ATXN1

Summary

ATXN1 (ataxin 1, HGNC:10548) is a protein-coding gene on chromosome 6p22.3, encoding Ataxin-1 (P54253). Chromatin-binding factor that repress Notch signaling in the absence of Notch intracellular domain by acting as a CBF1 corepressor.

The autosomal dominant cerebellar ataxias (ADCA) are a heterogeneous group of neurodegenerative disorders characterized by progressive degeneration of the cerebellum, brain stem and spinal cord. Clinically, ADCA has been divided into three groups: ADCA types I-III. ADCAI is genetically heterogeneous, with five genetic loci, designated spinocerebellar ataxia (SCA) 1, 2, 3, 4 and 6, being assigned to five different chromosomes. ADCAII, which always presents with retinal degeneration (SCA7), and ADCAIII often referred to as the `pure’ cerebellar syndrome (SCA5), are most likely homogeneous disorders. Several SCA genes have been cloned and shown to contain CAG repeats in their coding regions. ADCA is caused by the expansion of the CAG repeats, producing an elongated polyglutamine tract in the corresponding protein. The expanded repeats are variable in size and unstable, usually increasing in size when transmitted to successive generations. The function of the ataxins is not known. This locus has been mapped to chromosome 6, and it has been determined that the diseased allele contains 40-83 CAG repeats, compared to 6-39 in the normal allele, and is associated with spinocerebellar ataxia type 1 (SCA1). Alternative splicing results in multiple transcript variants, with one variant encoding multiple distinct proteins, ATXN1 and Alt-ATXN1, due to the use of overlapping alternate reading frames.

Source: NCBI Gene 6310 — RefSeq curated summary.

At a glance

• Gene–disease (curated): spinocerebellar ataxia type 1 (Strong, GenCC)
• GWAS associations: 48
• Clinical variants (ClinVar): 206 total — 5 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 76
• MANE Select transcript: NM_001128164

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10548
Approved symbol	ATXN1
Name	ataxin 1
Location	6p22.3
Locus type	gene with protein product
Status	Approved
Aliases	D6S504E, ATX1
Ensembl gene	ENSG00000124788
Ensembl biotype	protein_coding
OMIM	601556
Entrez	6310

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 12 protein_coding_CDS_not_defined, 3 protein_coding

ENST00000244769, ENST00000436367, ENST00000467008, ENST00000473388, ENST00000479680, ENST00000483591, ENST00000483954, ENST00000492857, ENST00000495178, ENST00000498374, ENST00000642969, ENST00000643828, ENST00000646259, ENST00000675689, ENST00000676138

RefSeq mRNA: 3 — MANE Select: NM_001128164 NM_000332, NM_001128164, NM_001357857

CCDS: CCDS34342, CCDS87367

Canonical transcript exons

ENST00000436367 — 8 exons

Exon	Start	End
ENSE00000848097	16326394	16328470
ENSE00001279728	16522627	16522688
ENSE00001279736	16585780	16585907
ENSE00001279744	16657776	16657901
ENSE00001279802	16299112	16306859
ENSE00001771379	16485972	16486109
ENSE00001840014	16761298	16761460
ENSE00003524794	16753233	16753347

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 97.33.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 41.3907 / max 434.1932, expressed in 1763 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
71983	40.3607	1761
71981	0.4465	213
71982	0.3821	184
71949	0.2014	88

Top tissues by expression

298 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	97.33	gold quality
Brodmann (1909) area 23	UBERON:0013554	97.11	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	95.21	gold quality
blood vessel layer	UBERON:0004797	95.13	gold quality
germinal epithelium of ovary	UBERON:0001304	94.75	gold quality
orbitofrontal cortex	UBERON:0004167	94.69	gold quality
Brodmann (1909) area 46	UBERON:0006483	94.64	gold quality
colonic epithelium	UBERON:0000397	94.54	gold quality
biceps brachii	UBERON:0001507	94.44	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	94.24	gold quality
cartilage tissue	UBERON:0002418	94.21	gold quality
visceral pleura	UBERON:0002401	94.02	gold quality
middle temporal gyrus	UBERON:0002771	94.01	gold quality
gluteal muscle	UBERON:0002000	93.98	gold quality
postcentral gyrus	UBERON:0002581	93.89	gold quality
parietal lobe	UBERON:0001872	93.83	gold quality
choroid plexus epithelium	UBERON:0003911	93.63	gold quality
buccal mucosa cell	CL:0002336	93.59	gold quality
entorhinal cortex	UBERON:0002728	93.23	gold quality
pleura	UBERON:0000977	93.11	gold quality
corpus callosum	UBERON:0002336	93.10	gold quality
superficial temporal artery	UBERON:0001614	93.09	gold quality
lateral nuclear group of thalamus	UBERON:0002736	92.96	gold quality
parietal pleura	UBERON:0002400	92.92	gold quality
superior frontal gyrus	UBERON:0002661	92.70	gold quality
medial globus pallidus	UBERON:0002477	92.68	gold quality
globus pallidus	UBERON:0001875	92.54	gold quality
occipital lobe	UBERON:0002021	92.14	gold quality
CA1 field of hippocampus	UBERON:0003881	92.13	gold quality
skin of hip	UBERON:0001554	91.85	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
CDH1	Activation

Upstream regulators (CollecTRI, top): CTBP2, MEF2A, ZBTB16

miRNA regulators (miRDB)

