Ataxin 3

Ataxin-3 is a protein that in humans is encoded by the ATXN3 gene.[5][6]

ATXN3
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1YZB, 2AGA, 2DOS, 2JRI, 2KLZ, 4WTH, 4YS9
Identifiers
Aliases	ATXN3, AT3, ATX3, JOS, MJD, MJD1, SCA3, Ataxin 3
External IDs	OMIM: 607047 MGI: 1099442 HomoloGene: 3658 GeneCards: ATXN3
Gene location (Human) Chr. Chromosome 14 (human)[1] Band 14q32.12 Start 92,044,496 bp[1] End 92,106,621 bp[1]
Gene location (Mouse) Chr. Chromosome 12 (mouse)[2] Band 12|12 E Start 101,918,901 bp[2] End 101,958,246 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • Lys63-specific deubiquitinase activity • cysteine-type peptidase activity • ATPase binding • Lys48-specific deubiquitinase activity • peptidase activity • GO:0001948 protein binding • identical protein binding • hydrolase activity • thiol-dependent ubiquitin-specific protease activity • ubiquitin protein ligase binding • thiol-dependent ubiquitinyl hydrolase activity • histone deacetylase activity Cellular component • endoplasmic reticulum membrane • nuclear matrix • nucleoplasm • cell nucleus • nucleolus • cytosol • cell membrane • cytoplasm • mitochondrial matrix • mitochondrial membranes • nuclear inclusion body Biological process • nucleotide-excision repair • regulation of transcription, DNA-templated • protein K48-linked deubiquitination • positive regulation of ERAD pathway • transcription, DNA-templated • nervous system development • proteolysis • protein K63-linked deubiquitination • intermediate filament cytoskeleton organization • protein localization to cytosolic proteasome complex involved in ERAD pathway • microtubule cytoskeleton organization • actin cytoskeleton organization • chemical synaptic transmission • protein deubiquitination • ubiquitin-dependent protein catabolic process • protein quality control for misfolded or incompletely synthesized proteins • regulation of cell-substrate adhesion • cellular response to heat • monoubiquitinated protein deubiquitination • proteasome-mediated ubiquitin-dependent protein catabolic process • cellular response to misfolded protein • exploration behavior • histone H3 deacetylation Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	4287	110616
Ensembl	ENSG00000066427	ENSMUSG00000021189
UniProt	P54252 Q4VBR4	Q9CVD2
RefSeq (mRNA)	NM_001024631 NM_001127696 NM_001127697 NM_001164774 NM_001164776 NM_001164777 NM_001164778 NM_001164779 NM_001164780 NM_001164781 NM_001164782 NM_004993 NM_030660	NM_001167914 NM_029705
RefSeq (protein)	NP_001121168 NP_001121169 NP_001158246 NP_001158248 NP_001158249 NP_001158250 NP_001158251 NP_001158252 NP_001158253 NP_001158254 NP_004984 NP_109376	NP_001161386 NP_083981
Location (UCSC)	Chr 14: 92.04 – 92.11 Mb	Chr 12: 101.92 – 101.96 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Clinical significance

Machado-Joseph disease, also known as spinocerebellar ataxia-3, is an autosomal dominant neurologic disorder. The protein encoded by the ATXN3 gene contains (CAG)n repeats in the coding region, and the expansion of these repeats from the normal 13-36 to 68-79 is the cause of Machado-Joseph disease. There is an inverse correlation between the age of onset and CAG repeat numbers. Alternatively spliced transcript variants encoding different isoforms have been described for this gene.[6]

Interactions

Ataxin 3 has been shown to interact with:

• RAD23A,[7]
• RAD23B,[7] and
• VCP.[8][9]

Model organisms

Model organisms have been used in the study of ATXN3 function. A conditional knockout mouse line called Atxn3^{tm1a(KOMP)Wtsi} was generated at the Wellcome Trust Sanger Institute.[10] Male and female animals underwent a standardized phenotypic screen[11] to determine the effects of deletion.[12][13][14][15] Additional screens performed: - In-depth immunological phenotyping[16] - in-depth bone and cartilage phenotyping[17]

Atxn3 knockout mouse phenotype

Characteristic	Phenotype
All data available at.[11][16][17]
Peripheral blood leukocytes 6 Weeks	Normal
Insulin	Normal
Haematology 6 Weeks	Normal
Homozygous viability at P14	Normal
Homozygous Fertility	Normal
Body weight	Normal
Neurological assessment	Normal
Grip strength	Normal
Dysmorphology	Normal
Indirect calorimetry	Normal
Glucose tolerance test	Normal
Auditory brainstem response	Normal
DEXA	Normal
Radiography	Normal
Eye morphology	Normal
Clinical chemistry	Normal
Haematology 16 Weeks	Normal
Peripheral blood leukocytes 16 Weeks	Normal
Heart weight	Normal
Salmonella infection	Normal
Cytotoxic T Cell Function	Normal
Spleen Immunophenotyping	Normal
Mesenteric Lymph Node Immunophenotyping	Normal
Bone Marrow Immunophenotyping	Normal
Epidermal Immune Composition	Normal
Influenza Challenge	Normal

