Spinocerebellar Ataxia 2 (ATXN2)
| Dred_ID | RD00002 |
| OMIM ID | 183090 |
| Disease name | Spinocerebellar Ataxia 2 |
| Alternative names | Spinocerebellar Atrophy II Sca2 Olivopontocerebellar Atrophy, Holguin Type Olivopontocerebellar Atrophy II opca2 Spinocerebellar Ataxia, Cuban type Cerebellar Degeneration with Slow Eye Movements Wadia-swami Syndrome Spinocerebellar Degeneration W |
| 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 2 (SCA2) is a progressive disorder that causes symptoms including uncoordinated movement (ataxia), speech and swallowing difficulties, muscle wasting, slow eye movement, and sometimes dementia. Signs and symptoms usually begin in mid-adulthood but can appear any time from childhood to late-adulthood. SCA2 is caused by mutations in the ATXN2 gene and is inherited in an autosomal dominant manner.
OMIM: Autosomal dominant cerebellar ataxias (ADCAs) are a heterogeneous group of disorders that were classified clinically by Harding (1983). Progressive cerebellar ataxia is the primary feature. In ADCA I, cerebellar ataxia of gait and limbs is invariably associated with supranuclear ophthalmoplegia, pyramidal or extrapyramidal signs, mild dementia, and peripheral neuropathy. In ADCA II, macular and retinal degeneration are added to the features. ADCA III is a pure form of late-onset cerebellar ataxia. ADCA I includes SCA1 (164400), SCA2, and SCA3, or Machado-Joseph disease (109150). These 3 are characterized at the molecular level by CAG repeat expansions on 6p24-p23, 12q24.1, and 14q32.1, respectively. |
| Miscellaneouse | OMIM: genetic anticipation mean age of onset in third decade rarely reported in infants extreme phenotypic variability may manifest as 'ataxic' phenotype without parkinsonian features may manifest as late-onset 'parkinsonian' phenotype without severe ataxic features high prevalence in holguin province of cuba |
| Prevalence | Prevalence: 1-9/100000 (Worldwide) [source: MalaCards] |
| Inheritance | Autosomal dominant |
| Anticipation | Yes |
| Evidence | Strong |
| Gene symbol | ATXN2 |
| Alias symbols | ATX2; SCA2; ASL13; TNRC13 |
| Gene name | ataxin 2 |
| Gene map locus | 12q24.1; chr12:111,443,485-111,599,676(-) |
| Ensembl Gene ID | ENSG00000204842 |
| 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 | This gene belongs to a group of genes that is associated with microsatellite-expansion diseases, a class of neurological and neuromuscular disorders caused by expansion of short stretches of repetitive DNA. The protein encoded by this gene has two globular domains near the N-terminus, one of which contains a clathrin-mediated trans-Golgi signal and an endoplasmic reticulum exit signal. The encoded cytoplasmic protein localizes to the endoplasmic reticulum and plasma membrane, is involved in endocytosis, and modulates mTOR signals, modifying ribosomal translation and mitochondrial function. The N-terminal region of the protein contains a polyglutamine tract of 14-31 residues that can be expanded in the pathogenic state to 32-200 residues. Intermediate length expansions of this tract increase susceptibility to amyotrophic lateral sclerosis, while long expansions of this tract result in spinocerebellar ataxia-2, an autosomal-dominantly inherited, neurodegenerative disorder. Genome-wide association studies indicate that loss-of-function mutations in this gene may be associated with susceptibility to type I diabetes, obesity and hypertension. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2016] |
| Repeat unit | CAG |
| Normal repeat copies | 13-31 |
| Pathogenic repeat copies | ≥33 |
| Gene | ATXN2 |
| Repeat location | CDS |
| Chromosome locus | chr12:111598949-111599018 (-) |
| Repeat conservation | Repeat Conservation from UCSC Genome Browser |
| Toxic cause | Protein |
| Possible toxicity | The ATXN2 promoter is located exon 1 of the ATXN2 gene in a typical CpG island devoid of a TATA box and is usually partially methylated. Using a methyl-specific PCR protocol, Laffita-Mesa et al. (2012) found differences in the methylation levels of the ATXN2 promoter in a family in which anticipation was observed without CAG repeat expansion. Specifically, the promoter was hypomethylated in an affected son with earlier onset of SCA2 compared to that of his affected mother with later onset of the disorder, even though both patients carried CAG expansions of 39 repeats on the pathogenic allele. In 9 SCA2 patients, quantitative analysis indicated that hypermethylation at the promoter, leading to partial or complete epigenetic silencing, was associated with longer expansions of the ATXN2 repeat and that alleles with pathogenic CAG expansions were preferentially hypermethylated. These findings may represent part of the cellular defense mechanism to reduce the burden of cytotoxic mutant ATXN2. Study of 2 patients with homozygous expansions of 43 and 39 CAG repeats, respectively, found an association between hypermethylation at the ATXN2 promoter and delayed age at onset. SCA3 (109150) is caused by a similar CAG repeat expansion in the ATXN3 gene (607047), which is closely connected to ATXN2. Laffita-Mesa et al. (2012) also found that hypermethylation at the ATXN2 promoter was associated with lower age of onset of SCA3, although methylation at the ATXN3 promoter had no effect on age at onset of SCA3. These findings suggested that the development of SCA3 may involve physiologic functions of ATXN2. Overall, the report of Laffita-Mesa et al. (2012) showed that methylation of the ATXN2 promoter can occur, consistent with epigenetic control of ATXN2 expression, and that differences in methylation may affect disease course. [By OMIM] |
| Pathway annotation | Reactome, KEGG |
| PMID | 24657153 |
| Authors | Velázquez-Pérez L, Rodríguez-Labrada R, Canales-Ochoa N, Montero JM, Sánchez-Cruz G, Aguilera-Rodríguez R, Almaguer-Mederos LE, Laffita-Mesa JM |
| Title | Progression of early features of spinocerebellar ataxia type 2 in individuals at risk: a longitudinal study |
| Journal | Lancet Neurol. 13(5):482-9 |
| Year | 2014 |
| PMID | 23635656 |
| Authors | Liu X, Lu M, Tang L, Zhang N, Chui D, Fan D |
| Title | ATXN2 CAG repeat expansions increase the risk for Chinese patients with amyotrophic lateral sclerosis |
| Journal | Neurobiol Aging. 34(9):2236.e5-8 |
| Year | 2013 |