RBCC Red Blood Cell Collection

ATXN3 (ATX3, MJD, MJD1, SCA3) [Confidence: low (only semi-automatic identification from reviews)]
Ataxin-3; 3.4.19.12 (Machado-Joseph disease protein 1; Spinocerebellar ataxia type 3 protein)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt P54252
ID ATX3_HUMAN Reviewed; 364 AA.
AC P54252; A7LFZ5; D6RDL9; E9PB63; O15284; O15285; O15286; Q8N189;
read moreAC Q96TC3; Q96TC4; Q9H3N0;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
DT 02-MAR-2010, sequence version 4.
DT 22-JAN-2014, entry version 144.
DE RecName: Full=Ataxin-3;
DE EC=3.4.19.12;
DE AltName: Full=Machado-Joseph disease protein 1;
DE AltName: Full=Spinocerebellar ataxia type 3 protein;
GN Name=ATXN3; Synonyms=ATX3, MJD, MJD1, SCA3;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), VARIANTS MET-212; GLY-306
RP DELINS GLN-GLN-GLN-GLN-GLN-GLN-GLN-GLN-GLN-GLN-GLN-GLN-ARG AND
RP 349-TYR--LEU-364 DEL, AND INVOLVEMENT IN SCA3.
RC TISSUE=Brain;
RX PubMed=7874163; DOI=10.1038/ng1194-221;
RA Kawaguchi Y., Okamoto T., Taniwaki M., Aizawa M., Inoue M.,
RA Katayama S., Kawakami H., Nakamura S., Nishimura M., Akiguchi I.,
RA Kimura J., Narumiya S., Kakizuka A.;
RT "CAG expansions in a novel gene for Machado-Joseph disease at
RT chromosome 14q32.1.";
RL Nat. Genet. 8:221-228(1994).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), AND VARIANTS MET-212;
RP GLY-306 DELINS GLN-GLN-GLN-GLN-GLN-GLN-GLN-GLN-GLN-GLN-GLN-GLN-ARG AND
RP 349-TYR--LEU-364 DEL.
RX PubMed=9274833; DOI=10.1016/S0168-0102(97)00056-4;
RA Goto J., Watanabe M., Ichikawa Y., Yee S.-B., Ihara N., Endo K.,
RA Igarashi S., Takiyama Y., Gaspar C., Maciel P., Tsuji S.,
RA Rouleau G.A., Kanazawa I.;
RT "Machado-Joseph disease gene products carrying different carboxyl
RT termini.";
RL Neurosci. Res. 28:373-377(1997).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORMS 1; 2 AND 3), AND VARIANT
RP 349-TYR--LEU-364 DEL.
RX PubMed=11450850; DOI=10.1007/s100380170060;
RA Ichikawa Y., Goto J., Hattori M., Toyoda A., Ishii K., Jeong S.-Y.,
RA Hashida H., Masuda N., Ogata K., Kasai F., Hirai M., Maciel P.,
RA Rouleau G.A., Sakaki Y., Kanazawa I.;
RT "The genomic structure and expression of MJD, the Machado-Joseph
RT disease gene.";
RL J. Hum. Genet. 46:413-422(2001).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT MET-212.
RG NIEHS SNPs program;
RL Submitted (JUL-2007) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=12508121; DOI=10.1038/nature01348;
RA Heilig R., Eckenberg R., Petit J.-L., Fonknechten N., Da Silva C.,
RA Cattolico L., Levy M., Barbe V., De Berardinis V., Ureta-Vidal A.,
RA Pelletier E., Vico V., Anthouard V., Rowen L., Madan A., Qin S.,
RA Sun H., Du H., Pepin K., Artiguenave F., Robert C., Cruaud C.,
RA Bruels T., Jaillon O., Friedlander L., Samson G., Brottier P.,
RA Cure S., Segurens B., Aniere F., Samain S., Crespeau H., Abbasi N.,
RA Aiach N., Boscus D., Dickhoff R., Dors M., Dubois I., Friedman C.,
RA Gouyvenoux M., James R., Madan A., Mairey-Estrada B., Mangenot S.,
RA Martins N., Menard M., Oztas S., Ratcliffe A., Shaffer T., Trask B.,
RA Vacherie B., Bellemere C., Belser C., Besnard-Gonnet M.,
RA Bartol-Mavel D., Boutard M., Briez-Silla S., Combette S.,
RA Dufosse-Laurent V., Ferron C., Lechaplais C., Louesse C., Muselet D.,
RA Magdelenat G., Pateau E., Petit E., Sirvain-Trukniewicz P., Trybou A.,
RA Vega-Czarny N., Bataille E., Bluet E., Bordelais I., Dubois M.,
RA Dumont C., Guerin T., Haffray S., Hammadi R., Muanga J., Pellouin V.,
RA Robert D., Wunderle E., Gauguet G., Roy A., Sainte-Marthe L.,
RA Verdier J., Verdier-Discala C., Hillier L.W., Fulton L., McPherson J.,
RA Matsuda F., Wilson R., Scarpelli C., Gyapay G., Wincker P., Saurin W.,
RA Quetier F., Waterston R., Hood L., Weissenbach J.;
RT "The DNA sequence and analysis of human chromosome 14.";
RL Nature 421:601-607(2003).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2), AND VARIANT
RP GLY-306 DELINS GLN-GLN-GLN-GLN-GLN-GLN-GLN-GLN-GLN-GLN-GLN-GLN-ARG.
RC TISSUE=Mammary gland;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [8]
RP SUBCELLULAR LOCATION.
RX PubMed=9580663; DOI=10.1093/hmg/7.6.991;
RA Tait D., Riccio M., Sittler A., Scherzinger E., Santi S., Ognibene A.,
RA Maraldi N.M., Lehrach H., Wanker E.E.;
RT "Ataxin-3 is transported into the nucleus and associates with the
RT nuclear matrix.";
RL Hum. Mol. Genet. 7:991-997(1998).
RN [9]
RP FUNCTION.
RX PubMed=12297501; DOI=10.1074/jbc.M205259200;
RA Li F., Macfarlan T., Pittman R.N., Chakravarti D.;
RT "Ataxin-3 is a histone-binding protein with two independent
RT transcriptional corepressor activities.";
RL J. Biol. Chem. 277:45004-45012(2002).
RN [10]
RP CATALYTIC ACTIVITY, AND FUNCTION.
RX PubMed=17696782; DOI=10.1515/BC.2007.107;
RA Tzvetkov N., Breuer P.;
RT "Josephin domain-containing proteins from a variety of species are
RT active de-ubiquitination enzymes.";
RL Biol. Chem. 388:973-978(2007).
RN [11]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [12]
RP FUNCTION, AND MUTAGENESIS OF CYS-14.
RX PubMed=23625928; DOI=10.1074/jbc.M113.463406;
RA Seki T., Gong L., Williams A.J., Sakai N., Todi S.V., Paulson H.L.;
RT "JosD1, a membrane-targeted deubiquitinating enzyme, is activated by
RT ubiquitination and regulates membrane dynamics, cell motility, and
RT endocytosis.";
RL J. Biol. Chem. 288:17145-17155(2013).
RN [13]
RP UBIQUITINATION AT MET-1 AND LYS-200.
RX PubMed=23696636; DOI=10.1074/jbc.C113.477596;
RA Scaglione K.M., Basrur V., Ashraf N.S., Konen J.R.,
RA Elenitoba-Johnson K.S., Todi S.V., Paulson H.L.;
RT "The ubiquitin-conjugating enzyme (E2) Ube2w ubiquitinates the N
RT terminus of substrates.";
RL J. Biol. Chem. 288:18784-18788(2013).
RN [14]
RP 3D-STRUCTURE MODELING.
RX PubMed=12486728; DOI=10.1002/prot.10280;
RA Albrecht M., Hoffmann D., Evert B.O., Schmitt I., Wuellner U.,
RA Lengauer T.;
RT "Structural modeling of ataxin-3 reveals distant homology to
RT adaptins.";
RL Proteins 50:355-370(2003).
RN [15]
RP STRUCTURE BY NMR OF 1-182.
RX PubMed=16020535; DOI=10.1073/pnas.0501732102;
RA Nicastro G., Menon R.P., Masino L., Knowles P.P., McDonald N.Q.,
RA Pastore A.;
RT "The solution structure of the Josephin domain of ataxin-3: structural
RT determinants for molecular recognition.";
RL Proc. Natl. Acad. Sci. U.S.A. 102:10493-10498(2005).
RN [16]
RP STRUCTURE BY NMR OF 1-185, FUNCTION, AND MUTAGENESIS OF CYS-14;
RP SER-236; SER-256 AND SER-335.
RX PubMed=16118278; DOI=10.1073/pnas.0506344102;
RA Mao Y., Senic-Matuglia F., Di Fiore P.P., Polo S., Hodsdon M.E.,
RA De Camilli P.;
RT "Deubiquitinating function of ataxin-3: insights from the solution
RT structure of the Josephin domain.";
RL Proc. Natl. Acad. Sci. U.S.A. 102:12700-12705(2005).
CC -!- FUNCTION: Deubiquitinating enzyme involved in protein homeostasis
CC maintenance, transcription, cytoskeleton regulation, myogenesis
CC and degradation of misfolded chaperone substrates. Binds long
CC polyubiquitin chains and trims them, while it has weak or no
CC activity against chains of 4 or less ubiquitins. Involved in
CC degradation of misfolded chaperone substrates via its interaction
CC with STUB1/CHIP: recruited to monoubiquitinated STUB1/CHIP, and
CC restricts the length of ubiquitin chain attached to STUB1/CHIP
CC substrates and preventing further chain extension. In response to
CC misfolded substrate ubiquitination, mediates deubiquitination of
CC monoubiquitinated STUB1/CHIP. Interacts with key regulators of
CC transcription and represses transcription: acts as a histone-
CC binding protein that regulates transcription.
CC -!- CATALYTIC ACTIVITY: Thiol-dependent hydrolysis of ester,
CC thioester, amide, peptide and isopeptide bonds formed by the C-
CC terminal Gly of ubiquitin (a 76-residue protein attached to
CC proteins as an intracellular targeting signal).
CC -!- SUBUNIT: Interacts with STUB1/CHIP (when monoubiquitinated) (By
CC similarity). Interacts with DNA repair proteins RAD23A and RAD23B.
CC -!- INTERACTION:
CC Self; NbExp=5; IntAct=EBI-946046, EBI-946046;
CC Q9BSU1:C16orf70; NbExp=2; IntAct=EBI-946046, EBI-946080;
CC P54727:RAD23B; NbExp=2; IntAct=EBI-946046, EBI-954531;
CC P0CG48:UBC; NbExp=2; IntAct=EBI-946046, EBI-3390054;
CC P55072:VCP; NbExp=10; IntAct=EBI-946068, EBI-355164;
CC -!- SUBCELLULAR LOCATION: Nucleus matrix. Note=Predominantly nuclear,
CC but not exclusively, inner nuclear matrix.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=5;
CC Name=1;
CC IsoId=P54252-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P54252-2; Sequence=VSP_002784;
CC Name=3;
CC IsoId=P54252-3; Sequence=VSP_002783, VSP_002784;
CC Name=4;
CC IsoId=P54252-4; Sequence=VSP_047086, VSP_002784;
CC Note=Gene prediction based on EST data;
CC Name=5;
CC IsoId=P54252-5; Sequence=VSP_047085, VSP_002784;
CC Note=Gene prediction based on EST data;
CC -!- TISSUE SPECIFICITY: Ubiquitous.
CC -!- DOMAIN: The UIM domains bind ubiquitin and interact with various
CC E3 ubiquitin-protein ligase, such as STUB1/CHIP. They are
CC essential to limit the length of ubiquitin chains (By similarity).
CC -!- PTM: Monoubiquitinated N-terminally by UBE2W, possibly leading to
CC activate the deubiquitinating enzyme activity.
CC -!- POLYMORPHISM: The poly-Gln region of ATXN3 is highly polymorphic
CC (14 to 41 repeats) in the normal population and is expanded to
CC about 55-82 repeats in spinocerebellar ataxia 3 (SCA3) patients.
CC -!- POLYMORPHISM: The MJD1a allele carries a single nucleotide
CC substitution in codon 349 generating a stop codon instead of a
CC Tyr. In the Japanese population, the MJD1a allele seems to be
CC significantly associated with Gln expansion.
CC -!- DISEASE: Spinocerebellar ataxia 3 (SCA3) [MIM:109150]:
CC Spinocerebellar ataxia is a clinically and genetically
CC heterogeneous group of cerebellar disorders. Patients show
CC progressive incoordination of gait and often poor coordination of
CC hands, speech and eye movements, due to cerebellum degeneration
CC with variable involvement of the brainstem and spinal cord. SCA3
CC belongs to the autosomal dominant cerebellar ataxias type I (ADCA
CC I) which are characterized by cerebellar ataxia in combination
CC with additional clinical features like optic atrophy,
CC ophthalmoplegia, bulbar and extrapyramidal signs, peripheral
CC neuropathy and dementia. The molecular defect in SCA3 is the a CAG
CC repeat expansion in ATX3 coding region. Longer expansions result
CC in earlier onset and more severe clinical manifestations of the
CC disease. Note=The disease is caused by mutations affecting the
CC gene represented in this entry.
CC -!- SIMILARITY: Contains 1 Josephin domain.
CC -!- SIMILARITY: Contains 3 UIM (ubiquitin-interacting motif) repeats.
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/atxn3/";
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/ATXN3";
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DR EMBL; S75313; AAB33571.1; -; mRNA.
DR EMBL; U64820; AAB63352.1; -; mRNA.
DR EMBL; U64821; AAB63353.1; -; mRNA.
DR EMBL; U64822; AAB63354.1; -; mRNA.
DR EMBL; AB050194; BAB18798.1; -; mRNA.
DR EMBL; AB038653; BAB55645.1; -; Genomic_DNA.
DR EMBL; AB038653; BAB55646.1; -; Genomic_DNA.
DR EMBL; EU009923; ABS29269.1; -; Genomic_DNA.
DR EMBL; AL049872; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL121773; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471061; EAW81472.1; -; Genomic_DNA.
DR EMBL; BC033711; AAH33711.1; -; mRNA.
DR PIR; S50830; S50830.
DR RefSeq; NP_001121168.1; NM_001127696.1.
DR RefSeq; NP_001158252.1; NM_001164780.1.
DR RefSeq; NP_004984.2; NM_004993.5.
DR RefSeq; NP_109376.1; NM_030660.4.
DR RefSeq; XP_005267709.1; XM_005267652.1.
DR UniGene; Hs.532632; -.
DR PDB; 1YZB; NMR; -; A=1-182.
DR PDB; 2AGA; NMR; -; A=1-185.
DR PDB; 2DOS; NMR; -; A=1-171.
DR PDB; 2JRI; NMR; -; A=1-182.
DR PDB; 2KLZ; NMR; -; A=222-263.
DR PDBsum; 1YZB; -.
DR PDBsum; 2AGA; -.
DR PDBsum; 2DOS; -.
DR PDBsum; 2JRI; -.
DR PDBsum; 2KLZ; -.
DR DisProt; DP00576; -.
DR ProteinModelPortal; P54252; -.
DR SMR; P54252; 1-185, 220-264.
DR IntAct; P54252; 22.
DR MINT; MINT-272839; -.
DR MEROPS; C86.001; -.
DR PhosphoSite; P54252; -.
DR DMDM; 290457685; -.
DR PaxDb; P54252; -.
DR PRIDE; P54252; -.
DR DNASU; 4287; -.
DR Ensembl; ENST00000340660; ENSP00000339110; ENSG00000066427.
DR Ensembl; ENST00000393287; ENSP00000376965; ENSG00000066427.
DR Ensembl; ENST00000502250; ENSP00000425322; ENSG00000066427.
DR Ensembl; ENST00000503767; ENSP00000426697; ENSG00000066427.
DR Ensembl; ENST00000532032; ENSP00000437157; ENSG00000066427.
DR GeneID; 4287; -.
DR KEGG; hsa:4287; -.
DR UCSC; uc010aug.3; human.
DR CTD; 4287; -.
DR GeneCards; GC14M092524; -.
DR HGNC; HGNC:7106; ATXN3.
DR HPA; CAB021976; -.
DR HPA; HPA024123; -.
DR MIM; 109150; phenotype.
DR MIM; 607047; gene.
DR neXtProt; NX_P54252; -.
DR Orphanet; 276238; Machado-Joseph disease type 1.
DR Orphanet; 276241; Machado-Joseph disease type 2.
DR Orphanet; 276244; Machado-Joseph disease type 3.
DR PharmGKB; PA134971833; -.
DR eggNOG; NOG327234; -.
DR HOVERGEN; HBG025648; -.
DR KO; K11863; -.
DR OrthoDB; EOG779NZ3; -.
DR EvolutionaryTrace; P54252; -.
DR GeneWiki; Ataxin_3; -.
DR GenomeRNAi; 4287; -.
DR NextBio; 16875; -.
DR PMAP-CutDB; A7LFZ5; -.
DR PRO; PR:P54252; -.
DR ArrayExpress; P54252; -.
DR Bgee; P54252; -.
DR Genevestigator; P54252; -.
DR GO; GO:0005737; C:cytoplasm; TAS:ProtInc.
DR GO; GO:0005759; C:mitochondrial matrix; IEA:Ensembl.
DR GO; GO:0031966; C:mitochondrial membrane; IEA:Ensembl.
DR GO; GO:0042405; C:nuclear inclusion body; IEA:Ensembl.
DR GO; GO:0016363; C:nuclear matrix; IEA:UniProtKB-SubCell.
DR GO; GO:0005654; C:nucleoplasm; TAS:ProtInc.
DR GO; GO:0004843; F:deubiquitinase activity; ISS:UniProtKB.
DR GO; GO:0008242; F:omega peptidase activity; IEA:InterPro.
DR GO; GO:0001012; F:RNA polymerase II regulatory region DNA binding; IEA:Ensembl.
DR GO; GO:0031625; F:ubiquitin protein ligase binding; ISS:UniProtKB.
DR GO; GO:0004221; F:ubiquitin thiolesterase activity; ISS:UniProtKB.
DR GO; GO:0030036; P:actin cytoskeleton organization; IMP:MGI.
DR GO; GO:0008219; P:cell death; IEA:UniProtKB-KW.
DR GO; GO:0034605; P:cellular response to heat; IEA:Ensembl.
DR GO; GO:0071218; P:cellular response to misfolded protein; ISS:UniProtKB.
DR GO; GO:0035640; P:exploration behavior; IEA:Ensembl.
DR GO; GO:0070932; P:histone H3 deacetylation; IEA:Ensembl.
DR GO; GO:0045104; P:intermediate filament cytoskeleton organization; IMP:MGI.
DR GO; GO:0000226; P:microtubule cytoskeleton organization; IMP:MGI.
DR GO; GO:0006515; P:misfolded or incompletely synthesized protein catabolic process; ISS:UniProtKB.
DR GO; GO:0035520; P:monoubiquitinated protein deubiquitination; ISS:UniProtKB.
DR GO; GO:0007399; P:nervous system development; TAS:ProtInc.
DR GO; GO:0006289; P:nucleotide-excision repair; TAS:ProtInc.
DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; ISS:UniProtKB.
DR GO; GO:0010810; P:regulation of cell-substrate adhesion; IMP:MGI.
DR GO; GO:0006355; P:regulation of transcription, DNA-dependent; IEA:UniProtKB-KW.
DR GO; GO:0007268; P:synaptic transmission; TAS:ProtInc.
DR GO; GO:0006351; P:transcription, DNA-dependent; IEA:UniProtKB-KW.
DR InterPro; IPR006155; Josephin.
DR InterPro; IPR003903; Ubiquitin-int_motif.
DR Pfam; PF02099; Josephin; 1.
DR Pfam; PF02809; UIM; 2.
DR PRINTS; PR01233; JOSEPHIN.
DR SMART; SM00726; UIM; 2.
DR PROSITE; PS50957; JOSEPHIN; 1.
DR PROSITE; PS50330; UIM; 2.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Complete proteome; Hydrolase;
KW Isopeptide bond; Neurodegeneration; Nucleus; Phosphoprotein;
KW Polymorphism; Protease; Reference proteome; Repeat;
KW Spinocerebellar ataxia; Thiol protease; Transcription;
KW Transcription regulation; Triplet repeat expansion; Ubl conjugation;
KW Ubl conjugation pathway.
FT CHAIN 1 364 Ataxin-3.
FT /FTId=PRO_0000053831.
FT DOMAIN 1 180 Josephin.
FT REPEAT 224 243 UIM 1.
FT REPEAT 244 263 UIM 2.
FT REPEAT 331 348 UIM 3.
FT COMPBIAS 292 305 Poly-Gln.
FT ACT_SITE 14 14 Nucleophile.
FT ACT_SITE 119 119 Proton acceptor (Probable).
FT ACT_SITE 134 134 Probable.
FT MOD_RES 219 219 Phosphoserine (By similarity).
FT CROSSLNK 1 1 Peptide (Met-Gly) (interchain with G-Cter
FT in ubiquitin).
FT CROSSLNK 200 200 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in ubiquitin).
FT VAR_SEQ 1 179 Missing (in isoform 5).
FT /FTId=VSP_047085.
FT VAR_SEQ 10 64 Missing (in isoform 3).
FT /FTId=VSP_002783.
FT VAR_SEQ 63 77 Missing (in isoform 4).
FT /FTId=VSP_047086.
FT VAR_SEQ 332 364 KACSPFIMFATFTLYLTYELHVIFALHYSSFPL -> DAMS
FT EEDMLQAAVTMSLETVRNDLKTEGKK (in isoform 2,
FT isoform 3, isoform 4 and isoform 5).
FT /FTId=VSP_002784.
FT VARIANT 212 212 V -> M (in dbSNP:rs1048755).
FT /FTId=VAR_013688.
FT VARIANT 306 306 G -> QQQQQQQQQQQQR.
FT /FTId=VAR_013689.
FT VARIANT 349 364 Missing (in allele MJD1a).
FT /FTId=VAR_013690.
FT MUTAGEN 14 14 C->A: Loss of deubiquitination activity.
FT MUTAGEN 236 236 S->A: Inhibits substrate trapping.
FT MUTAGEN 256 256 S->A: Inhibits substrate trapping.
FT MUTAGEN 335 335 S->A: No effect on ubiquitination.
FT CONFLICT 252 252 A -> T (in Ref. 2; AAB63352/AAB63353/
FT AAB63354).
FT HELIX 1 3
FT HELIX 14 22
FT STRAND 23 25
FT HELIX 30 49
FT TURN 53 55
FT HELIX 56 62
FT STRAND 70 73
FT HELIX 78 85
FT TURN 86 88
FT STRAND 90 96
FT TURN 97 100
FT HELIX 106 108
FT STRAND 109 116
FT STRAND 119 126
FT STRAND 129 134
FT STRAND 141 143
FT HELIX 145 158
FT STRAND 161 167
FT HELIX 173 176
FT HELIX 178 180
FT HELIX 222 240
FT STRAND 243 245
FT HELIX 246 257
SQ SEQUENCE 364 AA; 41781 MW; 4B2477EB67C30EFF CRC64;
MESIFHEKQE GSLCAQHCLN NLLQGEYFSP VELSSIAHQL DEEERMRMAE GGVTSEDYRT
FLQQPSGNMD DSGFFSIQVI SNALKVWGLE LILFNSPEYQ RLRIDPINER SFICNYKEHW
FTVRKLGKQW FNLNSLLTGP ELISDTYLAL FLAQLQQEGY SIFVVKGDLP DCEADQLLQM
IRVQQMHRPK LIGEELAQLK EQRVHKTDLE RVLEANDGSG MLDEDEEDLQ RALALSRQEI
DMEDEEADLR RAIQLSMQGS SRNISQDMTQ TSGTNLTSEE LRKRREAYFE KQQQKQQQQQ
QQQQQGDLSG QSSHPCERPA TSSGALGSDL GKACSPFIMF ATFTLYLTYE LHVIFALHYS
SFPL
//

