Spinocerebellar Ataxia 1 (ATXN1)
| Dred_ID | RD00001 |
| OMIM ID | 164400 |
| Disease name | Spinocerebellar Ataxia 1 |
| Alternative names | Spinocerebellar Atrophy I Olivopontocerebellar Atrophy I Opca I opca1 Cerebelloparenchymal Disorder I Cpd1 Menzel Type Opca Olivopontocerebellar Atrophy IV Opca IV Opca4 Schut-haymaker Type Opca |
| Category | Genetic diseases, Rare diseases, Neuronal diseases, Skin diseases, Eye diseases, Mental diseases, Ear diseases, Metabolic diseases, Fetal diseases, Liver diseases |
| Phenotype | NIH Rare Diseases: Spinocerebellar ataxia type 1 (SCA1) is a progressive movement disorder that typically begins in early adulthood (but can affect children and older adults as well). Early signs and symptoms includes problems with coordination and balance (ataxia), speech and swallowing difficulties, muscle stiffness, and weakness in the muscles that control eye movement. Over time, SCA1 may cause mental impairment, numbness, tingling, or pain in the arms and legs and uncontrolled muscle tensing, wasting, and twitches. SCA1 is caused by changes in the ATXN1 gene and is inherited in an autosomal dominant fashion. There is currently not a cure for SCA1, but treatments are available to help manage symptoms. People with SCA1 typically survive 10 to 30 years after symptoms first appear.
OMIM: 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). 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; Taroni and DiDonato, 2004). Historically, Harding (1982) proposed a clinical classification for autosomal dominant cerebellar ataxias (ADCAs). ADCA I was characterized by cerebellar ataxia in combination with various associated neurologic features, such as ophthalmoplegia, pyramidal and extrapyramidal signs, peripheral neuropathy, and dementia, among others. ADCA II was characterized by the cerebellar ataxia, associated neurologic features, and the additional findings of macular and retinal degeneration. ADCA III was a pure form of late-onset cerebellar ataxia without additional features. SCA1, SCA2 (183090), and SCA3, or Machado-Joseph disease (109150), are considered to be forms of ADCA I. These 3 disorders are characterized at the molecular level by CAG repeat expansions on 6p24-p23, 12q24.1, and 14q32.1, respectively. SCA7 (607640), caused by a CAG repeat expansion in the ATXN7 gene (607640) on chromosome 3p13-p12, is a form of ADCA II. SCA5 (600224), SCA31 (117210), SCA6 (183086), and SCA11 (600432) are associated with phenotypes most suggestive of ADCA III. However, Schelhaas et al. (2000) noted that there is significant phenotypic overlap between different forms of SCA as well as significant phenotypic variability within each subtype. Classic reviews of olivopontocerebellar atrophies and of inherited ataxias in general include those of Konigsmark and Weiner (1970), who identified 5 types of olivopontocerebellar atrophy, Berciano (1982), Harding (1993), Schelhaas et al. (2000), and Margolis (2003). |
| Miscellaneouse | OMIM: genetic anticipation onset in third or fourth decade paternal anticipation bias |
| Prevalence | Prevalence: 1-9/100000 (Worldwide) [source: MalaCards] |
| Inheritance | Autosomal dominant |
| Anticipation | Yes |
| Evidence | Strong |
| Gene symbol | ATXN1 |
| Alias symbols | ATX1; SCA1; D6S504E |
| Gene name | ataxin 1 |
| Gene map locus | 6p23; chr6:16,299,112-16,761,491(-) |
| Ensembl Gene ID | ENSG00000124788 |
| Gene expression and Gene Ontology | BioGPS |
| Protein expression | Human Protein Atlas |
| Gene sequence | Sequence |
| Variation | ClinVar, dbSNP | Gene conservation | Gene Conservation from UCSC Genome Browser |
| Gene Description | The autosomal dominant cerebellar ataxias (ADCA) are a heterogeneous group of neurodegenerative disorders characterized by progressive degeneration of the cerebellum, brain stem and spinal cord. Clinically, ADCA has been divided into three groups: ADCA types I-III. ADCAI is genetically heterogeneous, with five genetic loci, designated spinocerebellar ataxia (SCA) 1, 2, 3, 4 and 6, being assigned to five different chromosomes. ADCAII, which always presents with retinal degeneration (SCA7), and ADCAIII often referred to as the `pure' cerebellar syndrome (SCA5), are most likely homogeneous disorders. Several SCA genes have been cloned and shown to contain CAG repeats in their coding regions. ADCA is caused by the expansion of the CAG repeats, producing an elongated polyglutamine tract in the corresponding protein. The expanded repeats are variable in size and unstable, usually increasing in size when transmitted to successive generations. The function of the ataxins is not known. This locus has been mapped to chromosome 6, and it has been determined that the diseased allele contains 40-83 CAG repeats, compared to 6-39 in the normal allele, and is associated with spinocerebellar ataxia type 1 (SCA1). At least two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Nov 2017] |
| Repeat unit | CAG |
| Normal repeat copies | 6-39 |
| Pathogenic repeat copies | ≥41 |
| Gene | ATXN1 |
| Repeat location | CDS |
| Chromosome locus | chr6:16327624-16327721 (-) |
| Repeat conservation | Repeat Conservation from UCSC Genome Browser |
| Toxic cause | Protein |
| Possible toxicity | Lim et al. (2008) demonstrated that the expanded polyglutamine tract of ATXN1 differentially affects the function of the host protein in the context of different endogenous protein complexes. Polyglutamine expansion in ATXN1 favors the formation of a particular protein complex containing RBM17 (606935), contributing to SCA1 neuropathology by means of a gain-of-function mechanism. Concomitantly, polyglutamine expansion attenuates the formation and function of another protein complex containing ATXN1 and capicua, contributing to SCA1 through a partial loss-of-function mechanism. Lim et al. (2008) concluded that their model provides mechanistic insight into the molecular pathogenesis of SCA1 as well as other polyglutamine diseases.
Jain and Vale (2017) showed that repeat expansions create templates for multivalent basepairing, which causes purified RNA to undergo a sol-gel transition in vitro at a similar critical repeat number as observed in Huntington disease, spinocerebellar ataxia, myotonic dystrophy, and FTDALS1 (105550). In human cells, RNA foci form by phase separation of the repeat-containing RNA and can be dissolved by agents that disrupt RNA gelation in vitro. Jain and Vale (2017) concluded that, analogous to protein aggregation disorders, their results suggested that the sequence-specific gelation of RNAs could be a contributing factor to neurologic disease. [By OMIM] |
| Pathway annotation | Reactome, KEGG |
| PMID | 24155902 |
| Authors | de Chiara C1, Menon RP, Kelly G, Pastore A |
| Title | Protein-protein interactions as a strategy towards protein-specific drug design: the example of ataxin-1 |
| Journal | PLoS One. 8(10):e76456 |
| Year | 2013 |
| PMID | 23760502 |
| Authors | Bergeron D, Lapointe C, Bissonnette C, Tremblay G, Motard J, Roucou X |
| Title | An out-of-frame overlapping reading frame in the ataxin-1 coding sequence encodes a novel ataxin-1 interacting protein |
| Journal | J Biol Chem. 288(30):21824-35 |
| Year | 2013 |