ATN1

Summary

ATN1 (atrophin 1, HGNC:3033) is a protein-coding gene on chromosome 12p13.31, encoding Atrophin-1 (P54259). Transcriptional corepressor.

Dentatorubral pallidoluysian atrophy (DRPLA) is a rare neurodegenerative disorder characterized by cerebellar ataxia, myoclonic epilepsy, choreoathetosis, and dementia. The disorder is related to the expansion from 7-35 copies to 49-93 copies of a trinucleotide repeat (CAG/CAA) within this gene. The encoded protein includes a serine repeat and a region of alternating acidic and basic amino acids, as well as the variable glutamine repeat. Alternative splicing results in two transcripts variants that encode the same protein.

Source: NCBI Gene 1822 — RefSeq curated summary.

At a glance

• Gene–disease (curated): dentatorubral-pallidoluysian atrophy (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 1
• Clinical variants (ClinVar): 378 total — 6 pathogenic, 4 likely-pathogenic
• Phenotypes (HPO): 95
• Druggable target: yes
• MANE Select transcript: NM_001940

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3033
Approved symbol	ATN1
Name	atrophin 1
Location	12p13.31
Locus type	gene with protein product
Status	Approved
Aliases	B37
Ensembl gene	ENSG00000111676
Ensembl biotype	protein_coding
OMIM	607462
Entrez	1822

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 12 protein_coding, 2 retained_intron

ENST00000356654, ENST00000396684, ENST00000537488, ENST00000541029, ENST00000882240, ENST00000882241, ENST00000882242, ENST00000882243, ENST00000882244, ENST00000882245, ENST00000932523, ENST00000932524, ENST00000932525, ENST00000932526

RefSeq mRNA: 7 — MANE Select: NM_001940 NM_001007026, NM_001424176, NM_001424177, NM_001424178, NM_001424179, NM_001424180, NM_001940

CCDS: CCDS31734

Canonical transcript exons

ENST00000396684 — 10 exons

Exon	Start	End
ENSE00000716190	6937845	6938067
ENSE00000716191	6938481	6939177
ENSE00000866983	6934176	6934313
ENSE00000866984	6934465	6934578
ENSE00000866985	6935547	6937561
ENSE00000866988	6941374	6941554
ENSE00001405953	6933840	6934028
ENSE00001525920	6927959	6928384
ENSE00002321959	6941747	6942321
ENSE00003662585	6940880	6941023

Expression profiles

Bgee: expression breadth ubiquitous, 223 present calls, max score 99.14.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 49.2450 / max 523.9112, expressed in 1811 samples.

FANTOM5 promoters (20 alternative TSS)

Promoter ID	TPM avg	Samples expressed
123818	19.6270	1726
123814	12.0223	1722
123813	2.7762	1327
123812	1.9613	1043
123819	1.7967	1058
123825	1.6589	987
123810	1.5843	771
123821	1.4604	913
123822	1.2399	744
123820	1.0831	668

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right hemisphere of cerebellum	UBERON:0014890	99.14	gold quality
adenohypophysis	UBERON:0002196	99.00	gold quality
right uterine tube	UBERON:0001302	98.94	gold quality
left ovary	UBERON:0002119	98.94	gold quality
right ovary	UBERON:0002118	98.93	gold quality
right lobe of thyroid gland	UBERON:0001119	98.82	gold quality
left lobe of thyroid gland	UBERON:0001120	98.80	gold quality
cerebellar hemisphere	UBERON:0002245	98.80	gold quality
cerebellar cortex	UBERON:0002129	98.66	gold quality
body of uterus	UBERON:0009853	98.62	gold quality
mucosa of stomach	UBERON:0001199	98.61	gold quality
endocervix	UBERON:0000458	98.54	gold quality
muscle layer of sigmoid colon	UBERON:0035805	98.36	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	98.36	gold quality
lower esophagus muscularis layer	UBERON:0035833	98.35	gold quality
right frontal lobe	UBERON:0002810	98.34	gold quality
lower esophagus	UBERON:0013473	98.34	gold quality
right adrenal gland	UBERON:0001233	98.31	gold quality
left adrenal gland cortex	UBERON:0035825	98.31	gold quality
left uterine tube	UBERON:0001303	98.28	gold quality
left adrenal gland	UBERON:0001234	98.26	gold quality
right adrenal gland cortex	UBERON:0035827	98.25	gold quality
metanephros cortex	UBERON:0010533	98.00	gold quality
cortical plate	UBERON:0005343	97.95	gold quality
right coronary artery	UBERON:0001625	97.88	gold quality
ventricular zone	UBERON:0003053	97.87	gold quality
popliteal artery	UBERON:0002250	97.83	gold quality
tibial artery	UBERON:0007610	97.83	gold quality
tibial nerve	UBERON:0001323	97.82	gold quality
ascending aorta	UBERON:0001496	97.73	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-GEOD-84465	yes	22.18
E-ANND-3	yes	12.87
E-GEOD-124858	no	6.28

