

This report describes spinocerebellar ataxia 6 (SCA6), which is a subtype of spinocerebellar ataxia; SCA6 exhibits autosomal dominant inheritance. The human gene implicated in this disease, CACNA1A, is bicistronic: it encodes the α1A P/Q type calcium channel subunit, plus a putative transcription factor, α1ACT. The latter initiates from an alternative downstream start site in the CACNA1A gene and is 547aa in size. Some longer isoforms encode only the α1A calcium channel subunit; others appear to encode a fusion protein. There is one high-scoring fly ortholog of CACNA1A, cac, for which RNAi targeting constructs, alleles caused by insertional mutagenesis, and classical amorphic alleles have been generated. Drosophila cac protein isoforms have very little overlap with the short α1ACT isoform.

Most cases of SCA6 are associated with an expanded (CAG)n repeat within the region that encodes α1ACT; expanded (CAG)n repeats in this region are also associated with episodic ataxia 2 (OMIM:108500). Mutations in the region that encodes the α1A calcium channel subunit are also implicated in SCA6 and EA2, as well as multiple other diseases [familial hemiplegic migraine 1 (OMIM:141500), familial hemiplagic migraine 1 with progressive cerebellar ataxia (OMIM:141500), and early infantile epileptic encephalopathy 42 (OMIM:617106)].

UAS constructs of the α1ACT isoform of the human Hsap\CACNA1A gene have been introduced into flies, including the wild-type isoform, and a construct with expanded (CAG)n repeats. Full-length CACNA1A has not been introduced into flies. Variant(s) implicated in human disease tested (as transgenic human gene, α1ACT short isoform of CACNA1A): Q354_Q366 (CAG)n EXPANSION (location based on the 547aa sequence of the α1ACT isoform).

Amorphic mutations of cac are lethal in the embryonic stage. Less severe mutations exhibit neuroanatomy, neurophysiology, and behavioral defects. Physical and genetic interactions of Dmel\cac have been described; see below and in the cac gene report.

[updated Nov. 2019 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 6
OMIM report

[SPINOCEREBELLAR ATAXIA 6; SCA6](https://omim.org/entry/183086)

Human gene(s) implicated

[CALCIUM CHANNEL, VOLTAGE-DEPENDENT, P/Q TYPE, ALPHA-1A SUBUNIT; CACNA1A](https://omim.org/entry/601011)

Symptoms and phenotype

Spinocerebellar ataxia type 6 (SCA6) is characterized by adult-onset, slowly progressive cerebellar ataxia, dysarthria, and nystagmus. Mean age of onset is 43 to 52 years. Initial symptoms are gait unsteadiness, stumbling, and imbalance (in ~90%) and dysarthria (in ~10%). Eventually all persons have gait ataxia, upper-limb incoordination, intention tremor, and dysarthria. Dysphagia and choking are common. Visual disturbances may result from diplopia, difficulty fixating on moving objects, horizontal gaze-evoked nystagmus, and vertical nystagmus. Hyperreflexia and extensor plantar responses occur in up to 40%-50%. Basal ganglia signs, including dystonia and blepharospasm, occur in up to 25%. Mentation is generally preserved. [from GeneReviews, Spinocerebellar Ataxia Type 6, pubmed:20301319 2016.11.04]

Genetics

This form of autosomal dominant spinocerebellar ataxia, SCA6, is caused by heterozygous mutation in CACNA1A, the gene encoding the transmembrane pore-forming subunit of the P/Q-type or CaV2.1 voltage-gated calcium channel (VGCC) (Kordasiewicz et al., 2006, pubmed:16595610). The most common mutation is an expanded CAG(n) repeat in exon 47 of the CACNA1A gene. Normal alleles contain 4 to 18 repeats, whereas pathogenic alleles contain 19 to 33 repeats (Li et al., 2009, pubmed:19817876). Point mutations in the CACNA1A gene resulting in a G293R (Yue, et al., 1997, pubmed:9345107) or R583Q (Battistini et al., 1999, pubmed:10408534) protein substitution have also been associated with SCA6. [From OMIM:183086 and OMIM:601011, 2016.11.03]