MIM 109150
*RECORD*
*FIELD* NO
109150
*FIELD* TI
#109150 MACHADO-JOSEPH DISEASE; MJD
;;SPINOCEREBELLAR ATAXIA 3; SCA3;;
SPINOCEREBELLAR ATROPHY III;;
read moreAZOREAN NEUROLOGIC DISEASE;;
SPINOPONTINE ATROPHY;;
NIGROSPINODENTATAL DEGENERATION
*FIELD* TX
A number sign (#) is used with this entry because Machado-Joseph disease
(MJD), also known as spinocerebellar ataxia-3 (SCA3), is caused by a
(CAG)n trinucleotide repeat expansion encoding glutamine repeats in the
ataxin-3 gene (ATXN3; 607047).

Normal individuals have up to 44 glutamine repeats, and MJD patients
have between 52 and 86 glutamine repeats. Incomplete penetrance is
associated with 45 to 51 repeats (Todd and Paulson, 2010).

For a general discussion of autosomal dominant spinocerebellar ataxia,
see SCA1 (164400).

DESCRIPTION

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).

CLINICAL FEATURES

- Early Descriptions, Diagnostic Uncertainties, and Geographic
Distribution

Among Portuguese immigrants living in New England, Nakano et al. (1972)
described a form of dominantly inherited ataxia occurring in descendants
of William Machado, a native of an island in the Portuguese Azores. The
disorder began as ataxic gait after age 40. Six patients studied in
detail showed abnormally large amounts of air in the posterior fossa on
pneumoencephalogram, denervation atrophy of muscle, and diabetes
mellitus. Other families of Azorean origin living in Massachusetts
(Romanul et al., 1977; Woods and Schaumburg, 1972) and in California
(Rosenberg et al., 1976) were reported. Romanul et al. (1977) suggested
that all 4 reported kindreds had the same mutant gene despite
differences in expression. The progressive neurologic disorder was
characterized by gait ataxia, features similar to those in Parkinson
disease (PD; 168600) in some patients, limitation of eye movements,
widespread fasciculations of muscles, loss of reflexes in the lower
limbs, followed by nystagmus, mild cerebellar tremors, and extensor
plantar responses. Postmortem examinations showed loss of neurons and
gliosis in the substantia nigra, nuclei pontis (and in the putamen in
one case) as well as the nuclei of the vestibular and cranial nerves,
columns of Clarke and anterior horns. Rosenberg (1977) referred to the
disorder he and his colleagues described as Joseph disease (Rosenberg et
al., 1976) and questioned that one can be certain of its identity to the
disorder in other families of Azorean origin.

In January 1976, Corino Andrade (Coutinho et al., 1977) 'went to the
Azores...to investigate a degenerative disease of the central nervous
system known to exist there. We saw 40 patients belonging to 15 families
(in the islands of Flores and St. Michael)...It is our opinion that
different families just mentioned, which have been taken as separate
diseases, are only clinically diverse forms of the same disorder, of
which symptomatic pleomorphism is a conspicuous feature.' In the same
year, Romanul et al. (1977) arrived at the same conclusion. The full
paper by Coutinho and Andrade (1978) appeared the next year. Lima and
Coutinho (1980) described a mainland Portuguese family. The possibility
that the Joseph family was originally Sephardic Jewish was raised by
Sequeiros and Coutinho (1981). Mainland families originated in a
mountainous and relatively inaccessible region of northeastern Portugal
where large communities of Sephardic Jews settled at one time.

Under the designation 'spinopontine degeneration,' Boller and Segarra
(1969) reported 24 persons with late-onset ataxia in 4 generations of an
Anglo-Saxon family. Taniguchi and Konigsmark (1971) described 16
affected persons in 3 generations of a black family. The pathologic
findings were similar in the 2 families. The cerebellum was relatively
spared and the inferior olives were normal. The spinal cord showed loss
of myelinated fibers in the spinocerebellar tracts and posterior
funiculi. There was also marked loss of nuclei basis ponti. Pogacar et
al. (1978) followed up on the Boller-Segarra family (members of which
had lived in northern Rhode Island for over 300 years). In 2 clinical
cases and 1 autopsy, they questioned the separation from
olivopontocerebellar ataxia (SCA1; 164400), because they found abolished
tendon reflexes and flexion contractures of the legs in 1 patient, and
onset at 18 years of age, palatal myoclonus and optic atrophy in the
second. Dementia developed in both. Pathologic findings, in contrast to
earlier reports, showed involvement of the cerebellum and inferior
olivary nuclei.

Coutinho and Andrade (1978) proposed a 3-way phenotypic classification
for MJD: cerebellar ataxia, external ophthalmoplegia and pyramidal signs
(type 2), additional predominant extrapyramidal signs (type 1), and
additional distal muscular atrophy (type 3). Although not completely
specific to MJD, dystonia, facial and lingual fasciculations, and
peculiar, bulging eyes represent a constellation strongly suggestive of
this disease. Rosenberg (1983) added a fourth phenotype: neuropathy and
parkinsonism.

Coutinho et al. (1982) described the presumedly homozygotic son of 2
affected parents; the son had onset at age 8 and died of the disease at
age 15. Another son of these parents had onset at age 7. As with other
late-onset dominant spinocerebellar degenerations (notably the
olivopontocerebellar degenerations), there is considerable phenotypic
variation even within the same family. Barbeau et al. (1984) gave an
extensive review.

Sequeiros (1985) pointed out that the diagnosis of Machado-Joseph
disease had been made (Healton et al., 1980) in an American black family
originating from North Carolina; that on further check this proved to be
the family reported by Taniguchi and Konigsmark (1971); that Coutinho et
al. (1982), in commenting on the neuropathology of Machado-Joseph
disease, noted the similarity to the spinopontine atrophy reported by
Boller and Segarra (1969), Taniguchi and Konigsmark (1971), and Ishino
et al. (1971); and, finally, that the disorder reported in the last
family, Japanese, had been proved to be Machado-Joseph disease. See
Sequeiros and Suite (1986). Lazzarini et al. (1992) expanded on the
pedigree of the family first reported by Boller and Segarra (1969) and
concluded that the disorder represented a spinocerebellar ataxia
phenotypically similar to that of spinocerebellar ataxia type 1, which
shows linkage to HLA. However, linkage to HLA was excluded in this
kindred, leading to the designation SCA2 (183090) for this and other
HLA-unlinked SCA kindreds. Silveira et al. (1993) demonstrated that the
disorder designated Holguin ataxia, or SCA2, that is frequent in Cubans,
is genetically distinct from MJD; MJD was excluded from a location on
12q where linkage studies showed the SCA2 locus to be situated.

Eto et al. (1990) described a family of German extraction with
progressive ataxia, eye movement abnormalities, peripheral sensory loss,
and spinal muscular atrophy of adult onset. The pedigree pattern in 4
generations was consistent with autosomal dominant inheritance. Eto et
al. (1990) suggested that the form of spinopontine atrophy might be
different from Machado-Joseph disease: the eyes were not protuberant,
extraocular movements were abnormal to a minor degree, and
neuropathologically the substantia nigra and dentate nucleus were
spared. Eto et al. (1990) considered their family to resemble most that
reported by Boller and Segarra (1969).