553 targeting ATXN1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-196A-1-3P	99.99	72.15	2772

Literature-anchored findings (GeneRIF, showing 40)

• in spinocrebellar attaxia, a trinucleotide expansion disease…a possible role of this SCA1 allele with 31 repeats in triplet diseases…a possible role of the SCA1 region in pathological trinucleotide repeat expansions. (PMID:11807410)
• Spinocerebellar ataxia type 1 (SCA1): phenotype-genotype correlation studies in intermediate alleles (PMID:11973625)
• Two types of ataxin1 inclusions exist; those undergoing rapid, complete exchange with a nucleoplasmic pool, and those that contain varying levels of slow-exchanging ataxin1. The latter inclusions contain high ubiquitin levels, but low proteasome levels. (PMID:12360291)
• phylogenetic evidence from deletions in SCA1 (PMID:12411613)
• p80 coilin protein co-localizes with ataxin-1 aggregates in the nucleoplasm (PMID:12757932)
• analysis of SCA1 AXH domain structure (PMID:14583607)
• We demonstrate that abolishing full-length mutant human ataxin-7 transgene expression did not reverse retinopathy progression in SCA7 mice, raising the possibility that some polyQ-induced pathological events might be irreversible. (PMID:14985428)
• the structural role of the CAU interruptions in the SCA1 transcripts that destabilize the CAG repeat hairpin (PMID:15292212)
• SCA1 genotypes in a Polish population are significantly different in allele spectra & frequencies from other populations. The dynamic mutation of SCA1 may begin from the expansion of long pure repeat tracts without the prior loss of interruptions. (PMID:15300851)
• Ataxin-1 localization to inclusions and inclusion dynamics within the nucleus are RNA- and transcription-dependent. (PMID:15615787)
• polyglutamine-expanded ataxin-1 decreases the activity of the proteasome, implying that a disturbance in the ubiquitin-proteasome pathway is directly involved in the development of spinocerebellar ataxia type 1 (PMID:15750336)
• A novel phosphorylation site at serine 239 was demonstarted in ataxin-1. (PMID:15878393)
• Boat is an in vivo binding partner of ataxin-1 whose altered expression in Purkinje cells may contribute to their degeneration in causes spinocerebellar ataxia type 1 animals (PMID:16121196)
• An clinicopathological phenotype linked to small elongation of CAG repeat in SCA1 gene (PMID:16311891)
• We show an evolutionary scenario for acquisition of CAG repeats with interruptions in the human SCA1 gene. (PMID:16497448)
• Sca-1(+)/CD31(-) cells may hold therapeutic possibilities with regard to the treatment of ischemic heart disease. (PMID:16614004)
• Results show that CHIP and ataxin-1 proteins directly interact and co-localize in nuclear inclusions both in cell culture and spinocerebellar ataxia type-1 postmortem neurons. (PMID:16831871)
• linkage and association for three CAG triplet repeat markers (Spinocerebellar Ataxia Type 1, SCA1; Machado-Joseph Disease, MJD; Dentatorubro-pallidoluysian Atrophy, DRPLA) to assess their contribution to variation in cognitive ability (PMID:16967484)
• These data provide insight into the function of ATXN1 and suggest that SCA1 neuropathology depends on native, not novel, protein interactions. (PMID:17190598)
• aggregates of mutant ataxin-l may recruit calbindin-D28k via tissue transglutaminase 2 mediated covalent crosslinking (PMID:17442486)
• LANP and ATAXN1 interact in E4F-mediated transcriptional repression. (PMID:17557114)
• analysis of how ataxin-1 fusion partners alter polyQ lethality and aggregation (PMID:17925862)
• Data show that SCA1, 2 and 3 accounted for more than one third of the ataxia cases seen in the clinic, and in cases with established family history and autosomal dominant inheritance SCA1 was most prevalent followed by SCA2 and SCA3. (PMID:18160752)
• One common pathogenic response in transgenic SCA1 and SCA7 mice reveals the importance of intercellular mechanisms in the pathogenesis of spinocerebellar ataxias. (PMID:18216249)
• During mitosis, ataxin-1 accumulations redistributed equally among daughter cells, in contrast to polyQ aggregates. Interestingly, polyQ expansion did not affect the nuclear-cytoplasmic shuttling of ataxin-1 as proposed before (PMID:18231590)
• the expanded polyglutamine tract of ATXN1 differentially affects the function of the host protein in the context of different endogenous protein complexes (PMID:18337722)
• UbcH6 and ataxin-1 are E2-substrate cognate pairs in the ubiquitin-proteasome system. (PMID:18439907)
• UbcH6 modulates the transcriptional repression activity of ataxin-1 by modulating the degradation of ataxin-1. (PMID:18519031)
• rate of clinical disease progression at presentation is dependent on the CAG repeat size, and may commence linearly from birth (PMID:19049837)
• A phospho-resistant alanine at residue 776 of ATXN1, replacing a serine, destabilizes the protein in Purkinje cells; protein kinase A is a strong candidate for the ATXN1-serine776 kinase active in the transgenic mouse cerebellum. (PMID:19500214)
• SCA1 in a subset of oligozoospermia patients has an increased number of CAG repeats (PMID:19597981)
• p62 contributed to the assembly of proteasome-containing degradative compartments in the vicinity of nuclear aggregates containing polyglutamine-expanded Ataxin1Q84 and to the degradation of Ataxin1Q84. (PMID:20018885)
• ATXN1 functions as a genetic risk modifier that contributes to AD pathogenesis through a loss-of-function mechanism by regulating beta-secretase cleavage of APP and Abeta levels (PMID:20097758)
• Together these results indicate that SUMO modification of ataxin-1 promotes the aggregation of ataxin-1 and that oxidative stress and JNK pathway play roles in this process. (PMID:20132795)
• The neurochemical alterations detected in SCA1[82Q] transgenic mice are primarily due to expansion of the polyglutamine repeat in ataxin-1, rather than the overexpression of the human protein. (PMID:20220018)
• Phosphorylation of transgenic ataxin-1 at the serine-776 motif is critical for ataxin-1 mediated toxicity. (PMID:20477910)
• The ATXN1 gene is related to intelligence in an ADHD background. (PMID:21302343)
• This study demonstrates that ataxin-1 occupies the promoter region of E-cadherin in vivo and that ataxin-1 activates the promoter in a CtBP2-mediated transcriptional regulation manner. (PMID:21315774)
• Both ATXN1 and BOAT1 bind to the promoter region of Hey1 and inhibit the transcriptional output of Notch through direct interactions with CBF1, a transcription factor that is crucial for the Notch pathway. (PMID:21475249)
• dephosphorylation of pS776-ATXN1 by PP2A regulates the interaction of ATXN1 with the splicing factors RBM17 and U2AF65 (PMID:21835928)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	atxn1b	ENSDARG00000060862
danio_rerio	atxn1a	ENSDARG00000061687
mus_musculus	Atxn1	ENSMUSG00000046876
rattus_norvegicus	Atxn1	ENSRNOG00000016998
drosophila_melanogaster	Atx-1	FBGN0029907
caenorhabditis_elegans	K04F10.1	WBGENE00019394

