SCA3 ATXN3

Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease, is the most common subtype of type 1 autosomal dominant cerebellar ataxia (ADCA type 1), a neurodegenerative disorder, and is characterized by ataxia, external progressive ophthalmoplegia, and other neurological manifestations¹. Research suggests that length of ATXN2 expansions may affect the phenotype of SCA3².

Prevalence

2.1 100,000

1-5/100,000³. Most prevalent SCA subtype⁴. Found worldwide across ancestries/ethnicities⁵.

Age of Onset Details

Typical: 10-49⁵; 3⁶- 73^5,7.

Locus

hg19

chr14:92537354-92537396

hg38

chr14:92071010-92071052

t2t

chr14:86300519-86300603

Details

Benign alleles range from 11-44 repeats⁸, with intermediate alleles (45-59) associated with incomplete penetrance and non-classic phenotypes⁵. The threshold between incomplete and full penetrance is unclear, but presumed to occur at ~60 repeats^5,8. The interruption CAA has been observed⁹; AAG is present in hg38 reference sequence. The APOE ε4 allele appears to act as a disease modifier¹⁰; GLS expansions may also function as disease modifiers¹¹.

Mechanism

GoF

Polyglutamine expansion leading to gain of function; aggregated and mislocalized proteins in neurons^12,5.

Year

1994¹³

Location in Gene

Coding Exon 10

Gene Strand

Alleles

Ref. Motif

CTG

Pathogenic (ref.)

CTG

Pathogenic (gene)

AGC

gnomAD

References

Direct supporting references for info on this page.

Ontology Lookup Service (OLS)

mondo:0007182

Influence of ATXN2 intermediate CAG repeats, 9bp duplication and alternative splicing on SCA3 pathogenesis.

Marilena,Lauerer, Jennifer,Faber, Nicolas,Casadei, Magda M,Santana, Georg,Auburger, Michaela,Pogoda, Jakob,Admard, Lea,Kaupp, Patricia Laura,Kos, Mafalda,Raposo, Manuela,Lima, Luis Pereira,de Almeida, Hector,Garcia-Moreno, Paola,Giunti, Jeroen,de Vries, Bart P,van de Warrenburg, Judith,van Gaalen, Marcus,Grobe-Einsler, Berkan,Koyak, Kathrin,Reetz, Friedrich,Erdlenbruch, Heike,Jacobi, Jon,Infante, Holger,Hengel, Ludger,Schöls, Thomas,Klockgether, Olaf,Rieß, Jeannette,Hübener-Schmid

Acta neuropathologica communications · 2025-07-19

pmid:40684213

Profiling of Short-Tandem-Repeat Disease Alleles in 12,632 Human Whole Genomes.

Haibao,Tang, Ewen F,Kirkness, Christoph,Lippert, William H,Biggs, Martin,Fabani, Ernesto,Guzman, Smriti,Ramakrishnan, Victor,Lavrenko, Boyko,Kakaradov, Claire,Hou, Barry,Hicks, David,Heckerman, Franz J,Och, C Thomas,Caskey, J Craig,Venter, Amalio,Telenti

American journal of human genetics · 2017-11-02

pmid:29100084

Spinocerebellar Ataxia

Jenish,Bhandari, Pawan K.,Thada, Debopam,Samanta

StatPearls · 2026-01-01

genereviews:NBK557816

genereviews:NBK1196

Analysis of Short Tandem Repeat Expansions in a Cohort of 12,496 Exomes from Patients with Neurological Diseases Reveals Variable Genotyping Rate Dependent on Exome Capture Kits.

Clarissa,Rocca, David,Murphy, Chris,Clarkson, Matteo,Zanovello, Delia,Gagliardi, Queen Square,Genomics, Rauan,Kaiyrzhanov, Javeria,Alvi, Reza,Maroofian, Stephanie,Efthymiou, Tipu,Sultan, Jana,Vandrovcova, James,Polke, Robyn,Labrum, Henry,Houlden, Arianna,Tucci

Genes · 2025-01-28

pmid:40004498

Mitochondrial DNA haplogroups and age at onset of Machado-Joseph disease/spinocerebellar ataxia type 3: a study in patients from multiple populations.