References

1. GRCh38: Ensembl release 89: ENSG00000066427 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000021189 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Takiyama Y, Nishizawa M, Tanaka H, Kawashima S, Sakamoto H, Karube Y, Shimazaki H, Soutome M, Endo K, Ohta S (Jul 1993). "The gene for Machado-Joseph disease maps to human chromosome 14q". Nature Genetics. 4 (3): 300–4. doi:10.1038/ng0793-300. PMID 8358439.
6. "Entrez Gene: ATXN3 ataxin 3".
7. Wang G, Sawai N, Kotliarova S, Kanazawa I, Nukina N (Jul 2000). "Ataxin-3, the MJD1 gene product, interacts with the two human homologs of yeast DNA repair protein RAD23, HHR23A and HHR23B". Human Molecular Genetics. 9 (12): 1795–803. doi:10.1093/hmg/9.12.1795. PMID 10915768.
8. Doss-Pepe EW, Stenroos ES, Johnson WG, Madura K (Sep 2003). "Ataxin-3 interactions with rad23 and valosin-containing protein and its associations with ubiquitin chains and the proteasome are consistent with a role in ubiquitin-mediated proteolysis". Molecular and Cellular Biology. 23 (18): 6469–83. doi:10.1128/MCB.23.18.6469-6483.2003. PMC 193705. PMID 12944474.
9. Wang Q, Li L, Ye Y (Mar 2008). "Inhibition of p97-dependent protein degradation by Eeyarestatin I". The Journal of Biological Chemistry. 283 (12): 7445–54. doi:10.1074/jbc.M708347200. PMC 2276333. PMID 18199748.
10. Gerdin AK (2010). "The Sanger Mouse Genetics Programme: high throughput characterisation of knockout mice". Acta Ophthalmologica. 88: 925–7. doi:10.1111/j.1755-3768.2010.4142.x.
11. "International Mouse Phenotyping Consortium".
12. Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V, Mujica AO, Thomas M, Harrow J, Cox T, Jackson D, Severin J, Biggs P, Fu J, Nefedov M, de Jong PJ, Stewart AF, Bradley A (Jun 2011). "A conditional knockout resource for the genome-wide study of mouse gene function". Nature. 474 (7351): 337–42. doi:10.1038/nature10163. PMC 3572410. PMID 21677750.
13. Dolgin E (Jun 2011). "Mouse library set to be knockout". Nature. 474 (7351): 262–3. doi:10.1038/474262a. PMID 21677718.
14. Collins FS, Rossant J, Wurst W (Jan 2007). "A mouse for all reasons". Cell. 128 (1): 9–13. doi:10.1016/j.cell.2006.12.018. PMID 17218247.
15. White JK, Gerdin AK, Karp NA, Ryder E, Buljan M, Bussell JN, Salisbury J, Clare S, Ingham NJ, Podrini C, Houghton R, Estabel J, Bottomley JR, Melvin DG, Sunter D, Adams NC, Sanger Institute Mouse Genetics Project, Tannahill D, Logan DW, Macarthur DG, Flint J, Mahajan VB, Tsang SH, Smyth I, Watt FM, Skarnes WC, Dougan G, Adams DJ, Ramirez-Solis R, Bradley A, Steel KP (2013). "Genome-wide generation and systematic phenotyping of knockout mice reveals new roles for many genes". Cell. 154 (2): 452–64. doi:10.1016/j.cell.2013.06.022. PMC 3717207. PMID 23870131.
16. "Infection and Immunity Immunophenotyping (3i) Consortium".
17. "OBCD Consortium".