Paralogs (1): ATXN1L (ENSG00000224470)

Protein

Protein identifiers

Ataxin-1 — P54253 (reviewed: P54253)

Alternative names: Spinocerebellar ataxia type 1 protein

All UniProt accessions (2): A0A2R8YCF3, P54253

UniProt curated annotations — full annotation on UniProt →

Function. Chromatin-binding factor that repress Notch signaling in the absence of Notch intracellular domain by acting as a CBF1 corepressor. Binds to the HEY promoter and might assist, along with NCOR2, RBPJ-mediated repression. Binds RNA in vitro. May be involved in RNA metabolism. In concert with CIC and ATXN1L, involved in brain development.

Subunit / interactions. Homooligomer. Interacts with CIC. Interacts with ANP32A, PQBP1, UBQLN4, ATXN1L and USP7. Directly interacts with RBPJ; this interaction is disrupted in the presence of Notch intracellular domain. Competes with ATXN1L for RBPJ-binding. Found in a complex with CIC and ATXN1L.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Widely expressed throughout the body.

Post-translational modifications. Ubiquitinated by UBE3A, leading to its degradation by the proteasome. The presence of expanded poly-Gln repeats in spinocerebellar ataxia 1 (SCA1) patients impairs ubiquitination and degradation, leading to accumulation of ATXN1 in neurons and subsequent toxicity. Phosphorylation at Ser-775 increases the pathogenicity of proteins with an expanded polyglutamine tract. Sumoylation is dependent on nuclear localization and phosphorylation at Ser-775. It is reduced in the presence of an expanded polyglutamine tract.

Disease relevance. Spinocerebellar ataxia 1 (SCA1) [MIM:164400] Spinocerebellar ataxia is a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to cerebellum degeneration with variable involvement of the brainstem and spinal cord. SCA1 belongs to the autosomal dominant cerebellar ataxias type I (ADCA I) which are characterized by cerebellar ataxia in combination with additional clinical features like optic atrophy, ophthalmoplegia, bulbar and extrapyramidal signs, peripheral neuropathy and dementia. SCA1 is caused by expansion of a CAG repeat in the coding region of ATXN1. Longer expansions result in earlier onset and more severe clinical manifestations of the disease. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by expansion of the polyglutamine tract to about 40-83 repeats, causing accumulation in neurons and exerting toxicity.

Domain organisation. The AXH domain is required for interaction with CIC.

Induction. ATXN1 protein levels are directly regulated by PUM1 protein: PUM1 acts by binding to the 3’-UTR of ATXN1 mRNA, affecting ATXN1 mRNA stability and leading to reduced ATXN1 protein levels.

Polymorphism. The poly-Gln region of ATXN1 is highly polymorphic (4 to 39 repeats) in the normal population and is expanded to about 40-83 repeats in spinocerebellar ataxia 1 (SCA1) patients.

Miscellaneous. Self-association seems to be necessary for formation of nuclear aggregates which are associated with pathogenesis.

Similarity. Belongs to the ATXN1 family.