A,Ramos, M,Planchat, A R,Vieira Melo, M,Raposo, U,Shamim, V,Suroliya, A K,Srivastava, M,Faruq, H,Morino, R,Ohsawa, H,Kawakami, L,Bannach Jardim, M L,Saraiva-Pereira, J,Vasconcelos, C,Santos, M,Lima

European journal of neurology · 2018-12-07

pmid:30414314

The Frequency of Intermediate Alleles in Patients with Cerebellar Phenotypes.

Elena,Capacci, Silvia,Bagnoli, Giulia,Giacomucci, Costanza Maria,Rapillo, Alessandra,Govoni, Valentina,Bessi, Cristina,Polito, Irene,Giotti, Alice,Brogi, Elisabetta,Pelo, Sandro,Sorbi, Benedetta,Nacmias, Camilla,Ferrari

Cerebellum (London, England) · 2023-10-31

pmid:37906407

Comprehensive genetic diagnosis of tandem repeat expansion disorders with programmable targeted nanopore sequencing.

Igor,Stevanovski, Sanjog R,Chintalaphani, Hasindu,Gamaarachchi, James M,Ferguson, Sandy S,Pineda, Carolin K,Scriba, Michel,Tchan, Victor,Fung, Karl,Ng, Andrea,Cortese, Henry,Houlden, Carol,Dobson-Stone, Lauren,Fitzpatrick, Glenda,Halliday, Gianina,Ravenscroft, Mark R,Davis, Nigel G,Laing, Avi,Fellner, Marina,Kennerson, Kishore R,Kumar, Ira W,Deveson

Science advances · 2022-03-04

pmid:35245110

Apolipoprotein E epsilon4 allele is associated with better performance language and visual memory in spinocerebellar ataxia type 3.

Xuanyu,Chen, Kunxin,Lin, Zhixian,Ye, Liangliang,Qiu, Yusen,Qiu, Ruying,Yuan, Xintong,Yu, Chunyu,Huang, Bi,Cheng, Wei,Lin, Tianmin,Lai, Wanjin,Chen, Ning,Wang, Shirui,Gan, Qiuni,Su, Ying,Fu

European journal of neurology · 2025-01-01

pmid:39731318

Genetic Analysis of GCA Repeats in the GLS Gene: Implications for Undiagnosed Ataxia and Spinocerebellar Ataxia 3 in Mainland China.

Lijing,Lei, Linliu,Peng, Linlin,Wan, Zhao,Chen, Chunrong,Wang, Huirong,Peng, Rong,Qiu, Beisha,Tang, Hong,Jiang

Movement disorders : official journal of the Movement Disorder Society · 2024-12-19

pmid:39699045

Clinical and neuroimaging review of triplet repeat diseases.

Ryo,Kurokawa, Mariko,Kurokawa, Akihiko,Mitsutake, Moto,Nakaya, Akira,Baba, Yasuhiro,Nakata, Toshio,Moritani, Osamu,Abe

Japanese journal of radiology · 2022-09-28

pmid:36169768

CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1.

Y,Kawaguchi, T,Okamoto, M,Taniwaki, M,Aizawa, M,Inoue, S,Katayama, H,Kawakami, S,Nakamura, M,Nishimura, I,Akiguchi

Nature genetics · 1994-11-01

pmid:7874163

Additional Literature

Additional literature related to this locus.

Raw PubMed search results
(All PubMed results returned by searching for this gene, tandem repeats, and disease, in medline format)

Association of rare apolipoprotein E ε4 homozygosity with an earlier age at onset in spinocerebellar ataxia type 3.