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CTCF

miRNA regulators (miRDB)

49 targeting ATN1, 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-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-3605-5P	99.96	67.12	932
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-944	99.82	70.85	3042
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-6752-5P	99.59	67.32	1243
HSA-MIR-4472	99.56	66.08	1478
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-4688	99.48	64.68	828
HSA-MIR-6743-5P	99.48	63.60	721
HSA-MIR-6083	99.47	68.73	2393
HSA-MIR-6722-3P	99.45	67.62	1919
HSA-MIR-5683	99.36	68.59	2083
HSA-MIR-410-3P	99.27	69.98	2457
HSA-MIR-4667-3P	99.26	65.45	1608
HSA-MIR-6852-5P	99.17	66.69	2073

Literature-anchored findings (GeneRIF, showing 28)

• Nuclear localization of a non-caspase truncation product of this protein, with an expanded polyglutamine repeat, increases cellular toxicity. (PMID:12464607)
• DRPLA protein is a phosphoprotein, and c-Jun NH(2)-terminal kinase (JNK) is one of the major factors involved in its phosphorylation (PMID:12812981)
• The molecular architecture of CAG repeats in mutant DRPLA was studied. (PMID:15223312)
• In DRPLA, the expression ratio of two mRNA isoforms was generated by alternative splicing. The glutamine-included protein isoform was more predominantly localized in the cell nucleus. (PMID:16091834)
• mutant atropphin with polyglutamine expansion does not simply function in a dominant negative manner (PMID:16407196)
• Status epilepticus during sleep caused by an expansion of the CAG repeat in the DRPLA gene. (PMID:16534126)
• 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)
• Both Drosophila and human Brakeless and Atrophin interact in vitro. Brakeless homologs may influence the toxicity of polyglutamine-expanded Atrophin-1. (PMID:17503969)
• data suggest that a founder effect accounts for some of the high prevalence of Dentatorubral pallidoluysian and ATN1 expansion polymorphism in Wales. (PMID:17965145)
• 244 Patients with the diagnosis of Huntington’s Disease and without mutation of the IT15 gene revealed one case of SCA17 but did not disclose the presence of two other diseases with a similar clinical manifestation: DRPLA and HDL2. (PMID:18651325)
• The dentatorubral-pallidoluysian atrophy transgenic mice showed severe neurological phenotypes with progressive brain atrophy and premature death. (PMID:19039037)
• Molecular testing for dentatorubral pallidoluysian atrophy revealed abnormal “cytosine-adenine-guanosine” expansion in the atrophin-1 gene. (PMID:20196398)
• Atrophin-1 promote neurodegeneration with autophagic hallmarks both in neuronal photoreceptors and glial cells. (PMID:20339376)
• The CAG repeat length of DRPLA may have a considerable effect on not only the disease onset but also the disease milestones and prognosis in DRPLA patients. (PMID:20589872)
• the C-terminal fragment plays a principal role in the pathological accumulation of ATN1 in dentatorubral-pallidoluysian atrophy (PMID:20977674)
• A pair of monozygotic twins is diagnosed with dentatorubro pallidoluysian atrophy, identical CAG repeats, and different clinical courses. (PMID:21749564)
• This sttudy suggested that age-dependent and CAG repeat-dependent intranuclear accumulation of mutant DRPLA leading to nuclear dysfunctions are suggested to be the essential pathophysiologic mechanisms in Dentatorubral-pallidoluysian atrophy. (PMID:21827919)
• This study demonistrated that Atn1 is response for Dentatorubral-pallidoluysian atrophy. (PMID:22083836)
• In cerebrum and cerebellum of DRPLA transgenic mouse lines at 4, 8, and 12 weeks it is demonstrated that both the number and expression levels of the altered genes are highly dependent on CAG repeat length and age in both brain regions. (PMID:22342974)
• This study demonistrated that hypoalbuminemia in early onset DRPLA revealed the possibility of multiorgan involvement. (PMID:23263592)
• results suggest that expanded polyQ repeats in ATN1 may contribute to neurodegeneration via alterations in both protein aggregation and intracellular localization. (PMID:23933208)
• These data demonstrate that the expanded trinucleotide repeat within ATN-1 mRNA is a potential target for compounds designed to achieve allele-selective inhibition of ATN-1 protein, and one agent may allow the targeting of multiple disease genes. (PMID:24981774)
• Juvenile myoclonic epilepsy is not associated with the DRPLA gene in a European population. (PMID:25398822)
• Epigenetic regulation of ATN1 by LSD1 is required for cortical progenitor maintenance. (PMID:25519973)
• Data indicate that the size of the expanded CAG repeats od dentatorubral-pallidoluysian atrophy protein (DRPLA) was inversely correlated with the age at onset. (PMID:27577205)
• De Novo Variants Disrupting the HX Repeat Motif of ATN1 Cause a Non-Progressive Neurocognitive Syndrome. (PMID:30827498)
• CHEDDA syndrome is an underrecognized neurodevelopmental disorder with a highly restricted ATN1 mutation spectrum. (PMID:34212383)
• Atrophin-1 Function and Dysfunction in Dentatorubral-Pallidoluysian Atrophy. (PMID:36809552)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	atn1	ENSDARG00000092067
mus_musculus	Atn1	ENSMUSG00000004263
rattus_norvegicus	Atn1	ENSRNOG00000060594
drosophila_melanogaster	Gug	FBGN0010825
caenorhabditis_elegans		WBGENE00001194