Isoforms (1)

UniProt ID	Names	Canonical?
P54253-1	1	yes

RefSeq proteins (3): NP_000323, NP_001121636, NP_001344786 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003652	Ataxin_AXH_dom	Domain
IPR020997	Ataxin-1_N	Domain
IPR036096	Ataxin_AXH_dom_sf	Homologous_superfamily
IPR043404	ATAXIN1-like	Family

Pfam: PF08517, PF12547

UniProt features (56 total): mutagenesis site 12, strand 10, region of interest 8, modified residue 5, cross-link 5, compositionally biased region 4, helix 4, sequence variant 2, turn 2, chain 1, domain 1, short sequence motif 1, sequence conflict 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
1OA8	X-RAY DIFFRACTION	1.7
6QIU	X-RAY DIFFRACTION	1.8
4AQP	X-RAY DIFFRACTION	2.45
4APT	X-RAY DIFFRACTION	2.5
4J2J	X-RAY DIFFRACTION	2.5
4J2L	X-RAY DIFFRACTION	3.15
2M41	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P54253-F1	51.44	0.15

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (10): 82, 88, 238, 253, 775, 16, 194, 609, 696, 745

Mutagenesis-validated functional residues (12):

Position	Phenotype
16	sumoylation reduced to 40% of wild-type.
194	sumoylation reduced to 46% of wild-type.
420	no effect on sumoylation.
529	sumoylation reduced to 57% of wild-type.
589	sumoylation reduced to 53% of wild-type.
594	sumoylation reduced to 68% of wild-type.
609	sumoylation reduced to 43% of wild-type.
691	no effect on sumoylation.
696	sumoylation reduced to 42% of wild-type.
745	sumoylation reduced to 44% of wild-type.
775	reduces phosphorylation but does not affect nuclear localization.
784	sumoylation reduced to 62% of wild-type.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 684 (showing top): GOBP_MEMORY, GCACCTT_MIR18A_MIR18B, TGGTGCT_MIR29A_MIR29B_MIR29C, FREAC2_01, GOBP_COGNITION, GGTGTGT_MIR329, GOBP_BEHAVIOR, LU_IL4_SIGNALING, TTTGTAG_MIR520D, GOBP_ADULT_BEHAVIOR, GOBP_ASSOCIATIVE_LEARNING, AREB6_03, TATTATA_MIR374, LINDGREN_BLADDER_CANCER_CLUSTER_3_DN, GTTAAAG_MIR302B

GO Biological Process (18): negative regulation of transcription by RNA polymerase II (GO:0000122), transcription by RNA polymerase II (GO:0006366), RNA processing (GO:0006396), brain development (GO:0007420), learning (GO:0007612), memory (GO:0007613), adult locomotory behavior (GO:0008344), visual learning (GO:0008542), social behavior (GO:0035176), negative regulation of insulin-like growth factor receptor signaling pathway (GO:0043569), negative regulation of DNA-templated transcription (GO:0045892), positive regulation of transcription by RNA polymerase II (GO:0045944), insulin-like growth factor receptor signaling pathway (GO:0048009), lung alveolus development (GO:0048286), nuclear export (GO:0051168), excitatory postsynaptic potential (GO:0060079), positive regulation of glial cell proliferation (GO:0060252), regulation of DNA-templated transcription (GO:0006355)

GO Molecular Function (8): DNA binding (GO:0003677), chromatin binding (GO:0003682), RNA binding (GO:0003723), poly(U) RNA binding (GO:0008266), POZ domain binding (GO:0031208), poly(G) binding (GO:0034046), identical protein binding (GO:0042802), protein binding (GO:0005515)

GO Cellular Component (9): nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), cytoplasm (GO:0005737), cytosol (GO:0005829), nuclear matrix (GO:0016363), protein-containing complex (GO:0032991), nuclear inclusion body (GO:0042405), postsynapse (GO:0098794)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
DNA-templated transcription	3
nuclear lumen	3
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
learning or memory	2
nucleic acid binding	2
binding	2
negative regulation of DNA-templated transcription	1
gene expression	1
RNA biosynthetic process	1
primary metabolic process	1
central nervous system development	1
animal organ development	1
head development	1
locomotory behavior	1
adult behavior	1
visual behavior	1
associative learning	1
behavior	1
biological process involved in intraspecies interaction between organisms	1
negative regulation of signal transduction	1
regulation of insulin-like growth factor receptor signaling pathway	1
insulin-like growth factor receptor signaling pathway	1
regulation of DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
positive regulation of DNA-templated transcription	1
cell surface receptor protein tyrosine kinase signaling pathway	1
lung development	1
anatomical structure development	1
nucleocytoplasmic transport	1
intercellular transport	1
regulation of postsynaptic membrane potential	1
chemical synaptic transmission, postsynaptic	1
positive regulation of cell population proliferation	1
glial cell proliferation	1
positive regulation of gliogenesis	1
regulation of glial cell proliferation	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1

Protein interactions and networks

STRING

1634 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ATXN1	UBQLN4	Q9NRR5	989
ATXN1	RBM17	Q96I25	966
ATXN1	NCOR2	Q9Y618	962
ATXN1	ATXN2	Q99700	955
ATXN1	PQBP1	O60828	925
ATXN1	ATXN3	P54252	908
ATXN1	ATXN7	O15265	898
ATXN1	HTT	P42858	894
ATXN1	ATN1	P54259	859
ATXN1	GFI1	Q99684	846
ATXN1	RBFOX2	O43251	843
ATXN1	CIC	Q96RK0	813
ATXN1	CACNA1A	P78510	801
ATXN1	COIL	P38432	796
ATXN1	RORA	P35397	777

IntAct

2234 interactions, top by confidence:

