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FB2026_01
,
released March 12, 2026
This report describes spinocerebellar ataxia 8 (SCA8), which is a subtype of spinocerebellar ataxia; SCA8 is inherited as an autosomal dominant. SCA8 is one of a number spinocerebellar ataxias caused by expansion of trinucleotide repeats within the coding -- or noncoding -- region of the causative gene. The human genes implicated in SCA8 are ATXN8, which encodes a nearly pure polyglutamine protein in the CAG direction; and ATXN8OS, which is antisense to ATXN8 and is transcribed to produce a noncoding CUG RNA. The wild-type function of neither gene is known. Expansion of the CTG/CAG trinucleotide repeat is associated with SCA8. ATXN8OS is also antisense to the 5' end of the KLHL1 gene, but this region does not correspond to the trinucleotide repeat. No ortholog of ATXN8 or ATXN8OS has been identified in flies.
Multiple UAS constructs of the human gene Hsap\ATXN8OS have been introduced into flies, including wild-type ATXN8OS and ATXN8OS with expanded (CTG)n repeats. ATXN8 has not been introduced into flies. When expressed in the developing eye, the Hsap\ATXN8OS transcript with the pathogenic repeat expansion induces progressive neurodegeneration in the adult retina; this phenotype has been used to conduct genetic screens for interacting genes.
Variant(s) implicated in human disease tested (as transgenic human gene, ATXN8OS): ATXN8OS, (CTG)n EXPANSION in a modified transcript.
To investigate general mechanisms of RNA repeat diseases, work has been done in flies using UAS constructs to drive synthetic constructs of nucleotide repeats of variable composition and length; see FBhh0000059.
[updated Mar. 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 MIM: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 MIM:164400, 2015.10.27]
[SPINOCEREBELLAR ATAXIA 8; SCA8](https://omim.org/entry/608768)
[ATAXIN 8; ATXN8](https://omim.org/entry/613289)
[ATAXIN 8 OPPOSITE STRAND; ATXN8OS](https://omim.org/entry/603680)
SCA8 is a slowly progressive ataxia with disease onset typically occurring in adulthood. Onset ranges from age one to 73 years. The progression is typically over decades regardless of the age of onset. Common initial symptoms are scanning dysarthria with a characteristic drawn-out slowness of speech and gait instability; life span is typically not shortened. Some individuals present with nystagmus, dysmetric saccades and, rarely, ophthalmoplegia. Tendon reflex hyperreflexity and extensor plantar responses are present in some severely affected individuals. Life span is typically not shortened. [From GeneReviews, Spinocerebellar Ataxia Type 8, pubmed:20301445 2015.12.14]
This form of autosomal dominant spinocerebellar ataxia, SCA8, is caused by bidirectional transcription at the SCA8 locus on chromosome 13q21 involving both an expanded CTG trinucleotide repeat in the ATXN8OS gene (MIM:603680.0001) and the complementary CAG repeat in the ATXN8 gene (MIM:613289.0001). These variations result in expression of a CUG expansion mRNA transcript and a polyglutamine protein, respectively, suggesting a toxic gain of function at both the protein and RNA levels. The molecular defect is often referred to as the 'CTG*CAG' repeat expansion, referring to the complementary basepairs of the ATXN8OS and ATXN8 genes, reading 5-prime to 3-prime (review by Ikeda et al., 2008, pubmed:18418692). Normal alleles contain 15 to 50 repeats, whereas pathogenic alleles contain 71 to 1,300 repeats (Todd and Paulson, 2010, pubmed:20373340). [From MIM:608768, 2015.10.29]
In brain tissue from humans and mice with SCA8, ATXN8OS mRNA containing the expanded repeat was found to accumulate as ribonuclear inclusions, or RNA foci, that colocalized with the RNA-binding protein MBNL1 (MIM:606516) in selected cerebellar cortical neurons in the brain. In Sca8 mice, genetic loss of Mbnl1 enhanced motor deficits, suggesting that loss of MBNL1 plays a role in SCA8 pathogenesis. In Sca8 mice and SCA8 human brains, sequestration of MBNL1 in RNA foci resulted in the dysregulation of downstream splicing patterns normally regulated by the CUGBP1 (MIM:601074)/MBNL1 pathway, including that of mouse GABA transporter-4 (GAT4, or SLC6A11; MIM:607952). These changes in Gat4 were associated with loss of GABAergic inhibition in the granular cell layer. These data indicated that expanded CUG ATXN8OS mRNA transcripts can dysregulate gene pathways in the brain, similar to the mechanism involved in myotonic dystrophy (DM1; MIM:160900), which is caused by a CTG repeat expansion in the 3-prime UTR of the DMPK gene (MIM:605377) (Daughters et al., 2009, pubmed:19680539) [From MIM:608768, 2015.12.14]
SCA8 is a neurodegenerative disorder caused by a CTG/CAG trinucleotide repeat expansion (see MIM:603680.0001 and MIM:613289.0001). Two genes span the CTG/CAG repeat and are expressed in opposite directions: ATXN8, which encodes a nearly pure polyglutamine expansion protein in the CAG direction, and ATXN8OS, which, when transcribed, produces a noncoding CUG expansion RNA (Moseley et al., 2006, pubmed:16804541). [From MIM:613289 and MIM:603680, 2015.12.14]
No gene orthologous to human ATXN8OS in Drosophila (DIOPT).
No gene orthologous to human ATXN8 in Drosophila (DIOPT).