Paralogs (1): RERE (ENSG00000142599)

Protein

Protein identifiers

Atrophin-1 — P54259 (reviewed: P54259)

Alternative names: Dentatorubral-pallidoluysian atrophy protein

All UniProt accessions (1): P54259

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional corepressor. Recruits NR2E1 to repress transcription. Promotes vascular smooth cell (VSMC) migration and orientation. Corepressor of MTG8 transcriptional repression. Has some intrinsic repression activity which is independent of the number of poly-Gln (polyQ) repeats.

Subunit / interactions. Interacts with NR2E1; the interaction represses the transcriptional activity of NR2E1. Interacts (via its N-terminus) with FAT1 (via a C-terminal domain). Interacts with BAIAP2, WWP1, WWP2, WWP3 and RERE. Interacts (via its N-terminus) with MTG8; the interaction enhances transcriptional repression of MTG8. Interacts with PQBP1.

Subcellular location. Nucleus. Cytoplasm. Perinuclear region. Cell junction.

Tissue specificity. Widely expressed in various tissues including heart, lung, kidney, ovary, testis, prostate, placenta, skeletal Low levels in the liver, thymus and leukocytes. In the adult brain, broadly expressed in amygdala, caudate nucleus, corpus callosum, hippocampus, hypothalamus, substantia nigra, subthalamic nucleus, and thalamus. High levels in fetal tissues, especially brain.

Post-translational modifications. Phosphorylated in vitro by MAPK8/JNK1 on Ser-739. Mutant ATN1 sequences with expanded poly-Gln (polyQ) traits are more slowly phosphorylated. Proteolytically cleaved, probably in the nucleus, to produce two C-terminal fragments of 140 kDa (F1) and 125 kDa (F2) each containing poly-Gln (polyQ) tracts. F2 is produced by cleavage by caspases and is exported into the cytoplasm. In vitro, cleavage increases with an increase in the number of polyQ tracts. C-terminal proteolytic products appear to be the cause of cell toxicity. In vitro cleavage at Asp-109.