A	B	Type	Score
ATXN1	ATXN1	psi-mi:“MI:0915”(physical association)	0.900
ATXN1	ATXN1	psi-mi:“MI:0407”(direct interaction)	0.900
ATXN1	TRAF2	psi-mi:“MI:0915”(physical association)	0.860
ATXN1	C1orf94	psi-mi:“MI:0915”(physical association)	0.860
ATXN1	TENT5B	psi-mi:“MI:0915”(physical association)	0.830
CIC	ATXN1	psi-mi:“MI:0915”(physical association)	0.820
ATXN1	CIC	psi-mi:“MI:0915”(physical association)	0.820
ESRP1	ATXN1	psi-mi:“MI:0915”(physical association)	0.810
ATXN1	ESRP1	psi-mi:“MI:0915”(physical association)	0.810
RBFOX2	ATXN1	psi-mi:“MI:0915”(physical association)	0.790
ATXN1	RBFOX2	psi-mi:“MI:0915”(physical association)	0.790
ATXN1	ZNF488	psi-mi:“MI:0915”(physical association)	0.780
ATXN1	PLEKHN1	psi-mi:“MI:0915”(physical association)	0.720
ATXN1	USP54	psi-mi:“MI:0915”(physical association)	0.720
ATXN1	RBPMS	psi-mi:“MI:0915”(physical association)	0.720
IST1	ATXN1	psi-mi:“MI:0915”(physical association)	0.720
ATXN1	LASP1	psi-mi:“MI:0915”(physical association)	0.720
ATXN1	METTL27	psi-mi:“MI:0915”(physical association)	0.720

BioGRID (597): SUMO1 (Two-hybrid), ATXN1 (Two-hybrid), ATXN1 (Two-hybrid), TBX15 (Two-hybrid), TRAF2 (Two-hybrid), RBPMS (Two-hybrid), RBFOX2 (Two-hybrid), ESRP1 (Two-hybrid), C1orf94 (Two-hybrid), PRR20A (Two-hybrid), ATXN1 (Affinity Capture-Western), COIL (Two-hybrid), CIC (Affinity Capture-MS), ATXN1 (Affinity Capture-MS), UBQLN4 (Two-hybrid)

ESM2 similar proteins: A0JME2, A5D7F6, F8VPZ9, O88873, O89090, P08047, P31367, P52591, P54253, P58929, P70178, P78364, Q01714, Q02086, Q07916, Q08E26, Q13227, Q14863, Q2VPU4, Q3U182, Q5E9U0, Q64028, Q66JY2, Q6AI39, Q6T264, Q7Z3K3, Q8BLM0, Q8BZH4, Q8CHH5, Q8CHP6, Q8IXK0, Q8IZL2, Q8K3Z9, Q8K4J6, Q8N196, Q8N1G0, Q8NDX5, Q8QHL5, Q8VHG2, Q91VX2

Diamond homologs: P0C7T5, P0C7T6, P54253, P54254, Q2KJ34, Q63540

SIGNOR signaling

7 interactions.

A	Effect	B	Mechanism
AKT	“up-regulates quantity by stabilization”	ATXN1	phosphorylation
AKT1	“up-regulates quantity by stabilization”	ATXN1	phosphorylation
ATXN1	“up-regulates quantity by expression”	CDH1	“transcriptional regulation”
DZIP3	“down-regulates quantity by destabilization”	ATXN1	polyubiquitination
STUB1	“down-regulates quantity by destabilization”	ATXN1	ubiquitination
MDM2	“down-regulates quantity by destabilization”	ATXN1	ubiquitination
RPS6KA5	“up-regulates quantity by stabilization”	ATXN1	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

206 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	1
Uncertain significance	126
Likely benign	40
Benign	17

Top pathogenic / likely-pathogenic (6)

Variant ID	HGVS	Classification
1809386	GRCh37/hg19 6p24.1-22.3(chr6:12005630-22849647)x1	Pathogenic
3062894	GRCh37/hg19 6p24.1-22.3(chr6:12872219-17276508)x1	Pathogenic
442457	GRCh37/hg19 6p23-22.3(chr6:13693852-24225515)x1	Pathogenic
688193	GRCh37/hg19 6p23-22.3(chr6:13910125-22000204)x1	Pathogenic
8071	NM_000332.4(ATXN1):c.589CAG[36_38] (p.Gln208[36_38])	Pathogenic
1527225	GRCh37/hg19 6p22.3(chr6:16348584-16559316)	Likely pathogenic

SpliceAI

4835 predictions. Top by Δscore:

Variant	Effect	Δscore
6:16306368:AACCT:A	donor_gain	1.0000
6:16306372:T:TA	donor_gain	1.0000
6:16389491:T:TA	donor_gain	1.0000
6:16485970:A:AC	donor_gain	1.0000
6:16485971:C:CC	donor_gain	1.0000
6:16485971:CAA:C	donor_gain	1.0000
6:16485986:A:AC	donor_gain	1.0000
6:16485987:C:CC	donor_gain	1.0000
6:16488913:T:TA	donor_gain	1.0000
6:16488914:C:A	donor_gain	1.0000
6:16522622:CTCA:C	donor_loss	1.0000
6:16522623:TCA:T	donor_loss	1.0000
6:16522624:CAC:C	donor_loss	1.0000
6:16522625:A:AT	donor_loss	1.0000
6:16522625:AC:A	donor_gain	1.0000
6:16522626:CC:C	donor_gain	1.0000
6:16522689:C:CC	acceptor_gain	1.0000
6:16657897:GTATG:G	acceptor_gain	1.0000
6:16657898:TATG:T	acceptor_gain	1.0000
6:16657899:ATG:A	acceptor_gain	1.0000
6:16657900:TG:T	acceptor_gain	1.0000
6:16657902:C:CC	acceptor_gain	1.0000
6:16657902:CT:C	acceptor_loss	1.0000
6:16657903:T:A	acceptor_loss	1.0000
6:16742271:T:TA	donor_gain	1.0000
6:16747551:CAG:C	donor_gain	1.0000
6:16753251:C:A	donor_gain	1.0000
6:16753382:C:CT	acceptor_gain	1.0000
6:16753382:C:T	acceptor_gain	1.0000
6:16306367:TA:T	donor_gain	0.9900