Takiyama et al. (1994) compared the clinical and pathologic features of
SCA1 and SCA2 to those in a large Japanese family with Machado-Joseph
disease that had previously been linked to markers on chromosome 14q.
Although many of the clinical features and the age of onset were similar
to those of SCA1 and SCA2, other features were more distinctive for
Machado-Joseph disease. These included dystonia, difficulty in opening
of the eyelids, slowness of movements, bulging eyes, and facial-lingual
fasciculations. One autopsy showed few changes in either the inferior
olive or the Purkinje cells, in sharp contrast to SCA1 and SCA2 where
such changes are pronounced. The subthalamopallidal system of the MJD
patient showed marked degeneration, which has not been described in SCA1
or SCA2.

Seto and Tsujihata (1999) studied a cluster of MJD in a small rural town
near Nagasaki City, Japan. They stated that Sakai et al. (1983)
described the first family with MJD in Japan, and that Japan had the
largest number of reported MJD families in the world. One family studied
by Seto and Tsujihata (1999) had 20 affected persons among 73 descending
from an ancestor born in 1839. This ancestor had been told that he was a
child of unknown non-Japanese parentage (probably Portuguese). The
second family had 12 affected persons among 43 with a common ancestor
born in 1897. Unsteady gait was the most frequent initial symptom. Age
at onset varied from 11 to 51 years with a mean in males of 36.5 and in
females of 39.7 years. Anticipation was observed in both families. Three
patients had shown only ocular signs: nystagmus, external
ophthalmoplegia, and/or blepharoptosis. Bulging eyes were found in only
4 patients. The authors stated that Nagasaki was the only open Japanese
port during the Edo period (1635 to 1868).

Livingstone and Sequeiros (1984) noted that 28 families with
Machado-Joseph disease had been described in the Azorean Islands, mainly
Flores and Sao Miguel, and 3 non-Azorean families in northeast Portugal.
Burt et al. (1993) described a dominantly inherited form of ataxia
resembling Machado-Joseph disease in members of 4 families of the Arnhem
Land Aboriginal people of northern Australia. Portuguese ancestry was
possible, although not proven. Goldberg-Stern et al. (1994) reported a
family of Machado-Joseph disease in a Yemenite Jewish kindred that
originated from a remote village named Ta'izz. This family, incidentally
named Yoseph, had no documentation of Portuguese ancestry. Portuguese
trade connections with the Yemenites most likely did not reach Ta'izz
which is far from the coast and is almost inaccessible because of a wall
of high mountains.

- Oculomotor Abnormalities

Among 65 patients with SCA1, SCA2, or SCA3, Burk et al. (1996) found
reduced saccade velocity in 56%, 100%, and 30% of patients,
respectively. MRI showed severe olivopontocerebellar atrophy in SCA2,
similar but milder changes in SCA1, and very mild atrophy with sparing
of the olives in SCA3. Careful examination of 3 major criteria of eye
movements, saccade amplitude, saccade velocity, and presence of
gaze-evoked nystagmus, permitted Rivaud-Pechoux et al. (1998) to assign
over 90% of patients with SCA1, SCA2, or SCA3 to their genetically
confirmed patient group. In SCA1, saccade amplitude was significantly
increased, resulting in hypermetria. In SCA2, saccade velocity was
markedly decreased. In SCA3, the most characteristic finding was the
presence of gaze-evoked nystagmus.

In an investigation of oculomotor function, Buttner et al. (1998) found
that all 3 patients with SCA1, all 7 patients with SCA3, and all 5
patients with SCA6 (183086) had gaze-evoked nystagmus. Three of 5
patients with SCA2 did not have gaze-evoked nystagmus, perhaps because
they could not generate corrective fast components. Rebound nystagmus
occurred in all SCA3 patients, 33% of SCA1 patients, 40% of SCA6
patients, and none of SCA2. Spontaneous downbeat nystagmus only occurred
in SCA6. Peak saccade velocity was decreased in 100% of patients with
SCA2, 1 patient with SCA1, and no patients with SCA3 or SCA6. Saccade
hypermetria was found in all types, but was most common in SCA3. Burk et
al. (1999) found that gaze-evoked nystagmus was not associated with
SCA2. However, severe saccade slowing was highly characteristic of SCA2.
Saccade velocity in SCA3 was normal to mildly reduced. The gain in
vestibuloocular reflex was significantly impaired in SCA3 and SCA1. Eye
movement disorders of SCA1 overlapped with both SCA2 and SCA3.

The reticulotegmental nucleus of the pons (RTTG), also known as the
nucleus of Bechterew, is a precerebellar nucleus important in the
premotor oculomotor circuits crucial for the accuracy of horizontal
saccades and the generation of horizontal smooth pursuit. By postmortem
examination, Rub et al. (2004) identified neuronal loss and astrogliosis
in the RTTG in 1 of 2 SCA1 patients, 2 of 4 SCA2 patients, and 4 of 4
SCA3 patients that correlated with clinical findings of hypometric
saccades and slowed and saccadic smooth pursuits. The 3 patients without
these specific oculomotor findings had intact RTTG regions. The authors
concluded that the neurodegeneration associated with SCA1, SCA2, and
SCA3 affects premotor networks in addition to motor nuclei in a subset
of patients.

OTHER FEATURES

In 19 of 27 (70%) patients with confirmed SCA types 1, 2, 3, 6, or 7
(164500), van de Warrenburg et al. (2004) found electrophysiologic
evidence of peripheral nerve involvement. Eight patients (30%) had
findings compatible with a dying-back axonopathy, whereas 11 patients
(40%) had findings consistent with a primary neuronopathy involving
dorsal root ganglion and/or anterior horn cells; the 2 types were
clinically almost indistinguishable. Of 8 patients with SCA3, 5 had a
neuronopathy and 4 had a sensorimotor axonopathy.

In a detailed neuropsychologic study, Kawai et al. (2004) found that 16
Japanese MJD patients had verbal and visual memory deficits, impaired
verbal fluency, and impaired visuospatial and constructional function
compared to controls. In addition, the patients were more depressed and
anxious than controls. There was no correlation between cognitive
impairment and CAG repeat length. The findings were consistent with
widespread dysfunction of the cerebral cortex and/or impairment of the
cerebellar cortical circuits.

Yeh et al. (2005) reported autonomic dysfunction among patients with MJD
confirmed by genetic analysis. Ten (66%) of 15 patients reported at
least 3 diverse autonomic symptoms, most commonly nocturia, cold
intolerance, orthostatic dizziness, dry eyes, dry mouth, and impaired
near vision. Electrophysiologic studies showed parasympathetic
cardiovagal dysfunction in 71% of patients and sympathetic sudomotor
dysfunction in 73% of patients.

Franca et al. (2007) found that 33 (47%) of 70 patients with MJD
reported chronic pain, most often in the lumbar back and lower limbs.

Franca et al. (2008) observed muscle excitability abnormalities in 41
(82%) of 50 men with MJD, 10 (20%) of whom reported muscle cramps as the
presenting complaint. Fifteen patients had fasciculations on clinical
exam, and 25 had fasciculations identified on EMG testing. Those with
fasciculations had a higher frequency of peripheral neuropathy. Franca
et al. (2008) noted that damage to motor axons in classic motor neuron
disease leads to collateral nerve sprouting with overexpression of ionic
channels that results in spontaneous ectopic activity and muscle
cramping. While this mechanism may be at work in some MJD patients,
others may have cramps and/or fasciculations due to altered excitatory
inputs from damaged corticospinal fibers. Kanai and Kuwabara (2009)
commented that they considered muscle cramps in MJD to be primarily a
symptom of peripheral motor nerve sprouting and hyperexcitability,
particularly in the early stages of the disease.

- Clinical Variability

Munchau et al. (1999) described a German woman who presented with severe
generalized dystonia beginning at the age of 18 years when she noticed
involuntary twisting and cramping of her right hand and twisting of both
feet shortly thereafter. Symptoms worsened when she was stressed. At the
age of 19 years, she began to grimace when talking and laughing, and her
speech became difficult to understand. Over a period of 2 years her
symptoms deteriorated, and she became unable to walk without support.
She was found to be heterozygous for the ATXN3 gene, with a CAG repeat
length of 81 +/- 2 and 14 +/- 1 in the mutated expanded allele and in
the normal allele, respectively. Remarkably, cerebellar function was
normal apart from mild oculomotor abnormalities. Severe dystonia as a
presenting feature had never been described in patients from Germany,
where MJD represented 50% of autosomal dominant cerebellar ataxia (ADCA)
cases.

In a family of African descent in which 3 members presented with
phenotypic features reminiscent of typical Parkinson disease (PD;
168600), Gwinn-Hardy et al. (2001) identified pathogenic expansions in
the ATXN3 gene (607047). Features suggestive of PD included
bradykinesis, facial masking, rigidity, postural instability, shuffling,
asymmetric onset, dopamine responsiveness, and lack of atypical features
often associated with SCA3. A fourth, mildly symptomatic patient also
carried the repeat expansion. The authors suggested that the low numbers
of repeats in this family (67-75; normal, 16-34) presenting with
parkinsonism may be associated with ethnic background and that
evaluation for SCA3 should be considered in similar cases.

In a study of 412 individuals with MJD, Kieling et al. (2007) found that
the estimated mean survival time was 63.96 years, compared to 78.61
years in unaffected relatives. For a subset of 366 patients, mean age at
onset was 36.37 years with a survival of 21.18 years. Early onset and
increased CAG length predicted shorter overall survival times.

INHERITANCE

Machado-Joseph disease is an autosomal dominant disorder. Sequeiros and
Coutinho (1981) identified 9 cases of 'skipped generations' (penetrance
= 94.5%).

DIAGNOSIS

Dawson et al. (1982) suggested that the electrooculogram may be useful
in early detection.

The finding of 'intermediate alleles' presented a problem in the
Portuguese MJD Predictive Testing Program. A second problem was the
issue of homoallelism, i.e., homozygosity for 2 normal alleles with
exactly the same (CAG)n length, which was found in about 10% of all test
results. Maciel et al. (2001) reported a study in which an affected
patient carried a 71 and a 51 CAG repeat and 2 asymptomatic relatives
carried the 51 CAG repeat and normal-size alleles. The results suggested
that the 51 CAG repeat is not associated with disease. The intermediate
alleles were not present in a large sample of the healthy population
from the same region. Intragenic polymorphisms allowed distinction of
the 2 different normal alleles in all cases of homoallelism. An improved
protocol for molecular testing for MJD was proposed.

MAPPING

In 7 French autosomal dominant SCA families, previously excluded from
linkage to the region of chromosome 6 carrying SCA1, Gispert et al.
(1993) also excluded linkage to the region of chromosome 12 carrying the
SCA2 locus (183090), thus providing evidence for the existence of a
third SCA locus, SCA3.

Stevanin et al. (1994) reported linkage studies in 3 of these French
families, in 2 of which location of the gene at 14q24.3-qter was
possible. Combined analysis of the families placed the SCA3 locus in a
15-cM interval between markers D14S67 and D14S81. Stevanin et al. (1995)
narrowed the mapping of SCA3 to a 3-cM interval on 14q. In the third
family, Stevanin et al. (1994) excluded linkage to the sites of SCA1,
SCA2, and SCA3, thus indicating the existence of a fourth ADCA type I
locus.

In Japanese kindreds with MJD, Takiyama et al. (1993) assigned the
disease locus to 14q24.3-q32 by genetic linkage to microsatellite loci
D14S55 and D14S48; multipoint maximum lod score = 9.719. Using 4
microsatellite DNA polymorphisms (STRPs), Sequeiros et al. (1994)
likewise mapped the MJD gene to 14q. Using HOMOG, Sequeiros et al.
(1994) could find no evidence for heterogeneity with the 5 Japanese
families in whom linkage had been reported. St. George-Hyslop et al.
(1994) provided evidence that MJD in 5 pedigrees of Azorean descent was
also linked to 14q in an 18-cM region between the markers D14S67 and
AACT (107280); multipoint lod score = 7.00 near D14S81. They also
reported molecular evidence for homozygosity at the MJD locus in an
MJD-affected subject with severe, early-onset symptoms.

Twist et al. (1995) studied 6 MJD families of Portuguese/Azorean origin
and 1 of Brazilian origin, using 9 microsatellite markers mapped to
14q24.3-q32.

A fourth SCA locus was suggested by the report of Twells et al. (1994)
in which linkage to the regions of chromosomes 6, 12, and 14, where
forms of SCA had previously been mapped, was excluded in a large Thai
kindred in which dominant cerebellar ataxia was often combined with
frontal lobe signs and dementia. Similarly, Lopes-Cendes et al. (1994)
excluded linkage with these 3 loci in a large French-Canadian kindred
with 4 generations of living affected individuals in 4 generations.

MOLECULAR GENETICS

Kawaguchi et al. (1994) identified a common mutation in the MJD gene as
the cause of Machado-Joseph disease. In normal individuals, the gene was
found to contain between 13 and 36 CAG repeats, whereas most of the
patients with clinically diagnosed MJD and all of the affected members
of a family with the clinical and pathologic diagnosis of MJD showed
expansion of the repeat number to the range of 68 to 79 (607047.0001).
Schols et al. (1995) provided definitive proof that mutation in the
ATXN3 gene cause SCA3.

Giunti et al. (1995) surveyed members of 63 families with a variety of
autosomal dominant late-onset cerebellar ataxias for the CAG repeat
expansion described in association with Machado-Joseph disease. The MJD
mutation was identified in 9 families segregating progressive
adult-onset cerebellar degeneration with variable supranuclear
ophthalmoplegia, optic atrophy, mild dementia, peripheral neuropathy, or
extrapyramidal dysfunction, corresponding to Harding's classification of
ADCA type I (Harding, 1982). Most of the patients with ADCA type I have
olivopontocerebellar atrophy at autopsy. Giunti et al. (1995) noted that
this mutation was also identified in a further family affected with
parkinsonism, peripheral neuropathy and dystonia but little cerebellar
disease. The origins of these 10 families were the United Kingdom,
India, Pakistan, the West Indies, France, Brazil, and Ghana. The authors
could find no clinical feature that distinguished ADCA type I patients
with the SCA3 mutation from those who did not have it. Giunti et al.
(1995) found that the CAG repeat length ranged from 13 to 41 copies on
normal chromosomes and 62 to 80 copies on affected chromosomes. The
families in which Giunti et al. (1995) detected the Machado-Joseph
disease trinucleotide repeat expansion included the historic 'Drew
family of Walworth' (Harding, 1982).

Since some clinical features of MJD overlap with those of SCA, Schols et
al. (1995) sought MJD mutations in 38 German families with autosomal
dominant SCA. The MJD (CAG)n trinucleotide expansion was identified in
19 families. In contrast, the trinucleotide expansion was not observed
in 21 ataxia patients without a family history of the disease. Analysis
of the (CAG)n repeat length in 30 patients revealed an inverse
correlation with the age of onset. The (CAG)n stretch of the affected
allele varied between 67 and 78 trinucleotide units; the normal alleles
carried between 12 and 28 simple repeats. These results demonstrated
that the MJD mutation causes the disease phenotype of most SCA patients
in Germany. Schols et al. (1995) pointed out that in SCA3 as observed in
Germany, features characteristic of Machado-Joseph disease, such as
dystonia, bulging eyes, and faciolingual fasciculations, are rare.

