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]
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 7; SCA7](https://omim.org/entry/164500)
[ATAXIN 7; ATXN7](https://omim.org/entry/607640)
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]
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]
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]
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).