Charlotte Clara,Meyer, Eduardo Preusser,de Mattos, Rahel Maria,Burger, Gunnar,Blumenstock, Priscila,Pereira Sena, Carlos,Gordon, Roy,Zaltzman, Marcondes Cavalcante,França, Maria-Luiza,Saraiva-Pereira, Mario R,Cornejo-Olivas, Peter,Bauer, Ludger,Schöls, Bart P,van de Warrenburg, Alexandra,Durr, Alexis,Brice, Thomas,Klockgether, Laura Bannach,Jardim, Olaf,Riess, Thorsten,Schmidt

Human molecular genetics · 2026-02-23

pmid:41854058

Modulation of the Stress Granule Component Carhsp1 Mitigates Disease-Associated Deficits in Spinocerebellar Ataxia Type 3 Mouse Models.

Tiago,Moreira-Gomes, Adriana,Marcelo, Ana Teresa,Rajado, Rafael G,Costa, Ricardo,Afonso-Reis, Cristiana R,Madeira, Inês T,Afonso, David V C,Brito, Adriana A,Vaz, Clévio,Nóbrega

Movement disorders : official journal of the Movement Disorder Society · 2026-03-19

pmid:41853947

Retrotransposition Events Shape the Evolution of the Ataxin-3 Gene Family in Primates.

Daniela,Felício, Inês M,Martins, Andreia,Pinto, Jorge,Sequeiros, António,Amorim, Alexandra M,Lopes, Susana,Seixas, Sandra,Martins

Genome biology and evolution · 2026-03-02

pmid:41818480

Metformin improves RAN protein pathology, alternative splicing, and behavioral phenotypes in SCA8 mice.

Lisa El,Romano, Setsuki,Tsukagoshi, Emily E,Davey-Osuch, Ramadan,Ajredini, Kamat,Manasi, Tala Vr,Ortiz, Eduardo,Rijos, Nathan J,Bourgon, S Elaine,Ames, Timothy J,Garrett, John D,Cleary, Eric T,Wang, Laura Pw,Ranum

Life science alliance · 2026-03-02

pmid:41771688

Pediatric-onset spinocerebellar ataxia type 3 with dual

Dedong,Wang, Mengyao,Zhou, Kang,Du, Yue,Wang, Kunzhi,Tang, Yuanfang,Duan, Mengting,Shi, Haohao,Wu

Frontiers in genetics · 2026-02-10

pmid:41736717

TCF4 intronic CAG repeat length modulates the effect of ATXN3 on age at onset in spinocerebellar ataxia type 3.

Na,Wan, Qi,Wu, Linlin,Wan, Qian,Jiang, Linliu,Peng, Chunrong,Wang, Lijing,Lei, Zhe,Long, Lang,He, Yuting,Shi, Rong,Qiu, Beisha,Tang, Zhao,Chen, Hong,Jiang

Journal of advanced research · 2026-02-17

pmid:41713739

Single-Cell RNA Sequencing Reveals Impaired CHIP-Mediated Heat Stress Response in SCA3 Pathogenesis.

Mi-Bo,Tang, Shi-Feng,Sheng, Zheng-Wei,Hu, Hai-Yang,Luo, Meng-Jie,Li, Shuo,Zhang, Xiao-Yan,Hao, Cheng-Yuan,Mao, Shao-Hua,Li, Hui-Fang,Sun, Zhi-Hua,Yang, Yi,Song, Chang-He,Shi, Yu-Ming,Xu

Molecular neurobiology · 2026-02-17

pmid:41701293

Early transcriptomic perturbations highlight the spinal cord as a key pathogenic region in spinocerebellar ataxia type 3.

Jacen,Emerson, Brianna S,Nelthrope, Emma A,Walker, Grace,Mao, Hannah K,Shorrock, Hayley S,McLoughlin

Frontiers in cellular neuroscience · 2026-01-14

pmid:41613623

Non-Huntington's disease chorea: an expanding universe with acquired causes.

Francisco,Cardoso, Débora,Maia, Ricardo,Maciel, Jonathan,Carr, Taku,Hatano, Alexandra,Durr, Werner,Poewe

Brain : a journal of neurology · 2026-01-30

pmid:41612618