Disease relevance. Dentatorubral-pallidoluysian atrophy (DRPLA) [MIM:125370] Autosomal dominant neurodegenerative disorder characterized by a loss of neurons in the dentate nucleus, rubrum, glogus pallidus and Luys’body. Clinical features are myoclonus epilepsy, dementia, and cerebellar ataxia. Onset of the disease occurs usually in the second decade of life and death in the fourth. The disease is caused by variants affecting the gene represented in this entry. Congenital hypotonia, epilepsy, developmental delay, and digital anomalies (CHEDDA) [MIM:618494] An autosomal dominant neurodevelopmental syndrome characterized by severe global developmental delay, impaired intellectual development, poor or absent language, significant motor disability with inability to walk, dysmorphic facial features, skeletal anomalies, and variable congenital malformations. Most patients also have seizures and structural brain abnormalities. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The HX repeat motif is a specific pH-dependent interaction motif for ions and/or proteins or other biomolecules. This motif could be involved in the control of embryonic development.

Polymorphism. The poly-Gln region of ATN1 is highly polymorphic (7 to 23 repeats) in the normal population and is expanded to about 49-75 repeats in DRPLA and HRS patients. Longer expansions result in earlier onset and more severe clinical manifestations of the disease.

RefSeq proteins (7): NP_001007027, NP_001411105, NP_001411106, NP_001411107, NP_001411108, NP_001411109, NP_001931* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002951	Atrophin-like	Family
IPR017993	Atrophin-1	Family

Pfam: PF03154

UniProt features (58 total): compositionally biased region 16, modified residue 16, sequence variant 10, region of interest 6, sequence conflict 3, mutagenesis site 2, short sequence motif 2, chain 1, site 1, cross-link 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P54259-F1	49.25	0.03

Functional residue map

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

Catalytic / active sites (1): 109–110 (cleavage; by casp-3)

Post-translational modifications (17): 34, 77, 79, 101, 103, 107, 632, 641, 653, 661, 669, 739, 746, 748, 896, 1115, 1183

Mutagenesis-validated functional residues (2):

Position	Phenotype
109	prevents cleavage and suppresses apoptosis.
739	abolishes phosphorylation.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-8943724	Regulation of PTEN gene transcription
R-HSA-1257604	PIP3 activates AKT signaling
R-HSA-162582	Signal Transduction
R-HSA-6807070	PTEN Regulation
R-HSA-9006925	Intracellular signaling by second messengers

MSigDB gene sets: 364 (showing top): TAATAAT_MIR126, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_CELL_POLARITY, XU_HGF_TARGETS_REPRESSED_BY_AKT1_DN, GOBP_GROWTH, GOBP_RESPONSE_TO_FOOD, GOBP_MALE_GAMETE_GENERATION, GGGTGGRR_PAX4_03, CAIRO_HEPATOBLASTOMA_CLASSES_DN, GOBP_REPRODUCTIVE_SYSTEM_DEVELOPMENT, HNF4_DR1_Q3, GOBP_MULTICELLULAR_ORGANISM_GROWTH, HNF4_01, GOBP_MAINTENANCE_OF_CELL_POLARITY, PPAR_DR1_Q2, GATA1_04

GO Biological Process (13): negative regulation of transcription by RNA polymerase II (GO:0000122), cell killing (GO:0001906), spermatogenesis (GO:0007283), central nervous system development (GO:0007417), determination of adult lifespan (GO:0008340), male gonad development (GO:0008584), post-embryonic development (GO:0009791), cell migration (GO:0016477), maintenance of cell polarity (GO:0030011), response to food (GO:0032094), multicellular organism growth (GO:0035264), neuron apoptotic process (GO:0051402), positive regulation of DNA-templated transcription (GO:0045893)