Durr et al. (1996) screened 173 index patients with adult-onset
cerebellar ataxia of whom 125 were classified as ADCA type I (cerebellar
signs with supranuclear ophthalmoplegia, extrapyramidal signs, dementia,
and amyotrophy); 9 of whom were ADCA type II (cerebellar ataxia with
retinal degeneration in all family members); and 4 were ADCA type III
(pure cerebellar signs after a disease duration of more than 10 years).
The SCA3-MJD mutation represented 28% of all their ADCA type I families,
whereas SCA1 only accounted for 13% in their population. The number of
CAG repeats in the expanded allele ranged from 64 to 82 with a median of
73. In contrast, normal alleles contained between 14 and 40 CAG repeats.
The mean expansion between generations was +0.86 CAG repeat units
without a statistically significant difference between paternally and
maternally transmitted alleles. Durr et al. (1996) found no correlation
between the CAG repeat length and the tendency to expansion. All SCA3
patients had cerebellar ataxia; 46% had extensor plantar responses; 55%
had decreased vibratory sensation; and supranuclear ophthalmoplegia was
present in 47% of the patients. Dystonia and parkinsonian signs were
only found in 18% of the patients. Two of 49 patients had retinal
degeneration; 60% of patients had axonal neuropathy. Bulging eyes were
noticed in 23% of SCA3 patients, which was similar to the frequency
observed in SCA1 patients.

Lopes-Cendes et al. (1997) reported 25 unrelated Brazilian families with
MJD. Molecular analysis showed that normal alleles ranged from 12 to 33
CAG repeats, whereas expanded pathogenic alleles ranged from 66 to 78
CAG repeats. There was a significant negative correlation between age at
onset and length of CAG tract. However, repeat contractions were also
detected, and Lopes-Cendes et al. (1997) estimated that only 40% of the
variation in age at disease onset could be attributed to length of the
expanded repeat.

Ramesar et al. (1997) investigated 14 South African kindreds and 22
sporadic individuals with SCA for expanded SCA1 (601556.0001) and MJD
repeats. The authors stated that SCA1 mutations accounted for 43% of
known ataxia families in the Western Cape region of South Africa. They
found that expanded SCA1 and CAG repeats cosegregated with the disorder
in 6 of the families, 5 of mixed ancestry and 1 Caucasian, and were also
observed in a sporadic case from the indigenous Black African
population. The use of the microsatellite markers D6S260, D6S89, and
D6S274 provided evidence that the expanded SCA1 repeats segregated with
3 distinct haplotypes in the 6 families. None of the families nor the
sporadic individuals showed expansion of the MJD repeat.

Studying 77 German families with autosomal dominant cerebellar ataxia of
SCA types 1, 2, 3, and 6 (183086), Schols et al. (1997) found that the
SCA1 mutation accounted for 9%, SCA2 for 10%, SCA3 for 42%, and SCA6 for
22%. There was no family history of ataxia in 7 of 27 SCA6 patients. Age
at onset correlated inversely with repeat length in all subtypes. Yet
the average effect of 1 CAG unit on age of onset was different for each
SCA subtype. Schols et al. (1997) compared clinical, electrophysiologic,
and magnetic resonance imaging (MRI) findings to identify phenotypic
characteristics of genetically defined SCA subtypes. Slow saccades,
hyporeflexia, myoclonus, and action tremor suggested SCA2. SCA3 patients
frequently developed diplopia, severe spasticity or pronounced
peripheral neuropathy, and impaired temperature discrimination, apart
from ataxia. SCA6 presented with a predominantly cerebellar syndrome,
and patients often had onset after 55 years of age. SCA1 was
characterized by markedly prolonged peripheral and central motor
conduction times in motor evoked potentials. MRI scans showed pontine
and cerebellar atrophy in SCA1 and SCA2. In SCA3, enlargement of the
fourth ventricle was the main sequel of atrophy. SCA6 presented with
pure cerebellar atrophy on MRI. Overlap between the 4 SCA subtypes was
broad, however.

GENOTYPE/PHENOTYPE CORRELATIONS

Kawaguchi et al. (1994) found a negative correlation between age of
onset and CAG repeat numbers in MJD. Southern blot analyses and genomic
cloning demonstrated the existence of related genes and raised the
possibility that similar abnormalities in related genes may give rise to
diseases similar to MJD.

Maruyama et al. (1995) examined the molecular features of the CAG
repeats and the clinical manifestations in 90 MJD individuals from 62
independent Japanese MJD families and found that the MJD repeat length
was inversely correlated with the age of onset (r = -0.87). The MJD
chromosomes contained 61-84 repeat units, whereas normal chromosomes
displayed 14-34 repeats. In the normal chromosomes, 14 repeat units were
the most common and the shortest.

Takiyama et al. (1995) examined the size of the (CAG)n repeat array in
the 3-prime end of the ATXN3 gene and the haplotype at a series of
microsatellite markers surrounding the ATXN3 gene in a large cohort of
Japanese and Caucasian subjects with MJD. Expansion of the array from
the normal range of 14-37 repeats to 68-84 repeats was found, with no
instances of expansions intermediate in size between those of the normal
and MJD affected groups. The expanded allele associated with MJD
displayed intergenerational instability, particularly in male meiosis,
and this instability was associated with the clinical phenomenon of
anticipation. The size of the expanded allele was not only inversely
correlated with the age-of-onset of MJD, but was also correlated with
the frequency of other clinical features, such as pseudoexophthalmos and
pyramidal signs were more frequent in subjects with larger repeats. The
disease phenotype was significantly more severe and had an early age of
onset (16 years) in a subject homozygous for the expanded allele, which
contrasts with Huntington disease (HD; 143100), in which the homozygous
subject has a disorder indistinguishable from that in the heterozygous
subject. The observation in MJD suggests that the expanded allele may
exert its effect either by a dominant-negative effect (putatively
excluded in HD) or by a gain-of-function effect as proposed for HD.
Japanese and Caucasian subjects affected with MJD shared haplotypes at
several markers surrounding the ATXN3 gene, these markers being uncommon
in the normal Japanese and Caucasian populations, thus suggesting the
existence either of common founders in these populations or of
chromosomes susceptible to pathologic expansion of the CAG repeat in the
ATXN3 gene.

Ranum et al. (1995) made use of the fact that the genes involved in 2
forms of autosomal dominant ataxia, that for MJD and that for SCA1, have
been isolated to assess the frequency of trinucleotide repeat expansions
among individuals diagnosed with ataxia. They collected and analyzed DNA
from individuals with both disorders. In both cases, the genes
responsible for the disorder were found to have an expansion of an
unstable CAG trinucleotide repeat. These individuals represented 311
families with adult-onset ataxia of unknown etiology, of which 149
families had dominantly inherited ataxia. Ranum et al. (1995) found that
of these, 3% had SCA1 trinucleotide repeat expansions, whereas 21% were
positive for the MJD trinucleotide expansion. For the 57 patients with
MJD trinucleotide repeat expansions, strong inverse correlation between
CAG repeat size and age at onset was observed (r = -0.838). Among the
MJD patients, the normal and affected ranges of CAG repeat size were 14
to 40 and 68 to 82 repeats, respectively. For SCA1, the normal and
affected ranges were much closer, namely 19 to 38 and 40 to 81 CAG
repeats, respectively.

Cancel et al. (1995) documented the marked phenotypic heterogeneity
associated with expansion of the CAG repeat sequence at the SCA3/MJD
locus. They studied 3 French families with type I autosomal dominant
cerebellar ataxia and a French family with neuropathologic findings
suggesting the ataxochoreic form of dentatorubropallidoluysian atrophy
(DRPLA; 125370). A strong correlation was found between size of the
expanded CAG repeat and age at onset of clinical disease. Instability of
the expanded triplet repeat was not found to be affected by sex of the
parent transmitting the mutation. Both somatic and gonadal mosaicism for
alleles carrying expanded trinucleotide repeats was found. The 4 French
families had no known Portuguese ancestry. Faciolingual myokymia, said
to be a hallmark of MJD, increased tendon reflexes, ophthalmoplegia, and
dystonia occur significantly more frequently among Azorean MJD patients,
while decreased vibratory sense and dementia were found more often among
the French cerebellar ataxia type I patients. Myoclonus, present in 1 of
the 5 patients in the French family with the DRPLA-like disorder, had
never been reported in SCA3 or MJD kindreds.

Igarashi et al. (1996) investigated the association of intergenerational
instability of the expanded CAG repeat in MJD with a CAG/CAA
polymorphism in the CAG repeat and a CGG/GGG polymorphism at the 3-prime
end of the CAG array. Their results strongly suggested that an
interallelic interaction is involved in the intergenerational
instability of the expanded CAG repeat. Igarashi et al. (1996) reported
that normal chromosomes with the CGG allele are more frequently
associated with larger CAG repeats than normal chromosomes with the GGG
allele. They also reported that 80 of 88 independent MJD chromosomes had
the CGG allele, which is in striking contrast to the CGG allele
frequency in the normal chromosome. Igarashi et al. (1996) investigated
the effect of gender on the intergenerational instability of the
expanded CAG repeat. They obtained significant evidence that the
expanded CAG repeats were less stable in paternal transmission than in
maternal transmission.

Size of the expanded repeat and gene dosage are factors in the severity
and early onset of MJD. Another factor pointed out by Kawakami et al.
(1995) is gender. In a total of 14 sib pairs, the mean of the
differences in age of onset between the sibs of different sexes was 12.7
+/-1.7 (n = 7) and between the sibs of the same sex was 3.9 +/-1.7 (n =
7). The difference was statistically significant, whereas the variance
in length of CAG repeats between these 2 groups was not significant.

Van Alfen et al. (2001) reported a Dutch family in which 4 members in 2
generations had intermediate repeat lengths (53 and 54) in the ATXN3
gene. All but the youngest had a restless legs syndrome with
fasciculations and a sensorimotor axonal polyneuropathy. The authors
concluded that intermediate repeat lengths can be pathogenic and may
predispose for restless legs and peripheral nerve disorder.

Van de Warrenburg et al. (2005) applied statistical analysis to examine
the relationship between age at onset and number of expanded triplet
repeats from a Dutch-French cohort of 802 patients with SCA1 (138
patients), SCA2 (166 patients), SCA3 (342 patients), SCA6 (53 patients),
and SCA7 (103 patients). The size of the expanded repeat explained 66 to
75% of the variance in age at onset for SCA1, SCA2, and SCA7, but less
than 50% for SCA3 and SCA6. The relation between age at onset and CAG
repeat was similar for all groups except for SCA2, suggesting that the
polyglutamine repeat in the ataxin-2 protein exerts its pathologic
effect in a different way. A contribution of the nonexpanded allele to
age at onset was observed for only SCA1 and SCA6. Van de Warrenburg et
al. (2005) acknowledged that their results were purely mathematical, but
suggested that they reflected biologic variations among the diseases.

Padiath et al. (2005) reported a 3-generation Indian pedigree in which
the proband had 45 CAG repeats in the ATXN3 gene. The proband had
clinical features of spinocerebellar ataxia as well as signs of
cerebellar and brainstem atrophy. The 45-repeat allele was unstable on
intergenerational transmission and was associated with a haplotype found
in the majority of MJD/SCA3 patients worldwide. Padiath et al. (2005)
noted that this was the smallest unstable allele in the ATXN3 gene
reported to that time.

- Allelic Transmission

Maruyama et al. (1995) analyzed parent-child transmission in association
with the clinical anticipation of the disease and showed the
unidirectional expansion of CAG repeats with no case of diminution in
the affected family. The differences in CAG repeat length between parent
and child and between sibs were greater in paternal transmission than in
maternal transmission. Detailed analysis showed that a large degree of
expansion was associated with a shorter length of the ATXN3 gene in
paternal transmission. On the other hand, the increments of increase
were similar for shorter and longer expansions in maternal transmission.
Among the 3 clinical subtypes, type 1 MJD with dystonia showed a larger
degree of expansion in CAG repeats of the gene and younger ages of onset
than the other types.

Ikeuchi et al. (1996) analyzed segregation patterns in 80 transmissions
in 7 MJD pedigrees and in 211 transmissions in 24 DRPLA pedigrees with
the diagnoses confirmed by molecular testing. The significant
distortions in favor of transmission of the mutant alleles were found in
male meiosis, where the mutant alleles were transmitted to 73% of all
offspring in MJD (P less than 0.01) and to 62% of all offspring in DRPLA
(P less than 0.01). The results were consistent with meiotic drive in
these 2 disorders. The authors commented that, since more prominent
meiotic instability of the length of the CAG trinucleotide repeats is
observed in male meiosis than in female meiosis and meiotic drive is
observed only in male meiosis, these results raised the possibility that
a common molecular mechanism underlies the meiotic drive and the meiotic
instability in male meiosis.

Rubinsztein and Leggo (1997) investigated the transmission of alleles
with larger versus smaller CAG repeat numbers in the ATXN3 gene in
normal heterozygotes from the 40 CEPH families. Their data suggested
that there was no segregation distortion in male meioses, while the
smaller CAG allele was inherited in 57% of female meioses (p less than
0.016). The pattern of inheritance of smaller versus larger CAG alleles
at this locus was significantly different when male and female meioses
were compared. While previous data suggested that meiotic drive may be a
feature of certain human diseases, including the trinucleotide disease
MJD, myotonic dystrophy, and DRPLA, the data of Rubinsztein and Leggo
(1997) were compatible with meiotic drive also occurring among
non-disease-associated CAG sizes.

In German patients with SCA3, Riess et al. (1997) likewise found
transmission distortion of the mutant alleles, but the segregation
distortion was observed during maternal transmission in German families,
rather than in paternal inheritance, as observed in Japanese pedigrees.

Grewal et al. (1999) performed a sperm typing study of 5 MJD patients of
French descent. Analysis of the pooled data showed a ratio of mutant to
normal alleles of 379:436 (46.5%:53.5%). To confirm these results, sperm
typing analysis was also performed using a polymorphic marker, D14S1050,
closely linked to the ATXN3 gene. Among 910 sperm analyzed, the allele
linked to the disease chromosome was detected in 50.3% of the samples,
and the allele linked to the normal chromosome was found in 49.6% of the
sperm. The difference in frequency of these 2 alleles was not
significant.

In an analysis of 428 meioses among 102 healthy Portuguese sibships,
Bettencourt et al. (2008) observed preferential transmission of the
smaller ATXN3 wildtype allele. There were no mutational events. There
was a positive correlation between the difference in length between the
2 ATXN3 alleles of the transmitter's genotype and the frequency of
transmission of the smaller alleles. The authors concluded that the
genotypic composition of the transmitters in a sample should be taken
into account in studies of segregation ratio distortion.

In a large population-based study of 82 MJD families from Rio Grande do
Sul, Brazil, Prestes et al. (2008) found that fitness among affected
individuals was increased compared to the general population and
compared to unaffected family members. Affected individuals had
significantly more children than unaffected relatives, with no sign of
parental gender effect. In addition, affected individuals had a lower
age at first delivery and earlier onset of menopause compared to
unaffected relatives; however, affected women who did not have children
had larger CAG tracts than those who had children. Prestes et al. (2008)
noted that since disease onset usually occurs after reproductive age,
most affected individuals have children before knowing their genetic
status. The findings overall suggested enhanced fitness of the mutant
allele.

PATHOGENESIS

Ikeda et al. (1996) demonstrated the induction of apoptosis in cultured
cells expressing a portion of the ATXN3 gene that included the expanded
CAG repeats. Cell death occurred only when the CAG repeat was translated
into polyglutamine residues, which apparently precipitated in large
covalently modified forms. Sisodia (1998) reviewed the significance of
nuclear inclusions in glutamine repeat disorders.

