Spinocerebellar Ataxia 3 (ATXN3)
| Dred_ID | RD00003 |
| OMIM ID | 109150 |
| Disease name | Spinocerebellar Ataxia 3 |
| Alternative names | Azorean Ataxia, MJD, Machado-Joseph Disease, SCA3 |
| Category | Genetic diseases, Rare diseases, Neuronal diseases |
| Phenotype | NIH Rare Diseases: Spinocerebellar ataxia 3 (SCA3) is a rare, inherited form of ataxia. Signs and symptoms may begin between childhood and late adulthood and vary greatly. Symptoms may include slowly progressive clumsiness in the arms and legs; a manner of walking (gait) that may be mistaken for drunkenness; difficulty speaking and swallowing; impaired eye movements or vision; and lower limb spasticity. Some people with SCA3 develop dystonia or symptoms similar to those of Parkinson’s disease; twitching of the face or tongue; nerve damage (neuropathy); or problems with urination and the autonomic nervous system. SCA3 is caused by a mutation in the ATXN3 gene and inheritance is autosomal dominant. There is no medication that slows the progressive course of the disease; management aims to relieve some symptoms and improve quality of life. Life expectancy ranges from the mid-30s for those with the most severe forms, to a nearly normal life expectancy for those with milder forms.
OMIM: Machado-Joseph disease, named for affected families of Azorean extraction, is an autosomal dominant progressive neurologic disorder characterized principally by ataxia, spasticity, and ocular movement abnormalities. Although independently described as a seemingly separate disorder, spinocerebellar ataxia-3 is now known to be the same as Machado-Joseph disease. Three classic clinical subtypes of MJD are recognized: type 1 with early onset and marked pyramidal and dystonic signs; type 2, or pure, with predominant cerebellar ataxia; and type 3 with later-onset and peripheral neuropathy (Franca et al., 2008). |
| Miscellaneouse | OMIM: progressive disorder onset in third to fourth decade wide clinical variability normal alleles contain up to 44 repeats pathogenic alleles contain 52 to 86 repeats incomplete penetrance with 45 to 51 repeats genetic anticipation |
| Prevalence | Prevalence: 1-9/100000 (Worldwide),1-9/100000 (Portugal),1-9/100000 (Japan) [source: MalaCards] |
| Inheritance | Autosomal dominant |
| Anticipation | Yes |
| Evidence | Strong |
| Gene symbol | ATXN3 |
| Alias symbols | AT3; JOS; MJD; ATX3; MJD1; SCA3 |
| Gene name | ataxin 3 |
| Gene map locus | 14q21;chr14:92,044,496-92,106,621(-) |
| Ensembl Gene ID | ENSG00000066427 |
| 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 | Machado-Joseph disease, also known as spinocerebellar ataxia-3, is an autosomal dominant neurologic disorder. The protein encoded by this gene contains (CAG)n repeats in the coding region, and the expansion of these repeats from the normal 12-44 to 52-86 is one cause of Machado-Joseph disease. There is a negative correlation between the age of onset and CAG repeat numbers. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jul 2016] |
| Repeat unit | CAG |
| Normal repeat copies | 12-44 |
| Pathogenic repeat copies | ≥52 |
| Gene | ATXN3 |
| Repeat location | CDS |
| Chromosome locus | chr14:92071009-92071033 (-) |
| Repeat conservation | Repeat Conservation from UCSC Genome Browser |
| Toxic cause | Protein |
| Possible toxicity | Haacke et al. (2006) found that full-length recombinant human AT3 formed detergent-resistant fibrillar aggregates in vitro with extremely low efficiency, even when it contained a pathogenic polyQ tract of 71 residues (AT3Q71). However, an N-terminally truncated form, called 257cQ71, which began with residue 257 and contained only the C terminus with an expanded polyQ region, readily formed detergent-insoluble aggregates and recruited full-length nonpathogenic AT3Q22 into the aggregates. The efficiency of recruitment increased with expansion of the polyQ stretch. FRET analysis revealed that the interaction of AT3Q22 with the polyQ tract of 257cQ71 caused a conformational change that affected the active-site cysteine within the Josephin domain of AT3Q22. Similar results were found in vivo with transfected mouse neuroblastoma cells: 257cQ71 formed inclusions in almost all cells, and full-length AT3 proteins did not readily aggregate unless coexpressed with 257cQ71. AT3Q71 also formed inclusions, but it appeared to do so following its partial degradation. Use of an engineered protease-sensitive form of AT3 suggested that release of expanded polyQ fragments initiates the formation of cellular inclusions. Haacke et al. (2006) concluded that recruitment of functional AT3 into aggregates by expanded polyQ-containing fragments reduces cellular AT3 content and thus impairs its function. ［By OMIM］ |
| Pathway annotation | Reactome, KEGG |
| PMID | 20308049 |
| Authors | Alves S, Nascimento-Ferreira I, Dufour N, Hassig R, Auregan G, Nóbrega C, Brouillet E, Hantraye P, Pedroso de Lima MC, Déglon N, de Almeida LP |
| Title | Silencing ataxin-3 mitigates degeneration in a rat model of Machado-Joseph disease: no role for wild-type ataxin-3? |
| Journal | Hum Mol Genet. 19(12):2380-94 |
| Year | 2010 |
| PMID | 19666958 |
| Authors | Boy J, Schmidt T, Wolburg H, Mack A, Nuber S, Böttcher M, Schmitt I, Holzmann C, Zimmermann F, Servadio A, Riess O |
| Title | Reversibility of symptoms in a conditional mouse model of spinocerebellar ataxia type 3 |
| Journal | Hum Mol Genet. 18(22):4282-95 |
| Year | 2009 |