Cellular phenotype and pathology

In SCA6 brains, numerous oval or rod-shaped aggregates were seen exclusively in the cytoplasm of Purkinje cells. These cytoplasmic inclusions were not ubiquitinated, which contrasts with the neuronal intranuclear inclusions of other CAG repeat/polyglutamine diseases. In cultured cells, formation of perinuclear aggregates of the channel protein and apoptotic cell death were seen when transfected with full-length CACNA1A coding an expanded polyglutamine tract. The authors concluded that the mechanism of neurodegeneration in SCA6 is associated with cytoplasmic aggregations of the alpha-1A calcium channel protein caused by a small CAG repeat/polyglutamine expansion in CACNA1A (Ishikawa et al., 1999, pubmed:10369863). [From OMIM:183086, 2016.11.04]

Molecular information

CACNA1A encodes the transmembrane pore-forming subunit of the P/Q-type or CaV2.1 voltage-gated calcium channel (VGCC). Voltage-dependent Ca(2+) channels not only mediate the entry of Ca(2+) ions into excitable cells but are also involved in a variety of Ca(2+)-dependent processes, including muscle contraction, hormone or neurotransmitter release, and gene expression (Kordasiewicz et al., 2006, pubmed:16595610). In addition to full-length CACNA1A, use of an internal ribosomal entry site in the CACNA1A transcript generates the CACNA1A C-terminal polypeptide, or alpha-1ACT, which functions as a transcription factor that mediates cerebellar development (Du et al., 2013, pubmed:23827678). [From OMIM:601011, 2016.11.04]

Translation of α1ACT starts at the Met at position 1960 in the full-length CACNA1A protein isoform (which is 2506 aa) (Du et al., 2013, pubmed:23827678).

External links
Disease synonyms
spinocerebellar ataxia 6; SCA6
SCA6
spinocerebellar ataxia type 6
Search term: calcium channelopathy
Ortholog Information
Human gene(s) in FlyBase
Human gene (HGNC)
D. melanogaster ortholog (based on DIOPT)
Comments on ortholog(s)

Many to one: 3 human to 1 Drosophila. The other human genes are CACNA1B and CACNA1E.

Other mammalian ortholog(s) used
    D. melanogaster Gene Information (1)
    Gene Snapshot
    cacophony (cac) encodes the primary structural subunit of a voltage-gated calcium channel, which is located at presynaptic active zones. It functions in evoked neurotransmitter release at neuromuscular synapses. It contributes to male courtship behavior and a wide range of neurophysiological processes. [Date last reviewed: 2019-03-07]
    Gene Groups / Pathways
    Comments on ortholog(s)

    Ortholog of human CACNA1B, CACNA1E, and CACNA1A (1 Drosophila to 3 human). Dmel\cac shares 44% identity and 53% similarity with human CACNA1B, 43% identity and 55S% similarity with human CACNA1E, 43% identity and 54% similarity with human CACNA1A.

    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 (3 groups)
    protein-protein
    Interacting group
    Assay
    References
    proximity ligation assay, fluorescence microscopy
    two hybrid, x-ray crystallography, isothermal titration calorimetry, predetermined participant
    RNA-protein
    Interacting group
    Assay
    References
    anti bait coimmunoprecipitation, quantitative reverse transcription pcr
    Alleles Reported to Model Human Disease (Disease Ontology) (9 alleles)
    Models Based on Experimental Evidence ( 4 )
    Modifiers Based on Experimental Evidence ( 4 )
    Models Based on Experimental Evidence ( 2 )
    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
    ethyl methanesulfonate
    amorphic allele - genetic evidence
    FLPase
    References (10)