Studying the link between intranuclear expression of expanded
polyglutamine and neuronal dysfunction, Perez et al. (1999) demonstrated
that ataxin-3 adopts a unique conformation when expressed within the
nucleus of transfected cells. They found that this novel conformation of
intranuclear ataxin-3 is not due to proteolysis, suggesting instead that
association with nuclear protein(s) alters the structure of full-length
ataxin-3, exposing the polyglutamine domain. This conformationally
altered ataxin-3 was bound to the nuclear matrix. The pathologic form of
ataxin-3 with an expanded polyglutamine domain also associates with the
nuclear matrix. These data suggested that an early event in the
pathogenesis of SCA3/MJD may be an altered conformation of ataxin-3
within the nucleus that exposes the polyglutamine domain.

Chai et al. (1999) presented 2 lines of evidence implicating the
ubiquitin-proteasome pathway in the pathogenesis of SCA3/MJD. First,
studies of both human disease tissue and in vitro models showed
redistribution of the 26S proteasome complex into polyglutamine
aggregates. In neurons from SCA3/MJD brain, the proteasome localized to
intranuclear inclusions containing the mutant protein ataxin-3. In
transfected cells, the proteasome redistributed into inclusions formed
by 3 expanded polyglutamine proteins: a pathologic ataxin-3 fragment,
full-length mutant ataxin-3, and an unrelated GFP-polyglutamine fusion
protein. Inclusion formation by the full-length mutant ataxin-3 required
nuclear localization of the protein and occurred within specific
subnuclear structures recently implicated in the regulation of cell
death. In a second set of experiments, inhibitors of the proteasome
caused a repeat length-dependent increase in aggregate formation,
implying that the proteasome plays a direct role in suppressing
polyglutamine aggregation in disease. These results supported a central
role for protein misfolding in the pathogenesis of SCA3/MJD and
suggested that modulating proteasome activity is a potential approach to
altering the progression of this and other polyglutamine diseases.

Evert et al. (1999) generated ataxin-3-expressing rat mesencephalic
CSM14.1 cells to study the effects of long-term expression of ataxin-3.
The isolated stable cell lines provided high level expression of human
full-length ataxin-3 with either the normal nonexpanded CAG repeats
(SCA3-Q23) or the pathogenic expanded CAG repeats (SCA3-Q70). When
cultured at a nonpermissive temperature (39 degrees C), CSM14.1 cells
expressing the expanded full-length ataxin-3 developed nuclear inclusion
bodies, strong indentations of the nuclear envelope, and cytoplasmic
vacuolation, whereas cells expressing the nonexpanded form and control
cells did not. The ultrastructural alterations resembled those found in
affected neurons of SCA3 patients. Cells with such changes exhibited
increased spontaneous nonapoptotic cell death.

Gaspar et al. (2000) explored the possibility that frameshift mutations
in expanded CAG tracts of ATXN3 can generate polyalanine mutant proteins
and form intranuclear inclusions. Antisera were raised against a
synthetic peptide corresponding to the C terminus of ATXN3, which would
result from a frameshift within the CAG repeat motif with an intervening
polyalanine stretch. Corresponding proteins were evident in MJD patients
by Western blot analysis of lymphoblastoid proteins and in situ
hybridization of MJD pontine neurons. Transfection experiments suggested
that frameshifts are more likely to occur in longer CAG repeats and that
alanine polymers alone may be harmful to cells. The authors suggested
that a similar pathogenic mechanism may occur in other CAG repeat
disorders.

Ishikawa et al. (2002) reported 4 patients with MJD, confirmed by
expanded CAG repeat in the ATXN3 gene, who had symptoms of dementia and
delirium. The common features of the patients, 2 of whom were sibs, were
relatively early age of onset (16-36 years), long latency to the
occurrence of dementia and delirium (13-25 years), and much longer CAG
repeat lengths (74-79) compared with the mean repeat length found in
patients with MJD. Abnormal mental activity began after age 40 and
consisted of abnormal episodes of crying, excitation, delusion,
disorientation, and inappropriate behavior, suggesting a delirious
state. Dementia followed soon after. Pathologic examination of 2
patients showed cerebrocortical and thalamic neuronal intranuclear
inclusions that stained with an antipolyglutamine antibody. Ishikawa et
al. (2002) suggested that symptoms of delirium and dementia may occur in
late stages of MJD, particularly in those with longer expanded repeats,
and may be caused by dysfunction of cerebrocortical neurons.

Toulouse et al. (2005) established a cellular model of transcript
frameshifting of expanded CAG tracts, resulting from ribosomal slippage
to the -1 frame exclusively. Ribosomal frameshifting depended on the
presence of long CAG tracts, and polyalanine-frameshifted proteins may
enhance polyglutamine-associated toxicity, possibly contributing to
pathogenesis. Anisomycin, a ribosome-interacting drug that reduces -1
frameshifting, also reduced toxicity, suggesting a therapeutic
opportunity for these disorders.

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.

Reina et al. (2010) showed that interactions of ATXN3 with
valosin-containing protein (VCP; 601023) and HHR23B (RAD23B; 600062)
were dynamic and modulated by proteotoxic stresses. Heat shock, a
general proteotoxic stress, also induced wildtype and pathogenic ATXN3
to accumulate in the nucleus. Mapping studies showed that 2 regions of
ATXN3, the Josephin domain and the C terminus, regulated heat
shock-induced nuclear localization. Atxn3-null mouse cells were more
sensitive to toxic effects of heat shock, suggesting that ATXN3 had a
protective function in the cellular response to heat shock. Oxidative
stress also induced nuclear localization of ATXN3; both wildtype and
pathogenic ATXN3 accumulated in the nucleus of SCA3 patient fibroblasts
following oxidative stress. Heat shock and oxidative stress were the
first processes identified that increased nuclear localization of ATXN3.
Reina et al. (2010) suggested that the nucleus may be a key site for
early pathogenesis of SCA3.

Koch et al. (2011) showed that L-glutamate-induced excitation of
patient-specific induced pluripotent stem cell (iPSC)-derived neurons
initiates calcium-dependent proteolysis of ATXN3 followed by the
formation of SDS-insoluble aggregates. This phenotype could be abolished
by calpain (see 114220) inhibition, confirming a key role of this
protease in ATXN3 aggregation. Aggregate formation was further dependent
on functional sodium and potassium channels as well as ionotropic and
voltage-gated calcium channels, and was not observed in iPSCs,
fibroblasts, or glia, thereby providing an explanation for the
neuron-specific phenotype of Machado-Joseph disease. Koch et al. (2011)
concluded that iPSCs enable the study of aberrant protein processing
associated with late-onset neurodegenerative disorders in
patient-specific neurons.

POPULATION GENETICS

With the cloning of the ATXN3 gene and the firm identification of the
disorder in many populations, the hypothesis was raised that the present
world distribution of the disorder could have resulted from the spread
of an original founder mutation. Stevanin et al. (1995) reported strong
linkage disequilibrium of MJD chromosomes at the AFM343vf1 locus and
found a common haplotype that is frequently shared by Japanese and
Azorean MJD chromosomes, which suggests a founder effect or the presence
of predisposing chromosomes prone to expansions of the CAG repeat.

Lima et al. (1998) studied the genealogies of 32 Azorean families
containing a total of 103 patients with Machado-Joseph disease, using
parish records as the main source of data. These patients were
originally from the islands of Sao Miguel, Terceira, Graciosa, and
Flores. The genealogies of the 2 main Azorean American families, by the
names of Machado and Joseph, were also reconstructed. The family from
Terceira was linked to 3 different MJD families from Flores through
common ancestors. No kinship was observed, however, between the MJD
families from Sao Miguel and families from any other island. The
chronologic and geographic distribution indicated that more than one MJD
mutation was introduced in the Azores, probably by settlers coming from
the Portuguese mainland. The molecular evidence corroborated these
results, because 2 distinct haplotypes had been established, one on the
island of Sao Miguel and the other on Flores.

Among 202 Japanese and 177 Caucasian families with autosomal dominant
SCA, Takano et al. (1998) found that the prevalence of SCA3 was
significantly higher in the Japanese population (43%) compared to the
Caucasian population (30%). This corresponded to higher frequencies of
large normal ATXN3 CAG repeat alleles (greater than 27 repeats) in
Japanese controls compared to Caucasian controls. The findings suggested
that large normal alleles contribute to the generation of expanded
alleles that lead to dominant SCA.

Gaspar et al. (2001) analyzed linkage-disequilibrium of tightly linked
polymorphisms and by haplotype comparison in 249 families from different
countries. They typed 5 microsatellite markers surrounding the MJD locus
and 3 intragenic single-basepair polymorphisms. The results showed 2
different haplotypes, specific to the island of origin, in families of
Azorean extraction. In families from mainland Portugal, both Azorean
haplotypes could be found. The majority of non-Portuguese families also
shared the same intragenic ACA haplotype seen in the families coming
from the island of Flores, but at least 3 other haplotypes were seen.
These findings suggested 2 introductions of the mutation into the
Portuguese population. Worldwide, the sharing of the intragenic ACA
haplotype by most families studied supports a founder mutation in MJD.

Mittal et al. (2005) identified the common ACA haplotype in 9 Indian
families with MJD. This haplotype was also significantly associated with
large normal alleles (greater than 26 repeats) in unaffected Indian
individuals. The authors suggested that the pathogenic expanded alleles
may have originated from the pool of large normal alleles in this
population, possibly via a gene conversion event. The findings were
consistent with historical evidence related to Moorish sea trade and to
maritime links between Portugal and South Asia.

In a nationwide survey of Japanese patients, Hirayama et al. (1994)
estimated the prevalence of all forms of spinocerebellar degeneration to
be 4.53 per 100,000; of these, 2% were thought to have Machado-Joseph
disease. Watanabe et al. (1998) investigated 101 kindreds with
spinocerebellar ataxias from the central Honshu island of Japan, using a
molecular diagnostic approach with amplification of the CAG
trinucleotide repeat of the causative genes. Machado-Joseph disease was
the most common form, accounting for 33.7% of cases.

Storey et al. (2000) examined the frequency of mutations for SCA types
1, 2, 3, 6, and 7 (164500) in southeastern Australia. Of 63 pedigrees or
individuals with positive tests, 30% had SCA1, 15% had SCA2, 22% had
SCA3, 30% had SCA6, and 3% had SCA7. Ethnic origin was of importance in
determining SCA type: 4 of 9 SCA2 index cases were of Italian origin,
and 4 of 14 SCA3 index cases were of Chinese origin.

In 110 unrelated Portuguese and Brazilian families with spinocerebellar
ataxia due to a trinucleotide repeat expansion, Silveira et al. (2002)
found that 63% of dominantly inherited cases had an expansion in the
ATXN3 gene. Other tested loci included SCA2 (3%), DRPLA (2%), SCA6 (1%),
SCA7 (1%), and SCA8 (2%).

Van de Warrenburg et al. (2002) surveyed information from Dutch
diagnostic laboratories and determined that the minimal prevalence of
ADCA in the Netherlands was 3 per 100,000 (range, 2.8-3.8/100,000). Of
145 ADCA families, 44.1% had SCA3, 23.5% had SCA6, 11.7% had SCA7, 11.0%
had SCA2, and 9.7% had SCA1. CAG repeat length contributed to 52 to 76%
of age of onset variance, with similar regression slopes for SCA1, SCA2,
SCA3, and SCA7, which the authors suggested may reflect a similar
mechanism of polyglutamine-induced neurotoxicity in these diseases.

By haplotype analysis of 21 Dutch SCA3 families confirmed by genotype,
Verbeek et al. (2004) observed a highly conserved 1.4-Mb core genomic
region between markers D14S995 and D14S973 in 17 families. The 4
remaining families had a truncated form of this haplotype. Genealogic
research was able to link 10 SCA3 families into 4 clusters. Families
with a 6 allele at marker D14S617 were clustered in the eastern part of
the Netherlands (province of Drenthe) and those with a 7 allele at
marker D14S617 were clustered in the western part (province of South
Holland). The findings implicated 1 major founder SCA3 mutation in the
Dutch population. Similar results were found for SCA6.

Zhao et al. (2002) reported the prevalence and ethnic differences of
ADCA in Singapore. Among 204 patients with ataxia who underwent genetic
testing for 9 types, 58 (28.4%) from 36 families tested positive. SCA3
was identified in 31 (53.4%) patients from 15 families, SCA2 in 17
(29.3%) patients from 12 families, and SCA1 in 4 (6.9%) patients from 4
families. SCA2 was the only subtype identified among ethnic Malay and
ethnic Indian families.

Of 253 unrelated Korean patients with progressive cerebellar ataxia, Lee
et al. (2003) identified 52 (20.6%) with expanded CAG repeats. The most
frequent SCA type was SCA2 (33%), followed by SCA3 (29%), SCA6 (19%),
SCA1 (12%), and SCA7 (8%). There were characteristic clinical features,
such as hypotonia and optic atrophy for SCA1, hyporeflexia for SCA2,
nystagmus, bulging eye, and dystonia for SCA3, and macular degeneration
for SCA7.

Shimizu et al. (2004) estimated the prevalence of SCA in the Nagano
prefecture of Japan to be at least 22 per 100,000. Thirty-one of 86
families (36%) were positive for SCA disease-causing repeat expansions:
SCA6 was the most common form (19%), followed by DRPLA (10%), SCA3 (3%),
SCA1 (2%), and SCA2 (1%). The authors noted that the prevalence of SCA3
was lower compared to other regions in Japan, and that the number of
genetically undetermined SCA families in Nagano was much higher than in
other regions. Nagano is the central district of the main island of
Japan, located in a mountainous area surrounded by the Japanese Alps.
The restricted geography suggested that founder effects may have
contributed to the high frequency of genetically undetermined ADCA
families.

Among 114 Brazilian families with autosomal dominant SCA, Trott et al.
(2006) found that SCA3 was the most common form, present in 94 (84%)
families.

Among 113 Japanese families from the island of Hokkaido with autosomal
dominant SCA, Basri et al. (2007) found that SCA6 was the most common
form of the disorder, identified in 35 (31%) families. Thirty (27%)
families had SCA3, 11 (10%) had SCA1, 5 (4%) had SCA2, 5 (4%) had DRPLA,
10 (9%) had 16q22-linked SCA (117210), and 1 (1%) had SCA14 (605361).
The specific disorder could not be identified in 16 (14%) families.

Prestes et al. (2008) found a prevalence of 3.5 per 100,000 individuals
for MJD in the state of Rio Grande do Sul, Brazil.

Sura et al. (2009) reported that SCA3 was the most common type of SCA in
Thailand, occurring in 35 (19.2%) of 182 probands and 74 (22%) of 340
total patients. SCA1 and SCA2 were found in 11.5% and 10.4% of probands,
respectively. SCA3 frequency was less than that found in Chinese
studies, but more than that of most Indian studies.

HISTORY

Pierre Marie (1893), professor and head of the Department of Neurology
at Paris Medical School, proposed the designation 'l'heredo-ataxie
cerebelleuse' (HAC) to describe a hereditary cerebellar disorder
diagnosed in the Haudebourg family reported by Klippel and Durante
(1892). The last patient from the Haudebourg family was reported by
Guillain et al. (1941). In a reappraisal based on original handwritten
reports and pathology slides of the last case labeled with the diagnosis
of HAC, whose autopsy was recorded on October 15, 1943, and whose
clinicopathologic features were identical to those of patients from the
Haudebourg family, Uchihara et al. (2004) concluded that HAC is
consistent with Machado-Joseph disease.