AlphaMissense

5281 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:16306455:C:A	W774C	1.000
6:16306455:C:G	W774C	1.000
6:16306456:C:G	W774S	1.000
6:16306457:A:G	W774R	1.000
6:16306457:A:T	W774R	1.000
6:16306458:C:A	R773S	1.000
6:16306458:C:G	R773S	1.000
6:16306459:C:A	R773M	1.000
6:16306459:C:G	R773T	1.000
6:16306461:C:A	R772S	1.000
6:16306461:C:G	R772S	1.000
6:16306462:C:A	R772M	1.000
6:16306462:C:G	R772T	1.000
6:16306723:A:G	L685P	1.000
6:16306723:A:T	L685H	1.000
6:16306729:A:C	I683S	1.000
6:16306729:A:T	I683N	1.000
6:16306731:G:C	C682W	1.000
6:16306732:C:T	C682Y	1.000
6:16306733:A:G	C682R	1.000
6:16306741:C:A	G679V	1.000
6:16306750:A:G	L676P	1.000
6:16306750:A:T	L676H	1.000
6:16306765:A:G	L671S	1.000
6:16306801:G:A	S659F	1.000
6:16306805:A:G	S658P	1.000
6:16306806:C:A	W657C	1.000
6:16306806:C:G	W657C	1.000
6:16306807:C:G	W657S	1.000
6:16306808:A:G	W657R	1.000

dbSNP variants (sampled 300 via entrez): RS1000000070 (6:16299798 G>C), RS1000003533 (6:16602433 A>C), RS1000013863 (6:16351408 T>TA,TG), RS1000022928 (6:16425666 T>G), RS1000030062 (6:16479739 A>G), RS1000040935 (6:16635491 C>T), RS1000056454 (6:16595231 G>A,T), RS1000060303 (6:16463141 AC>A), RS1000062005 (6:16565004 T>G), RS1000063269 (6:16340811 G>C), RS1000068820 (6:16509220 C>T), RS1000072875 (6:16549683 A>G), RS1000075981 (6:16529860 G>A), RS1000079895 (6:16604177 G>T), RS1000083404 (6:16463227 C>A)

Disease associations

OMIM: gene MIM:601556 | disease phenotypes: MIM:164400, MIM:181500

GenCC curated gene-disease

Disease	Classification	Inheritance
spinocerebellar ataxia type 1	Strong	Autosomal dominant

Mondo (2): spinocerebellar ataxia type 1 (MONDO:0008119), schizophrenia (MONDO:0005090)

Orphanet (2): Spinocerebellar ataxia type 1 (Orphanet:98755), NON RARE IN EUROPE: Schizophrenia (Orphanet:3140)

HPO phenotypes

76 total (30 of 76 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000496	Abnormality of eye movement
HP:0000514	Slow saccadic eye movements
HP:0000543	Optic disc pallor
HP:0000597	Ophthalmoparesis
HP:0000623	Supranuclear ophthalmoplegia
HP:0000639	Nystagmus
HP:0000640	Gaze-evoked nystagmus
HP:0000641	Dysmetric saccades
HP:0000648	Optic atrophy
HP:0001151	Impaired horizontal smooth pursuit
HP:0001252	Hypotonia
HP:0001257	Spasticity
HP:0001260	Dysarthria
HP:0001265	Hyporeflexia
HP:0001272	Cerebellar atrophy
HP:0001283	Bulbar palsy
HP:0001284	Areflexia
HP:0001288	Gait disturbance
HP:0001290	Generalized hypotonia
HP:0001310	Dysmetria
HP:0001324	Muscle weakness
HP:0001332	Dystonia
HP:0001347	Hyperreflexia
HP:0001350	Slurred speech
HP:0002015	Dysphagia
HP:0002067	Bradykinesia
HP:0002070	Limb ataxia
HP:0002071	Abnormality of extrapyramidal motor function
HP:0002072	Chorea

GWAS associations

48 associations (top):