Further reading

• Goto J, Watanabe M, Ichikawa Y, Yee SB, Ihara N, Endo K, Igarashi S, Takiyama Y, Gaspar C, Maciel P, Tsuji S, Rouleau GA, Kanazawa I (Aug 1997). "Machado-Joseph disease gene products carrying different carboxyl termini". Neuroscience Research. 28 (4): 373–7. doi:10.1016/S0168-0102(97)00056-4. PMID 9274833.
• Schöls L, Vieira-Saecker AM, Schöls S, Przuntek H, Epplen JT, Riess O (Jun 1995). "Trinucleotide expansion within the MJD1 gene presents clinically as spinocerebellar ataxia and occurs most frequently in German SCA patients". Human Molecular Genetics. 4 (6): 1001–5. doi:10.1093/hmg/4.6.1001. PMID 7655453.
• Stevanin G, Cancel G, Dürr A, Chneiweiss H, Dubourg O, Weissenbach J, Cann HM, Agid Y, Brice A (Jan 1995). "The gene for spinal cerebellar ataxia 3 (SCA3) is located in a region of approximately 3 cM on chromosome 14q24.3-q32.2". American Journal of Human Genetics. 56 (1): 193–201. PMC 1801316. PMID 7825578.
• Kawaguchi Y, Okamoto T, Taniwaki M, Aizawa M, Inoue M, Katayama S, Kawakami H, Nakamura S, Nishimura M, Akiguchi I (Nov 1994). "CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1". Nature Genetics. 8 (3): 221–8. doi:10.1038/ng1194-221. PMID 7874163.
• Maruyama K, Sugano S (Jan 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
• Ikeda H, Yamaguchi M, Sugai S, Aze Y, Narumiya S, Kakizuka A (Jun 1996). "Expanded polyglutamine in the Machado-Joseph disease protein induces cell death in vitro and in vivo". Nature Genetics. 13 (2): 196–202. doi:10.1038/ng0696-196. PMID 8640226.
• Paulson HL, Das SS, Crino PB, Perez MK, Patel SC, Gotsdiner D, Fischbeck KH, Pittman RN (Apr 1997). "Machado-Joseph disease gene product is a cytoplasmic protein widely expressed in brain". Annals of Neurology. 41 (4): 453–62. doi:10.1002/ana.410410408. PMID 9124802.
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (Oct 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149.
• Wellington CL, Ellerby LM, Hackam AS, Margolis RL, Trifiro MA, Singaraja R, McCutcheon K, Salvesen GS, Propp SS, Bromm M, Rowland KJ, Zhang T, Rasper D, Roy S, Thornberry N, Pinsky L, Kakizuka A, Ross CA, Nicholson DW, Bredesen DE, Hayden MR (Apr 1998). "Caspase cleavage of gene products associated with triplet expansion disorders generates truncated fragments containing the polyglutamine tract". The Journal of Biological Chemistry. 273 (15): 9158–67. doi:10.1074/jbc.273.15.9158. PMID 9535906.
• Tait D, Riccio M, Sittler A, Scherzinger E, Santi S, Ognibene A, Maraldi NM, Lehrach H, Wanker EE (Jun 1998). "Ataxin-3 is transported into the nucleus and associates with the nuclear matrix". Human Molecular Genetics. 7 (6): 991–7. doi:10.1093/hmg/7.6.991. PMID 9580663.
• Wang G, Sawai N, Kotliarova S, Kanazawa I, Nukina N (Jul 2000). "Ataxin-3, the MJD1 gene product, interacts with the two human homologs of yeast DNA repair protein RAD23, HHR23A and HHR23B". Human Molecular Genetics. 9 (12): 1795–803. doi:10.1093/hmg/9.12.1795. PMID 10915768.
• Ichikawa Y, Goto J, Hattori M, Toyoda A, Ishii K, Jeong SY, Hashida H, Masuda N, Ogata K, Kasai F, Hirai M, Maciel P, Rouleau GA, Sakaki Y, Kanazawa I (2001). "The genomic structure and expression of MJD, the Machado-Joseph disease gene". Journal of Human Genetics. 46 (7): 413–22. doi:10.1007/s100380170060. PMID 11450850.
• Chai Y, Shao J, Miller VM, Williams A, Paulson HL (Jul 2002). "Live-cell imaging reveals divergent intracellular dynamics of polyglutamine disease proteins and supports a sequestration model of pathogenesis". Proceedings of the National Academy of Sciences of the United States of America. 99 (14): 9310–5. doi:10.1073/pnas.152101299. PMC 123137. PMID 12084819.
• Yoshida H, Yoshizawa T, Shibasaki F, Shoji S, Kanazawa I (Jul 2002). "Chemical chaperones reduce aggregate formation and cell death caused by the truncated Machado-Joseph disease gene product with an expanded polyglutamine stretch". Neurobiology of Disease. 10 (2): 88–99. doi:10.1006/nbdi.2002.0502. PMID 12127147.
• Li F, Macfarlan T, Pittman RN, Chakravarti D (Nov 2002). "Ataxin-3 is a histone-binding protein with two independent transcriptional corepressor activities". The Journal of Biological Chemistry. 277 (47): 45004–12. doi:10.1074/jbc.M205259200. PMID 12297501.
• Albrecht M, Hoffmann D, Evert BO, Schmitt I, Wüllner U, Lengauer T (Feb 2003). "Structural modeling of ataxin-3 reveals distant homology to adaptins". Proteins. 50 (2): 355–70. doi:10.1002/prot.10280. PMID 12486728.
• Marchal S, Shehi E, Harricane MC, Fusi P, Heitz F, Tortora P, Lange R (Aug 2003). "Structural instability and fibrillar aggregation of non-expanded human ataxin-3 revealed under high pressure and temperature". The Journal of Biological Chemistry. 278 (34): 31554–63. doi:10.1074/jbc.M304205200. PMID 12766160.

External links

• GeneReviews/NCBI/NIH/UW entry on Spinocerebellar Ataxia Type 3
• Human ATXN3 genome location and ATXN3 gene details page in the UCSC Genome Browser.