ANIMAL MODEL

Ikeda et al. (1996) created ataxic transgenic mice by expressing the
expanded polyglutamine stretch in Purkinje cells. The results
demonstrated the potential involvement of expanded polyglutamine regions
as the common etiologic agent for inherited neurodegenerative diseases
with CAG expansions.

Warrick et al. (1998) recreated this glutamine-repeat disease in
Drosophila using a segment of the SCA3/MJD protein. Targeted expression
of the protein with an expanded polyglutamine repeat led to nuclear
inclusion formation and late-onset cell degeneration. Differential
sensitivity to the mutant transgene was observed among different cell
types, with neurons being particularly susceptible. Nuclear inclusion
formation alone was not sufficient for degeneration. These results
demonstrated that cellular mechanisms of human glutamine-repeat disease
are conserved in invertebrates. This fly model is useful in identifying
additional factors that modulate neurodegeneration.

Data indicate that molecular chaperones can modulate polyglutamine
pathogenesis. To elucidate the basis of polyglutamine toxicity and the
mechanism by which chaperones suppress neurodegeneration, Chan et al.
(2000) studied transgenic Drosophila disease models of MJD and
Huntington disease (143100). They demonstrated that Hsp70 (see 140559)
and Hdj1, the Drosophila homolog of human DNAJB1 (604572), showed
substrate specificity for polyglutamine proteins as well as synergy in
suppression of neurotoxicity, and altered the solubility properties of
the mutant polyglutamine protein.

By comparing previously reported genetic modifiers in 3 Drosophila
models of human neurodegenerative disease, Ghosh and Feany (2004)
confirmed that protein folding, histone acetylation, and apoptosis are
common features of neurotoxicity. Two novel genetic modifiers, the
Drosophila homolog of ATXN2 (601517) and CGI7231, were identified.
Cell-type specificity was demonstrated as many, but not all, retinal
modifiers also modified toxicity in postmitotic neurons. Ghosh and Feany
(2004) identified nicotinamide, which has histone deacetylase-inhibiting
activity, as a potent suppressor of polyglutamine toxicity.

Jung and Bonini (2007) showed that the Drosophila model for the
CAG/polyglutamine disease spinocerebellar ataxia type-3 (Warrick et al.,
1998) recapitulates key features of human CAG repeat instability,
including large repeat changes and strong expansion bias. Instability is
dramatically enhanced by transcription and modulated by nuclear excision
repair and CREB-binding protein (600140), a histone acetyltransferase
whose decreased activity contributes to polyglutamine disease.
Pharmacologic treatment normalizes acetylation-suppressed instability.
Thus, Jung and Bonini (2007) concluded that toxic consequences of
pathogenic polyglutamine protein may include enhancing repeat
instability.

Alves et al. (2008) used a lentivirus to overexpress expanded human
ataxin-3 (72Q repeats) in specific areas of rat brain. In the substantia
nigra, mutant ataxin-3 was found in punctate and mainly nuclear
aggregates, colocalized with ubiquitin (UBB; 191339) and alpha-synuclein
(SNCA; 163890), reminiscent of Parkinson disease (168600), and depleted
TH (191290)-positive neurons. Animals with injection in the substantia
nigra developed motor deficits, including rotational asymmetry. These
findings were not observed in response to injection of wildtype
ataxin-3. Injection of expanded ataxin-3 in the striatum resulted in
dose- and time-dependent neuropathology, including intranuclear
aggregation of ubiquitinated mutant ataxin-3 and condensation of cell
nuclei. Striatal tissue from 3 human MJD patients showed similar
neuropathology, indicating that striatal dysfunction is involved in
disease pathogenesis. In mice, injection of mutant ataxin-3 in the
cerebral cortex resulted in some aggregation, but did not result in
major neuropathologic changes.

Boy et al. (2009) generated a conditional mouse model of SCA3.
Transgenic mice developed a progressive neurologic phenotype
characterized by neuronal dysfunction in the cerebellum, reduced
anxiety, hyperactivity, impaired performance on the rotarod test, and
lower body weight gain. When mutant ataxin-3 expression was turned off
in symptomatic mice in an early disease state, the transgenic mice were
indistinguishable from negative controls after 5 months of treatment.
Boy et al. (2009) concluded that reducing the production of pathogenic
ataxin-3 may be a promising approach to treat SCA3, provided that such
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Alves et al. (2010) both overexpressed and silenced wildtype ATX3 in the
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overexpression of wildtype ATX3 did not protect against MJD pathology,
that knockdown of wildtype ATX3 did not aggravate MJD pathology, and
that non-allele-specific silencing of ataxin-3 strongly reduced
neuropathology.

*FIELD* SA
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93. Seto, M.; Tsujihata, M.: Cluster of Machado-Joseph disease in
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94. Shimizu, Y.; Yoshida, K.; Okano, T.; Ohara, S.; Hashimoto, T.;
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95. Silveira, I.; Manaia, A.; Melki, J.; Magarino, C.; Lunkes, A.;
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96. Silveira, I.; Miranda, C.; Guimaraes, L.; Moreira, M.-C.; Alonso,
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repeats in 202 families with ataxia: a small expanded (CAG)n allele
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97. Sisodia, S. S.: Nuclear inclusions in glutamine repeat disorders:
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98. St. George-Hyslop, P.; Rogaeva, E.; Huterer, J.; Tsuda, T.; Santos,
J.; Haines, J. L.; Schlumpf, K.; Rogaev, E. I.; Liang, Y.; Crapper
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Cox, D. W.; Lang, A. E.; Wherrett, J. R.: Machado-Joseph disease
in pedigrees of Azorean descent is linked to chromosome 14. Am. J.
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99. Stevanin, G.; Cancel, G.; Didierjean, O.; Durr, A.; Abbas, N.;
Cassa, E.; Feingold, J.; Agid, Y.; Brice, A.: Linkage disequilibrium
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100. Stevanin, G.; Cancel, G.; Durr, A.; Chneiweiss, H.; Dubourg,
O.; Weissenbach, J.; Cann, H. M.; Agid, Y.; Brice, A.: The gene for
spinal cerebellar ataxia 3 (SCA3) is located in a region of about
3 cM on chromosome 14q24.3-q32.2. Am. J. Hum. Genet. 56: 193-201,
1995.

101. Stevanin, G.; Le Guern, E.; Ravise, N.; Chneiweiss, H.; Durr,
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102. Storey, E.; du Sart, D.; Shaw, J. H.; Lorentzos, P.; Kelly, L.;
Gardner, R. J. M.; Forrest, S. M.; Biros, I.; Nicholson, G. A.: Frequency
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with spinocerebellar ataxia. Am. J. Med. Genet. 95: 351-357, 2000.

103. Suite, N. D. A.; Sequeiros, J.; McKhann, G. M.: Machado-Joseph
disease in a Sicilian-American family. J. Neurogenet. 3: 177-182,
1986.

104. Sura, T.; Eu-ahsunthornwattana, J; Youngcharoen, S.; Busabaratana,
M.; Dejsuphong, D.; Trachoo, O.; Theerasasawat, S.; Tunteeratum, A.;
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105. Takano, H.; Cancel, G.; Ikeuchi, T.; Lorenzetti, D.; Mawad, R.;
Stevanin, G.; Didierjean, O.; Durr, A.; Oyake, M.; Shimohata, T.;
Sasaki, R.; Koide, R.; Igarashi, S.; Hayashi, S.; Takiyama, Y.; Nishizawa,
M.; Tanaka, H.; Zoghbi, H.; Brice, A.; Tsuji, S.: Close associations
between prevalences of dominantly inherited spinocerebellar ataxias
with CAG-repeat expansions and frequencies of large normal CAG alleles
in Japanese and Caucasian populations. Am. J. Hum. Genet. 63: 1060-1066,
1998.

106. Takiyama, Y.; Igarashi, S.; Rogaeva, E. A.; Endo, K.; Rogaev,
E. I.; Tanaka, H.; Sherrington, R.; Sanpei, K.; Liang, Y.; Saito,
M.; Tsuda, T.; Takano, H.; Ikeda, M.; Lin, C.; Chi, H.; Kennedy, J.
L.; Lang, A. E.; Wherrett, J. R.; Segawa, M.; Nomura, Y.; Yuasa, T.;
Weissenbach, J.; Yoshida, M.; Nishizawa, M.; Kidd, K. K.; Tsuji, S.;
St George-Hyslop, P. H.: Evidence for inter-generational instability
in the CAG repeat in the MJD1 gene and for conserved haplotypes at
flanking markers amongst Japanese and Caucasian subjects with Machado-Joseph
disease. Hum. Molec. Genet. 4: 1137-1146, 1995.

107. Takiyama, Y.; Nishizawa, M.; Tanaka, H.; Kawashima, S.; Sakamoto,
H.; Karube, Y.; Shimazaki, H.; Soutome, M.; Endo, K.; Ohta, S.; Kagawa,
Y.; Kanazawa, I.; Mizuno, Y.; Yoshida, M.; Yuasa, T.; Horikawa, Y.;
Oyanagi, K.; Nagai, H.; Kondo, T.; Inuzuka, T.; Onodera, O.; Tsuji,
S.: The gene for Machado-Joseph disease maps to human chromosome
14q. Nature Genet. 4: 300-304, 1993.

108. Takiyama, Y.; Oyanagi, S.; Kawashima, S.; Sakamoto, H.; Saito,
K.; Yoshida, M.; Tsuji, S.; Mizuno, Y.; Nishizawa, M.: A clinical
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109. Taniguchi, R.; Konigsmark, B. W.: Dominant spino-pontine atrophy:
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110. Todd, P. K.; Paulson, H. L.: RNA-mediated neurodegeneration
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111. Toulouse, A.; Au-Yeung, F.; Gaspar, C.; Roussel, J.; Dion, P.;
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112. Trott, A.; Jardim, L. B.; Ludwig, H. T.; Saute, J. A. M.; Artigalas,
O.; Kieling, C.; Wanderley, H. Y. C.; Rieder, C. R. M.; Monte, T.
L.; Socal, M.; Alonso, I.; Ferro, A.; Carvalho, T.; do Ceu Moreira,
M.; Mendonca, P.; Ferreirinha, F.; Silveira, I.; Sequeiros, J.; Giugliani,
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families: clinical and molecular findings. (Letter) Clin. Genet. 70:
173-176, 2006.

113. Twells, R.; Yenchitsomanus, P.-T.; Sirinavin, C.; Allotey, R.;
Poungvarin, N.; Viriyavejakul, A.; Cemal, C.; Weber, J.; Farrall,
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114. Twist, E. C.; Casaubon, L. K.; Ruttledge, M. H.; Rao, V. S.;
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115. Uchihara, T.; Duyckaerts, C.; Iwabuchi, K.; Iwata, M.; Yagishita,
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A.; Praamstra, P.; Kremer, B. P. H.; Horstink, M. W. I. M.: Intermediate
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117. van de Warrenburg, B. P. C.; Hendriks, H.; Durr, A.; van Zuijlen,
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118. van de Warrenburg, B. P. C.; Notermans, N. C.; Schelhaas, H.
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122. Watanabe, H.; Tanaka, F.; Matsumoto, M.; Doyu, M.; Ando, T.;
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123. Woods, B. T.; Schaumburg, H. H.: Nigro-spino-dentatal degeneration
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124. Yeh, T.-H.; Lu, C.-S.; Chou, Y.-H. W.; Chong, C.-C.; Wu, T.;
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125. Zhao, Y.; Tan, E. K.; Law, H. Y.; Yoon, C. S.; Wong, M. C.; Ng,
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ataxia in Singapore. Clin. Genet. 62: 478-481, 2002.

*FIELD* CS
INHERITANCE:
Autosomal dominant

HEAD AND NECK:
[Eyes];
Gaze-evoked nystagmus;
External ophthalmoplegia;
Supranuclear ophthalmoplegia;
Diplopia;
Dysmetric saccades;
Impaired horizontal smooth pursuit;
Blepharoptosis;
Bulging eyes;
Abnormal electrooculogram (EOG)

ABDOMEN:
[Gastrointestinal];
Dysphagia

GENITOURINARY:
[Bladder];
Sphincter disturbances

MUSCLE, SOFT TISSUE:
Muscle cramps;
Fasciculations

NEUROLOGIC:
[Central nervous system];
Cerebellar ataxia, progressive;
Limb ataxia;
Truncal ataxia;
Spasticity;
Pyramidal signs;
Extrapyramidal signs;
Facial-lingual fasciculations;
Parkinsonism;
Bradykinesia;
Postural instability;
Extensor plantar responses;
Dysarthria;
Rigidity;
Dementia (<20%);
Dystonia (<20%);
Chronic pain;
Fasciculation-like movements;
Autonomic dysfunction may occur;
Loss of neurons and gliosis in basal ganglia, cranial nerve nuclei,
and spinal cord;
Cerebellar atrophy, mild;
Enlarged fourth ventricle, mild;
Mild loss of neurons in the cerebellum;
Sparing of the inferior olives;
Spinocerebellar tract degeneration;
[Peripheral nervous system];
Peripheral neuropathy;
Decreased vibration sense;
Impaired thermal sense;
Decreased or absent ankle reflexes;
Distal muscular atrophy

MISCELLANEOUS:
Onset in third to fourth decade;
Wide clinical variability;
Progressive disorder;
Normal alleles contain up to 44 repeats;
Pathogenic alleles contain 52 to 86 repeats;
Incomplete penetrance with 45 to 51 repeats;
Genetic anticipation

MOLECULAR BASIS:
Caused by trinucleotide repeat expansion (CAG)n in the ataxin-3 gene
(MJD, 607047.0001)

*FIELD* CN
Cassandra L. Kniffin - updated: 8/3/2010
Cassandra L. Kniffin - updated: 1/5/2009
Cassandra L. Kniffin - updated: 4/19/2005
Cassandra L. Kniffin - revised: 6/20/2002

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
joanna: 07/02/2013
joanna: 9/26/2011
ckniffin: 8/3/2010
joanna: 2/18/2009
ckniffin: 1/5/2009
ckniffin: 3/28/2008
joanna: 3/16/2007
joanna: 12/14/2006
ckniffin: 11/9/2005
ckniffin: 8/22/2005
ckniffin: 4/19/2005
ckniffin: 6/20/2002