Study	Trait	p-value
GCST000406_7	Amyotrophic lateral sclerosis	4.000000e-06
GCST001601_4	Gambling	5.000000e-06
GCST001850_8	Major depressive disorder	1.000000e-06
GCST003622_16	Systemic lupus erythematosus	3.000000e-12
GCST003622_62	Systemic lupus erythematosus	3.000000e-08
GCST004610_8	White blood cell count	4.000000e-11
GCST004611_87	High light scatter reticulocyte count	2.000000e-11
GCST004612_7	High light scatter reticulocyte percentage of red cells	3.000000e-12
GCST004613_150	Sum neutrophil eosinophil counts	6.000000e-13
GCST004614_87	Granulocyte count	8.000000e-13
GCST004619_62	Reticulocyte fraction of red cells	7.000000e-14
GCST004620_65	Sum basophil neutrophil counts	3.000000e-13
GCST004622_204	Reticulocyte count	4.000000e-12
GCST004626_88	Myeloid white cell count	4.000000e-13
GCST004629_75	Neutrophil count	2.000000e-13
GCST004988_674	Breast cancer	2.000000e-08
GCST005175_44	Coronary artery calcified atherosclerotic plaque (90 or 130 HU threshold) in type 2 diabetes	1.000000e-07
GCST005752_14	Systemic lupus erythematosus	1.000000e-07
GCST005973_29	White blood cell count	2.000000e-09
GCST005974_15	Neutrophil count	6.000000e-09
GCST006061_180	Atrial fibrillation	9.000000e-21
GCST006061_59	Atrial fibrillation	6.000000e-21
GCST006135_12	Cortical amyloid beta load	1.000000e-06
GCST006269_680	General cognitive ability	8.000000e-10
GCST006414_93	Atrial fibrillation	2.000000e-25
GCST006443_5	Total body bone mineral density	5.000000e-06
GCST006547_1	Visceral adipose tissue attenuation (Hounslow unit scale)	8.000000e-06
GCST006549_1	Subcutaneous adipose tissue attenuation (Hounsfield unit scale)	1.000000e-08
GCST006549_2	Subcutaneous adipose tissue attenuation (Hounsfield unit scale)	1.000000e-07
GCST007353_8	Generalized epilepsy	2.000000e-09

EFO canonical traits (22, from GWAS)

EFO ID	Trait name
EFO:0004699	gambling behaviour
EFO:0007986	reticulocyte count
EFO:0004833	neutrophil count
EFO:0004842	eosinophil count
EFO:0007987	granulocyte count
EFO:0005090	basophil count
EFO:0004723	coronary artery calcification
EFO:0007707	cerebral amyloid deposition measurement
EFO:0004337	intelligence
EFO:0004784	self reported educational attainment
EFO:0010549	xanthosine measurement
EFO:0010403	triacylglycerol 48:0 measurement
EFO:0009695	household income
EFO:0008111	diet measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0007874	gut microbiome measurement
EFO:0005213	central corneal thickness
EFO:0007993	lymphocyte percentage of leukocytes
EFO:0005091	monocyte count
EFO:0007989	monocyte percentage of leukocytes
EFO:0007990	neutrophil percentage of leukocytes
EFO:0007789	BMI-adjusted waist circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

82 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression, affects methylation	6
Valproic Acid	affects expression, affects cotreatment, increases expression	5
Aflatoxin B1	decreases methylation, affects expression, affects methylation, decreases expression	5
Estradiol	decreases expression, decreases reaction, affects cotreatment, increases expression	4
Tetrachlorodibenzodioxin	affects cotreatment, increases expression	4
sodium arsenite	increases expression, decreases expression, affects cotreatment, increases abundance	3
Arsenic	affects methylation, affects cotreatment, decreases expression, increases abundance, affects expression	3
Cisplatin	affects cotreatment, decreases expression	3
Cadmium Chloride	increases abundance, increases expression	3
bisphenol A	affects cotreatment, affects methylation, increases expression, increases methylation	2
Zoledronic Acid	increases expression	2
Ethyl Methanesulfonate	decreases expression	2
Hydrogen Peroxide	affects localization, decreases reaction, increases reaction, increases expression	2
Methyl Methanesulfonate	decreases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tretinoin	increases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
Cyclosporine	increases expression	2
tert-Butylhydroperoxide	affects localization, decreases reaction, increases reaction, decreases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	increases expression	1
FR900359	increases phosphorylation	1
napabucasin	decreases expression	1
chloroacetaldehyde	decreases expression	1
methylmercuric chloride	decreases expression	1
methyleugenol	decreases expression	1
terbufos	increases methylation	1
trichostatin A	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
butyraldehyde	decreases expression	1