*FIELD* CN
George E. Tiller - updated: 08/05/2013
Cassandra L. Kniffin - updated: 3/19/2012
Ada Hamosh - updated: 2/7/2012
George E. Tiller - updated: 12/29/2010
Cassandra L. Kniffin - updated: 8/3/2010
Patricia A. Hartz - updated: 11/16/2009
Cassandra L. Kniffin - updated: 8/27/2009
Cassandra L. Kniffin - updated: 6/23/2009
Cassandra L. Kniffin - updated: 3/18/2009
Cassandra L. Kniffin - updated: 1/5/2009
George E. Tiller - updated: 12/9/2008
Cassandra L. Kniffin - updated: 10/6/2008
Cassandra L. Kniffin - updated: 7/7/2008
Cassandra L. Kniffin - updated: 3/31/2008
Cassandra L. Kniffin - updated: 3/6/2008
Cassandra L. Kniffin - updated: 1/14/2008
Ada Hamosh - updated: 4/13/2007
George E. Tiller - updated: 3/21/2007
Cassandra L. Kniffin - updated: 9/18/2006
Cassandra L. Kniffin - updated: 8/22/2005
John Logan Black, III - updated: 7/22/2005
Cassandra L. Kniffin - updated: 6/2/2005
Cassandra L. Kniffin - updated: 5/18/2005
Cassandra L. Kniffin - updated: 4/19/2005
Cassandra L. Kniffin - updated: 12/15/2004
Cassandra L. Kniffin - updated: 7/27/2004
Cassandra L. Kniffin - updated: 7/12/2004
Cassandra L. Kniffin - updated: 5/25/2004
Cassandra L. Kniffin - updated: 8/7/2003
Cassandra L. Kniffin - updated: 2/12/2003
Victor A. McKusick - updated: 12/26/2002
Cassandra L. Kniffin - updated: 12/6/2002
Cassandra L. Kniffin - updated: 9/4/2002
Cassandra L. Kniffin - updated: 8/15/2002
Cassandra L. Kniffin - reorganized: 6/21/2002
Cassandra L. Kniffin - updated: 6/17/2002
Victor A. McKusick - updated: 12/21/2001
Victor A. McKusick - updated: 7/18/2001
Victor A. McKusick - updated: 3/8/2001
George E. Tiller - updated: 2/5/2001
Sonja A. Rasmussen - updated: 1/9/2001
George E. Tiller - updated: 11/20/2000
George E. Tiller - updated: 10/25/2000
Victor A. McKusick - updated: 1/14/2000
Victor A. McKusick - updated: 12/9/1999
Victor A. McKusick - updated: 10/13/1999
Wilson H. Y. Lo - updated: 9/21/1999
Victor A. McKusick - updated: 9/15/1999
Wilson H. Y. Lo - updated: 8/10/1999
Victor A. McKusick - updated: 5/13/1999
Patti M. Sherman - updated: 3/8/1999
Victor A. McKusick - updated: 2/3/1999
Stylianos E. Antonarakis - updated: 10/8/1998
Stylianos E. Antonarakis - updated: 7/14/1998
Victor A. McKusick - updated: 5/12/1998
Ethylin Wang Jabs - updated: 7/21/1997
Victor A. McKusick - edited: 5/29/1997
Victor A. McKusick - updated: 4/21/1997
Victor A. McKusick - updated: 2/19/1997
Moyra Smith - updated: 8/15/1996
Orest Hurko - updated: 3/27/1996
Moyra Smith - updated: 3/26/1996

*FIELD* CD
Victor A. McKusick: 6/16/1986

*FIELD* ED
alopez: 08/05/2013
carol: 7/26/2013
carol: 3/20/2012
ckniffin: 3/19/2012
alopez: 2/8/2012
terry: 2/7/2012
alopez: 9/22/2011
wwang: 1/11/2011
terry: 12/29/2010
carol: 12/21/2010
ckniffin: 11/16/2010
wwang: 10/21/2010
wwang: 8/4/2010
ckniffin: 8/3/2010
mgross: 11/16/2009
wwang: 9/29/2009
ckniffin: 8/27/2009
wwang: 6/26/2009
ckniffin: 6/23/2009
wwang: 3/24/2009
ckniffin: 3/18/2009
wwang: 1/14/2009
ckniffin: 1/5/2009
wwang: 12/9/2008
carol: 12/2/2008
wwang: 10/16/2008
ckniffin: 10/6/2008
wwang: 7/10/2008
ckniffin: 7/7/2008
wwang: 4/7/2008
ckniffin: 3/31/2008
wwang: 3/19/2008
ckniffin: 3/6/2008
carol: 1/21/2008
ckniffin: 1/14/2008
carol: 8/17/2007
alopez: 4/13/2007
wwang: 3/22/2007
terry: 3/21/2007
wwang: 9/22/2006
ckniffin: 9/18/2006
wwang: 11/14/2005
ckniffin: 11/3/2005
wwang: 8/29/2005
ckniffin: 8/22/2005
carol: 7/25/2005
terry: 7/22/2005
wwang: 6/15/2005
wwang: 6/13/2005
ckniffin: 6/2/2005
wwang: 6/1/2005
wwang: 5/26/2005
ckniffin: 5/18/2005
tkritzer: 5/9/2005
ckniffin: 4/19/2005
tkritzer: 12/15/2004
ckniffin: 12/15/2004
tkritzer: 11/8/2004
tkritzer: 7/28/2004
ckniffin: 7/27/2004
tkritzer: 7/13/2004
ckniffin: 7/12/2004
tkritzer: 5/27/2004
ckniffin: 5/25/2004
tkritzer: 1/28/2004
ckniffin: 1/21/2004
tkritzer: 8/13/2003
ckniffin: 8/7/2003
carol: 2/25/2003
ckniffin: 2/12/2003
tkritzer: 12/27/2002
terry: 12/26/2002
carol: 12/16/2002
tkritzer: 12/16/2002
ckniffin: 12/6/2002
carol: 9/10/2002
ckniffin: 9/4/2002
carol: 8/22/2002
ckniffin: 8/22/2002
ckniffin: 8/15/2002
carol: 6/21/2002
ckniffin: 6/21/2002
ckniffin: 6/20/2002
carol: 6/17/2002
ckniffin: 6/17/2002
cwells: 5/29/2002
terry: 12/21/2001
mcapotos: 8/9/2001
terry: 7/18/2001
mcapotos: 3/20/2001
mcapotos: 3/16/2001
terry: 3/8/2001
cwells: 2/5/2001
cwells: 1/31/2001
mcapotos: 1/9/2001
mcapotos: 11/20/2000
mcapotos: 11/10/2000
mcapotos: 11/1/2000
mcapotos: 10/25/2000
mcapotos: 1/28/2000
terry: 1/14/2000
mgross: 12/13/1999
terry: 12/9/1999
mgross: 10/18/1999
terry: 10/13/1999
carol: 9/21/1999
mgross: 9/21/1999
mgross: 9/16/1999
terry: 9/15/1999
carol: 8/10/1999
mgross: 5/27/1999
mgross: 5/20/1999
terry: 5/13/1999
carol: 3/9/1999
psherman: 3/8/1999
carol: 2/11/1999
terry: 2/3/1999
carol: 12/3/1998
carol: 10/8/1998
dkim: 9/11/1998
carol: 7/14/1998
carol: 5/19/1998
joanna: 5/13/1998
carol: 5/12/1998
terry: 4/7/1998
alopez: 3/27/1998
terry: 3/25/1998
mark: 9/3/1997
terry: 9/2/1997
mark: 8/1/1997
mark: 7/31/1997
alopez: 7/30/1997
alopez: 7/9/1997
joanna: 5/29/1997
alopez: 4/21/1997
alopez: 4/17/1997
terry: 4/11/1997
mark: 2/19/1997
terry: 2/11/1997
terry: 8/15/1996
mark: 8/15/1996
mark: 8/8/1996
mark: 7/22/1996
mark: 5/31/1996
terry: 5/29/1996
mark: 4/27/1996
terry: 4/19/1996
terry: 4/15/1996
mark: 3/27/1996
mark: 3/26/1996
terry: 3/19/1996
mark: 10/19/1995
carol: 12/5/1994
terry: 7/28/1994
jason: 7/1/1994
davew: 6/8/1994
mimadm: 4/14/1994

MIM 607047
*RECORD*
*FIELD* NO
607047
*FIELD* TI
*607047 ATAXIN 3; ATXN3
;;AT3;;
MJD GENE; MJD1;;
SCA3 GENE
*FIELD* TX

DESCRIPTION
read more
ATXN3 has deubiquitinase activity and appears to be a component of the
ubiquitin proteasome system. It may also have roles in transcriptional
regulation and neuroprotection (summary by Haacke et al., 2006).

CLONING

To identify the gene affected by CAG expansion in Machado-Joseph disease
(MJD; 109150), Kawaguchi et al. (1994) isolated a cDNA with a CAG repeat
from a human brain cDNA library using an oligonucleotide probe with 13
CTG repeats, complementary to the CAG repeats. The cDNA, which they
designated MJD1, encodes a deduced 359-amino acid protein.

Goto et al. (1997) obtained 3 ATXN3 cDNAs from a human brain cDNA
library. Two of the cDNAs represent an ATXN3 variant that differs from
the cDNA reported by Kawaguchi et al. (1994) in splicing of the 3-prime
exons, resulting in a different C-terminal sequence in the protein. The
third cDNA has a stop codon polymorphism that results in additional
C-terminal amino acids. The deduced ATXN3 proteins, which range in size
from 360 to 374 amino acids, differ only at their C termini and in the
number of glutamines in the polyglutamine (polyQ) tract.

Schmitt et al. (1997) isolated rat Atxn3. They found that the rat and
human ATXN3 genes are highly homologous, with an overall sequence
identity of approximately 88%. However, the C-terminal end of the
putative rat protein differs strongly from the human sequence published
by Kawaguchi et al. (1994). The (CAG)n block in the rat cDNA consists of
only 3 interrupted units, suggesting that a long polyQ stretch is not
essential for normal function of the Atxn3 protein in rodents.
Transcription of rat Atxn3 was detected in most rat tissues, including
brain. In human brain sections, Schmitt et al. (1997) did not find
significantly higher ATXN3 mRNA levels in regions predominantly affected
in MJD, suggesting that additional molecules and/or regulatory events
are necessary to explain the exclusive degeneration of certain brain
areas in MJD.

Using immunohistochemistry of normal and MJD brain, Paulson et al.
(1997) showed that expression of ATXN3 was restricted to a limited
subset of neurons, particularly to those in the striatum. In normal and
diseased brain and in transfected cells, immunolocalization studies
revealed that ATXN3 was predominantly a cytoplasmic protein that
localized to neuronal processes as well.

Tait et al. (1998) studied the subcellular localization of full-length
ataxin-3 protein with a glutamine sequence in the normal range in 2
mammalian cell lines. By immunofluorescence and confocal laser scanning
microscopy, and by biochemical subcellular fractionations, they detected
the protein predominantly, but not exclusively, in the nucleus. The
ataxin-3 present in the nucleus of neuroblastoma cells associated with
the inner nuclear matrix. The authors concluded that the ataxin-3
protein, which contains a putative nuclear localization signal very
close to the glutamine tract, per se has the ability to be transported
into the nucleus and that an expanded glutamine repeat is not essential
for this transport.

Using Northern blot analysis, Ichikawa et al. (2001) showed that ATXN3
mRNA was ubiquitously expressed in human tissues. They detected at least
4 ATXN3 transcripts of 1.4, 1.8, 4.5, and 7.5 kb and suggested that the
different mRNA species probably result from differential splicing and
polyadenylation.

Burnett et al. (2003) stated that the major human AT3 isoform contains
an N-terminal deubiquitinating domain, called the Josephin domain,
followed by 2 ubiquitin-interacting motifs (UIMs) and a polyQ tract near
the C terminus. In some isoforms, the polyQ tract is followed by a third
UIM. Burnett et al. (2003) identified a catalytic triad of cys14,
his119, and asn134 and other highly conserved residues within the
Josephin domain of AT3.

GENE STRUCTURE

Ichikawa et al. (2001) determined that the ATXN3 gene spans 48,240 bp
and contains 11 exons.

MAPPING

By FISH, Kawaguchi et al. (1994) mapped the ATXN3 gene to chromosome
14q32.1.

GENE FUNCTION

Using a 2-hybrid system, Wang et al. (2000) found that ataxin-3
interacted with 2 human homologs of the yeast DNA repair protein RAD23,
HHR23A (RAD23A; 600061) and HHR23B (RAD23B; 600062). Both normal and
mutant ataxin-3 proteins interacted with the ubiquitin-like domain at
the N terminus of the HHR23 proteins, which is a motif important for
nucleotide excision repair. However, in HEK 293 cells, HHR23A was
recruited to intranuclear inclusions formed by the mutant ataxin-3 (see
MOLECULAR GENETICS) through its interaction with ataxin-3. The authors
suggested that this interaction may be associated with the normal
function of ataxin-3, and that some functional abnormality of the HHR23
proteins may exist in MJD.

By combining profile-based sequence analysis with genomewide functional
data in model organisms, Scheel et al. (2003) determined that ataxin-3
belongs to a novel group of cysteine proteases and is predicted to be
active against ubiquitin chains or related substrates. The catalytic
site of this enzyme class is similar to that found in UBP (see USP1;
603478)- and UCH (see UCHL3; 603090)-type ubiquitin proteases. They
suggested the finding had implications for disease pathogenesis by
providing a direct connection between SCA3 and ubiquitin metabolism.

Doss-Pepe et al. (2003) showed that both normal and polyQ-expanded human
ATXN3 associated with a number of proteasome subunits and with
ubiquitinated proteins. Truncation analysis showed that the UIMs of
ATXN3 bound polyubiquitin, but other factors in the full-length protein
increased the affinity of ATXN3 for polyubiquitin. Both normal and
polyQ-expanded ATXN3 inhibited formation of ubiquitin-conjugated histone
H2B (see 609904).

Burnett et al. (2003) showed that the UIM domain of AT3 bound ubiquitin
chains containing 4 or more ubiquitin units, the chain length required
for proteasome degradation. PolyQ-expanded AT3 showed similar binding to
ubiquitin chains. Both wildtype and pathologic AT3 also decreased the
degree of polyubiquitination of the test protein, iodinated lysosome,
suggesting that AT3 is a ubiquitin protease. AT3 was sensitive to a
specific ubiquitin protease inhibitor. Mutation of cys14 within the
Josephin domain to alanine reduced the ability of AT3 to remove
polyubiquitin chains from iodinated lysosome.

Winborn et al. (2008) showed that human ATXN3 bound both lys48- and
lys63-linked polyubiquitin chains, but preferentially cleaved lys63
linkages. ATXN3 showed greater activity toward mixed-linkage
polyubiquitin, cleaving lys63 linkages in chains that contained both
lys48 and lys63 linkages. PolyQ expansion did not alter the binding or
catalytic properties of ATXN3. The authors concluded that ATXN3 is a
mixed-linkage, chain-editing enzyme and that the UIM region of ATXN3
regulates its substrate specificity.

Mueller et al. (2009) showed that protein casein kinase-2 (CK2, see
115440)-dependent phosphorylation controlled the nuclear localization,
aggregation, and stability of ataxin-3. Ser340 and ser352 within the
third ubiquitin-interacting motif of ATXN3 were particularly important
for nuclear localization of normal and expanded ATXN3, and mutation of
these sites robustly reduced the formation of nuclear inclusions. A
putative nuclear leader sequence was not required. ATXN3 associated with
CK2-alpha (CSNK2A1; 115440), and pharmacologic inhibition of CK2
decreased nuclear ATXN3 levels and the formation of nuclear inclusions.
ATXN3 shifted to the nucleus upon thermal stress in a CK2-dependent
manner, suggesting a key role of CK2-mediated phosphorylation of ATXN3
in SCA3 pathophysiology.

Reina et al. (2010) showed that interactions of ATXN3 with
valosin-containing protein (VCP; 601023) and HHR23B were dynamic and
modulated by proteotoxic stresses. Heat shock, a general proteotoxic
stress, also induced wildtype and pathogenic ATXN3 to accumulate in the
nucleus. Mapping studies showed that 2 regions of ATXN3, the Josephin
domain and the C terminus, regulated heat shock-induced nuclear
localization. Atxn3-null mouse cells were more sensitive to toxic
effects of heat shock, suggesting that ATXN3 had a protective function
in the cellular response to heat shock. Oxidative stress also induced
nuclear localization of ATXN3; both wildtype and pathogenic ATXN3
accumulated in the nucleus of SCA3 patient fibroblasts following
oxidative stress. Heat shock and oxidative stress were the first
processes identified that increased nuclear localization of ATXN3. Reina
et al. (2010) suggested that the nucleus may be a key site for early
pathogenesis of SCA3.