Cellosaurus cell lines

10 cell lines: 6 induced pluripotent stem cell, 3 transformed cell line, 1 finite cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_C6TW	CJUHi001-A	Induced pluripotent stem cell	Female
CVCL_E6MA	UNIFEi001-A	Induced pluripotent stem cell	Male
CVCL_IN31	GM13536	Transformed cell line	Female
CVCL_IN32	GM13537	Transformed cell line	Male
CVCL_T903	GM06926	Transformed cell line	Male
CVCL_T904	GM06927	Finite cell line	Male
CVCL_VE42	LUMCi002-A	Induced pluripotent stem cell	Male
CVCL_VE43	LUMCi002-B	Induced pluripotent stem cell	Male
CVCL_VE44	LUMCi002-C	Induced pluripotent stem cell	Male
CVCL_ZA46	CSUXHi002-A	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00000374	PHASE4	COMPLETED	Treatment for First-Episode Schizophrenia
NCT00001656	PHASE4	COMPLETED	Comparison of Clozapine vs Olanzapine in Childhood-Onset Psychotic Disorders
NCT00007774	PHASE4	COMPLETED	To Determine if Olanzapine is More Cost Effective Than Haloperidol for the Treatment of Schizophrenia
NCT00014001	PHASE4	COMPLETED	CATIE- Schizophrenia Trial
NCT00018668	PHASE4	COMPLETED	Antipsychotic Response in Schizophrenia
NCT00034801	PHASE4	COMPLETED	Olanzapine Versus Active Comparator in the Treatment of Depression in Patients With Schizophrenia
NCT00034905	PHASE4	COMPLETED	A Comparison of Seroquel vs. Risperidone in Schizophrenia
NCT00036088	PHASE4	COMPLETED	Olanzapine Versus An Active Comparator in the Treatment of Schizophrenia
NCT00044187	PHASE4	COMPLETED	The Assessment of a Weight-Gain Agent for the Treatment of Olanzapine-Associated Anti-Obesity Agent in Patients With Schizophrenia, Schizophreniform Disorder, Schizoaffective Disorder, and Bipolar I Disorder
NCT00044655	PHASE4	COMPLETED	Switching Medication to Treat Schizophrenia
NCT00048828	PHASE4	COMPLETED	Treating Drug-Resistant Childhood Schizophrenia
NCT00053703	PHASE4	COMPLETED	Treatment of Early Onset Schizophrenia Spectrum Disorders (TEOSS)
NCT00056498	PHASE4	COMPLETED	Risperidone Treatment in Schizophrenia Patients Who Are Currently Taking Clozapine
NCT00061802	PHASE4	COMPLETED	Efficacy and Safety of Two Atypical Antipsychotics vs. Placebo in Patients With an Acute Exacerbation of Either Schizophrenia or Schizoaffective Disorder
NCT00080327	PHASE4	COMPLETED	Study of Three Doses of Aripiprazole in Patients With Acute Schizophrenia
NCT00088049	PHASE4	COMPLETED	Study of Olanzapine vs. Aripiprazole in the Treatment of Schizophrenia
NCT00090012	PHASE4	COMPLETED	Comparison of Continuing Olanzapine to Switching to Quetiapine in Overweight or Obese Patients With Schizophrenia and Schizoaffective Disorder
NCT00100776	PHASE4	COMPLETED	Efficacy of High Dose Olanzapine for the Treatment of Schizophrenia and Schizoaffective Disorder
NCT00103571	PHASE4	COMPLETED	Olanzapine Versus Aripiprazole in the Treatment of Acutely Ill Patients With Schizophrenia
NCT00108368	PHASE4	COMPLETED	The Effects of Risperidone and Olanzapine on Thinking
NCT00114595	PHASE4	COMPLETED	Ethyl-Eicosapentaenoic Acid and Tardive Dyskinesia
NCT00130923	PHASE4	COMPLETED	Risperidone Long-acting Versus Oral Risperidone in Patients With Schizophrenia and Alcohol Use Disorder
NCT00137020	PHASE4	COMPLETED	Clinical Effect Of Cross Titration Of Antipsychotics With Ziprasidone In Schizophrenia Or Schizoaffective Disorder
NCT00140166	PHASE4	COMPLETED	Treatment of Acute Schizophrenia With Vitamin Therapy
NCT00145847	PHASE4	COMPLETED	Naltrexone Treatment of Alcohol Abuse in Schizophrenia
NCT00148564	PHASE4	COMPLETED	Energy Homeostasis Under Treatment With Atypical Antipsychotics
NCT00156715	PHASE4	COMPLETED	Efficacy of Quetiapine in the Treatment of Patients With Schizophrenia and a Comorbid Substance Use Disorder
NCT00158223	PHASE4	COMPLETED	Effectiveness of Pimozide in Augmenting the Effects of Clozapine in the Treatment of Schizophrenia
NCT00159081	PHASE4	COMPLETED	One Year Drug Treatment in First-Episode Schizophrenia
NCT00159120	PHASE4	COMPLETED	Maintenance Treatment vs. Stepwise Drug Discontinuation in First-Episode Schizophrenia
NCT00159133	PHASE4	COMPLETED	Prodrome-Based Early Intervention With Antipsychotics vs. Benzodiazepines in First-Episode Schizophrenia
NCT00159757	PHASE4	TERMINATED	12 Week Open, Non-Comparative Switch Study Of Oral Ziprazidone In Previously Treated Schizophrenic Patients
NCT00167817	PHASE4	COMPLETED	Effect of Switch to Aripiprazole on Health and Smoking Parameters in Patients With Schizophrenia: A Pilot Study
NCT00169026	PHASE4	TERMINATED	Alcoholism and Schizophrenia: Effects of Clozapine
NCT00169039	PHASE4	TERMINATED	Clozapine Versus Chlorpromazine for Treatment-Unresponsive Schizophrenia
NCT00169065	PHASE4	COMPLETED	Effectiveness of Clozapine Versus Olanzapine for Treatment-resistant Schizophrenia
NCT00169091	PHASE4	TERMINATED	Clozapine Versus Haloperidol for Treating the First Episode of Schizophrenia
NCT00176423	PHASE4	COMPLETED	Efficacy Study of Galantamine for Cognitive Impairments in Schizophrenia
NCT00176436	PHASE4	COMPLETED	Atomoxetine for Treatment of Weight Gain in Olanzapine or Clozapine Patients
NCT00177008	PHASE4	COMPLETED	Aripiprazole for the Treatment of Schizophrenia With Co-Morbid Social Anxiety