Koch et al. (2011) showed that L-glutamate-induced excitation of
patient-specific induced pluripotent stem cell (iPSC)-derived neurons
initiates calcium-dependent proteolysis of ATXN3 followed by the
formation of SDS-insoluble aggregates. This phenotype could be abolished
by calpain (see 114220) inhibition, confirming a key role of this
protease in ATXN3 aggregation. Aggregate formation was further dependent
on functional sodium and potassium channels as well as ionotropic and
voltage-gated calcium channels, and was not observed in iPSCs,
fibroblasts, or glia, thereby providing an explanation for the
neuron-specific phenotype of Machado-Joseph disease. Koch et al. (2011)
concluded that iPSCs enable the study of aberrant protein processing
associated with late-onset neurodegenerative disorders in
patient-specific neurons.

Using immunoprecipitation analysis and protein pull-down studies, Araujo
et al. (2011) found that endogenous ATXN3 interacted directly with the
transcription factor FOXO4 (300033) in nuclear extracts of HeLa cells,
rat CSM14.1 mesencephalic cells, and mouse brain. The interaction
required the N-terminal Josephin domain of ATXN3. Expression of ATXN3
enhanced FOXO4-dependent expression of the antioxidant enzyme SOD2
(147460) in a manner independent of ATXN3 deubiquitinase activity.
Treatment of HeLa cells with H2O2 induced nuclear translocation of FOXO4
and ATXN3, enhanced binding of FOXO4 and ATXN3 to the SOD2 promoter, and
induced SOD2 expression. Coexpression of mutant ATXN3 with an expanded
polyglutamine tract or knockdown of ATXN3 via short hairpin RNA reduced
FOXO4 nuclear translocation and induction of SOD2. Lymphocytes from SCA3
patients exposed to oxidative stress showed reduced binding of FOXO4 to
the SOD2 promoter, concomitant with impaired upregulation of SOD2 and
enhanced oxidative cytotoxicity. Araujo et al. (2011) concluded that
ATXN3 stabilizes FOXO4 and acts as a transcriptional coactivator with
FOXO4 in the oxidative stress response.

MOLECULAR GENETICS

- CAG Expansion in ATXN3 in Machado-Joseph Disease

In 8 of 9 patients with clinically diagnosed MJD, Kawaguchi et al.
(1994) identified CAG expansions of between 68 to 79 in the ATXN3 gene
(607047.0001). In normal individuals, the ATXN3 gene was found to
contain between 13 and 36 CAG repeats.

Kawaguchi et al. (1994) found a negative correlation between age of
onset and CAG repeat numbers. Southern blot analyses and genomic cloning
demonstrated the existence of related genes and raised the possibility
that similar abnormalities in related genes may give rise to diseases
similar to MJD.

- Pathogenic Effects of Polyglutamine Expansion in ATXN3

Paulson et al. (1997) showed that ATXN3 with a polyglutamine sequence in
the pathologic range accumulated in ubiquitinated intranuclear
inclusions selectively in neurons of affected brain regions. They
provided evidence in vitro for a model of disease in which an expanded
polyglutamine-containing fragment recruits full-length protein into
insoluble aggregates.

Evert et al. (1999) generated ataxin-3-expressing rat mesencephalic
CSM14.1 cells to study the effects of long-term expression of ataxin-3.
The isolated stable cell lines provided high level expression of human
full-length ataxin-3 with either the normal nonexpanded CAG repeats
(SCA3-Q23) or the pathogenic expanded CAG repeats (SCA3-Q70). When
cultured at a nonpermissive temperature (39 degrees C), CSM14.1 cells
expressing the expanded full-length ataxin-3 developed nuclear inclusion
bodies, strong indentations of the nuclear envelope, and cytoplasmic
vacuolation, whereas cells expressing the nonexpanded form and control
cells did not. The ultrastructural alterations resembled those found in
affected neurons of SCA3 patients. Cells with such changes exhibited
increased spontaneous nonapoptotic cell death.

Gaspar et al. (2000) explored the possibility that frameshift mutations
in expanded CAG tracts of ATXN3 can generate polyalanine mutant proteins
and form intranuclear inclusions. Antisera were raised against a
synthetic peptide corresponding to the C terminus of ATXN3, which would
result from a frameshift within the CAG repeat motif with an intervening
polyalanine stretch. Corresponding proteins were evident in MJD patients
by Western blot analysis of lymphoblastoid proteins and in situ
hybridization of MJD pontine neurons. Transfection experiments suggested
that frameshifts are more likely to occur in longer CAG repeats and that
alanine polymers alone may be harmful to cells. The authors suggested
that a similar pathogenic mechanism may occur in other CAG repeat
disorders.

Toulouse et al. (2005) established a cellular model of transcript
frameshifting of expanded CAG tracts, resulting from ribosomal slippage
to the -1 frame exclusively. Ribosomal frameshifting depended on the
presence of long CAG tracts, and polyalanine-frameshifted proteins may
enhance polyglutamine-associated toxicity, possibly contributing to
pathogenesis. Anisomycin, a ribosome-interacting drug that reduces -1
frameshifting, also reduced toxicity, suggesting a therapeutic
opportunity for these disorders.

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.

- Suppression of Mutant ATXN3

In animal cell models, Miller et al. (2003) demonstrated that
allele-specific silencing of disease genes with small interfering RNA
(siRNA) could be achieved by targeting either a linked SNP or the
disease mutation directly. They determined that selective targeting of
the disease-causing CAG repeat in the ATXN3 gene was not possible and
then took advantage of an associated SNP to generate siRNA that
exclusively silenced the mutant ATXN3 allele while sparing expression of
the wildtype allele. Allele-specific suppression was accomplished with
all 3 siRNA delivery approaches in use at the time: in vitro-synthesized
duplexes and plasmid and viral expression of short hairpin RNA.

In vitro, Li et al. (2004) found that an siRNA targeted to a C/G
polymorphism immediately after the CAG repeat that is expanded in MJD
effectively suppressed expression of mutant ataxin-3 (79 repeats) by 96%
without significant effect on the wildtype protein. In addition, siRNA
decreased cell death by 63 to 76%.

- Susceptibility to Late-Onset Parkinson Disease

In a family of African descent in which 3 members presented with
phenotypic features reminiscent of typical Parkinson disease (168600),
Gwinn-Hardy et al. (2001) identified pathogenic expansions in the ATXN3
gene. Features suggestive of PD included bradykinesis, facial masking,
rigidity, postural instability, shuffling, asymmetric onset, dopamine
responsiveness, and lack of atypical features often associated with
SCA3. A fourth, mildly symptomatic patient also carried the repeat
expansion. The authors suggested that the low numbers of repeats in this
family (67-75; normal, 16-34) presenting with parkinsonism may be
associated with ethnic background and that evaluation for SCA3 should be
considered in similar cases.

EVOLUTION

By comparing wildtype haplotypes encompassing the ATXN3 CAG repeat in
431 chromosomes of European, Asian, and African origin, Martins et al.
(2006) concluded that the main mutation mechanism occurring in the
evolution of the polymorphic CAG repeat is a multistep process resulting
from gene conversion or DNA slippage, as opposed to a stepwise process.
The 4 most frequent haplotypes showed a bimodal CAG repeat length
frequency distribution, particularly in the European population, and
genetic distances among all the alleles from each population did not
reflect allele size differences.

ANIMAL MODEL

- Transgenic Rodent Models of Machado-Joseph Disease

Cemal et al. (2002) generated transgenic mice by introducing pathologic
ATXN3 alleles with polyglutamine tract lengths of 64, 67, 72, 76, and 84
repeats, as well as the wildtype with 15 repeats. The mice with expanded
alleles demonstrated a mild and slowly progressive cerebellar deficit,
manifesting as early as 4 weeks of age. As the disease progressed,
pelvic elevation became markedly flattened and was accompanied by
hypotonia and motor and sensory loss. Neuronal intranuclear inclusion
formation and cell loss was prominent in the pontine and dentate nuclei,
with variable cell loss in other regions of the cerebellum from 4 weeks
of age. Peripheral nerve demyelination and axonal loss was also detected
in symptomatic mice from 26 weeks of age. In contrast, transgenic mice
carrying the wildtype (CAG)15 allele of the ATXN3 locus appeared
completely normal at 20 months. Disease severity increased with the
level of expression of the expanded protein and the size of the repeat.

Boy et al. (2009) generated a conditional mouse model of SCA3.
Transgenic mice developed a progressive neurologic phenotype
characterized by neuronal dysfunction in the cerebellum, reduced
anxiety, hyperactivity, impaired performance on the rotarod test, and
lower body weight gain. When mutant ataxin-3 expression was turned off
in symptomatic mice in an early disease state, the transgenic mice were
indistinguishable from negative controls after 5 months of treatment.
Boy et al. (2009) concluded that reducing the production of pathogenic
ataxin-3 may be a promising approach to treat SCA3, provided that such
treatment is applied before irreversible damage has taken place and that
it is continued for a sufficiently long time.

Alves et al. (2010) both overexpressed and silenced wildtype ATX3 in the
rat model of MJD developed by Alves et al. (2008). They found that
overexpression of wildtype ATX3 did not protect against MJD pathology,
that knockdown of wildtype ATX3 did not aggravate MJD pathology, and
that non-allele-specific silencing of ataxin-3 strongly reduced
neuropathology.

- Transgenic Drosophila Models of Machado-Joseph Disease

Warrick et al. (2005) expressed normal and pathogenic forms of human
ATXN3 in Drosophila and found that the normal activity of ATXN3
mitigated polyQ-induced neurodegeneration. When both normal and
pathogenic proteins were expressed together throughout the nervous
system, flies lived longer and showed improved brain cortical structure
compared with flies expressing only the pathogenic protein. Normal ATXN3
reduced accumulation of pathogenic ATXN3 and of other polyQ disease
proteins. Mutations in the ubiquitin interaction motif or in the
ubiquitin protease domain of ATXN3 abrogated the protective effect.
Protection also required proteasome activity, indicating that the normal
function of ATXN3 requires the ubiquitin pathway of protein quality
control.

Jung and Bonini (2007) showed that a transgenic Drosophila model for
spinocerebellar ataxia type 3 recapitulated key features of human CAG
repeat instability, including large repeat changes and strong expansion
bias. Instability was dramatically enhanced by transcription and
modulated by nuclear excision repair and CREB-binding protein (600140),
a histone acetyltransferase whose decreased activity contributes to
polyglutamine disease. Pharmacologic treatment normalized
acetylation-suppressed instability. Thus, Jung and Bonini (2007)
concluded that toxic consequences of pathogenic polyglutamine protein
may include enhancing repeat instability.

Li et al. (2008) provided evidence of a pathogenic role for ATXN3 CAG
repeat RNA in polyQ toxicity. In a screen for modifiers of polyQ
degeneration induced by ATXN3 in a transgenic Drosophila model, the
authors isolated an upregulation allele of muscleblind (see MBNL1;
606516), a gene implicated in the RNA toxicity of CUG expansion
diseases. Upregulation of muscleblind enhanced ATXN3 toxicity. Altering
the ATXN3 repeat sequence to an interrupted CAACAG repeat within the
polyQ-encoding region resulted in dramatically mitigated toxicity in
flies. Expressing an untranslated CAG repeat of pathogenic length in
flies resulted neuronal degeneration. Li et al. (2008) concluded that
these studies reveal a role for RNA in polyQ toxicity, highlighting
common components in RNA-based and polyQ protein-based trinucleotide
repeat expansion diseases.

To gain insight into the significance of ataxin-3 cleavage, Jung et al.
(2009) developed a Drosophila SL2 cell-based model as well as transgenic
fly models of SCA3. Ataxin-3 protein cleavage was conserved in the fly
and may be caspase-dependent as reported previously. Comparison of flies
expressing either wildtype or caspase-site mutant proteins indicated
that ataxin-3 cleavage enhanced neuronal loss in vivo.

*FIELD* AV
.0001
MACHADO-JOSEPH DISEASE
PARKINSON DISEASE, LATE-ONSET, SUSCEPTIBILITY TO, INCLUDED
ATXN3, (CAG)n EXPANSION

Machado-Joseph disease (109150), also known as spinocerebellar ataxia-3,
results from an expansion of a (CAG)n repeat in the ATXN3 gene. In
normal individuals, the gene contains between 13 and 36 CAG repeats,
whereas most patients with clinically diagnosed MJD and all of the
affected members of a family with clinical and pathologic MJD showed
expansion of the repeat number in the range of 68 to 79 copies
(Kawaguchi et al., 1994).

Susceptibility to Late-Onset Parkinson Disease

In a family of African descent in which 3 members presented with
phenotypic features reminiscent of typical Parkinson disease (168600),
Gwinn-Hardy et al. (2001) identified pathogenic expansions in the ATXN3
gene. Features suggestive of PD included bradykinesis, facial masking,
rigidity, postural instability, shuffling, asymmetric onset, dopamine
responsiveness, and lack of atypical features often associated with
SCA3. A fourth, mildly symptomatic patient also carried the repeat
expansion. The authors suggested that the low numbers of repeats in this
family (67-75; normal, 16-34) presenting with parkinsonism may be
associated with ethnic background and that evaluation for SCA3 should be
considered in similar cases.

*FIELD* RF
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edits lys63 linkages in mixed linkage ubiquitin chains. J. Biol.
Chem. 283: 26436-26443, 2008.

*FIELD* CN
George E. Tiller - updated: 08/05/2013
Patricia A. Hartz - updated: 4/10/2013
Ada Hamosh - updated: 2/7/2012
George E. Tiller - updated: 12/29/2010
George E. Tiller - updated: 11/1/2010
George E. Tiller - updated: 10/4/2010
George E. Tiller - updated: 7/7/2010
Patricia A. Hartz - updated: 12/8/2009
Patricia A. Hartz - updated: 11/11/2009
George E. Tiller - updated: 12/9/2008
Ada Hamosh - updated: 7/9/2008
Ada Hamosh - updated: 4/12/2007
Cassandra L. Kniffin - updated: 9/25/2006
George E. Tiller - updated: 1/31/2006
Patricia A. Hartz - updated: 5/4/2005
Cassandra L. Kniffin - updated: 7/27/2004
Victor A. McKusick - updated: 7/14/2003
George E. Tiller - updated: 12/16/2002

*FIELD* CD
Cassandra L. Kniffin: 6/19/2002

*FIELD* ED
alopez: 08/05/2013
alopez: 8/5/2013
mgross: 4/10/2013
mgross: 1/29/2013
alopez: 2/8/2012
terry: 2/7/2012
wwang: 1/11/2011
terry: 12/29/2010
ckniffin: 11/16/2010
alopez: 11/5/2010
terry: 11/1/2010
wwang: 10/21/2010
terry: 10/4/2010
terry: 9/9/2010
wwang: 7/21/2010
terry: 7/7/2010
mgross: 1/12/2010
terry: 12/8/2009
mgross: 11/16/2009
terry: 11/11/2009
wwang: 12/9/2008
wwang: 7/17/2008
terry: 7/9/2008
alopez: 4/13/2007
terry: 4/12/2007
wwang: 9/26/2006
ckniffin: 9/25/2006
wwang: 2/7/2006
terry: 1/31/2006
mgross: 6/6/2005
terry: 5/4/2005
tkritzer: 11/8/2004
tkritzer: 7/28/2004
ckniffin: 7/27/2004
tkritzer: 7/23/2003
terry: 7/14/2003
cwells: 12/16/2002
carol: 6/21/2002
ckniffin: 6/21/2002