GO Molecular Function (4): transcription coactivator activity (GO:0003713), transcription corepressor activity (GO:0003714), protein domain specific binding (GO:0019904), protein binding (GO:0005515)

GO Cellular Component (6): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), nuclear matrix (GO:0016363), perinuclear region of cytoplasm (GO:0048471), anchoring junction (GO:0070161)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
PTEN Regulation	1
Intracellular signaling by second messengers	1
PIP3 activates AKT signaling	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
multicellular organismal process	3
negative regulation of DNA-templated transcription	2
transcription coregulator activity	2
nuclear lumen	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
cellular process	1
developmental process involved in reproduction	1
male gamete generation	1
nervous system development	1
system development	1
gonad development	1
development of primary male sexual characteristics	1
multicellular organism development	1
cell motility	1
establishment or maintenance of cell polarity	1
response to nutrient levels	1
response to chemical	1
developmental growth	1
apoptotic process	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
positive regulation of DNA-templated transcription	1
protein binding	1
binding	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cytoplasm	1
cell junction	1

Protein interactions and networks

STRING

1354 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ATN1	ATXN1	P54253	859
ATN1	ATXN2	Q99700	831
ATN1	NR2E1	Q9Y466	825
ATN1	MAGI1	Q96QZ7	811
ATN1	HTT	P42858	808
ATN1	ATXN3	P54252	785
ATN1	ATXN7	O15265	769
ATN1	WWP1	Q9H0M0	743
ATN1	QKI	Q96PU8	718
ATN1	RBPMS	Q93062	712
ATN1	BAIAP2	Q9UQB8	666
ATN1	CACNA1A	P78510	664
ATN1	ITCH	Q96J02	631
ATN1	WWP2	O00308	630
ATN1	ATXN3L	Q9H3M9	629

IntAct

154 interactions, top by confidence:

A	B	Type	Score
WDR5	KMT2D	psi-mi:“MI:0914”(association)	0.910
WDR5	SETD1A	psi-mi:“MI:0914”(association)	0.880
RBBP5	KMT2D	psi-mi:“MI:0914”(association)	0.840
WDR5	MEN1	psi-mi:“MI:0914”(association)	0.710
ATN1	BAIAP2	psi-mi:“MI:0915”(physical association)	0.630
BAIAP2	ATN1	psi-mi:“MI:0915”(physical association)	0.630
SIAH1	ATN1	psi-mi:“MI:0915”(physical association)	0.550
SYNGAP1	IGF2BP3	psi-mi:“MI:0914”(association)	0.530
ATN1	PLEKHA5	psi-mi:“MI:0915”(physical association)	0.510
ATN1	TRIP6	psi-mi:“MI:0915”(physical association)	0.510
RBFOX1	ATN1	psi-mi:“MI:0915”(physical association)	0.510
ZNF608	ATN1	psi-mi:“MI:0407”(direct interaction)	0.440
YAP1	ATN1	psi-mi:“MI:0407”(direct interaction)	0.440
Dlg4	ATN1	psi-mi:“MI:0407”(direct interaction)	0.440
ATN1	SERPINB8	psi-mi:“MI:0915”(physical association)	0.400
	ATN1	psi-mi:“MI:0915”(physical association)	0.370
ATN1	CBFA2T3	psi-mi:“MI:0915”(physical association)	0.370
ATN1	yscY	psi-mi:“MI:0915”(physical association)	0.370
ATN1	ompA	psi-mi:“MI:0915”(physical association)	0.370
ATN1	FXR1	psi-mi:“MI:0915”(physical association)	0.370
ATN1	FXR2	psi-mi:“MI:0915”(physical association)	0.370
ATN1	SHANK3	psi-mi:“MI:0915”(physical association)	0.370
ATN1	TSC1	psi-mi:“MI:0915”(physical association)	0.370
PROP1	ATN1	psi-mi:“MI:0915”(physical association)	0.370
ATN1	BECN1	psi-mi:“MI:0914”(association)	0.350
AUTS2	ZNF609	psi-mi:“MI:0914”(association)	0.350
WDR5	KDM6A	psi-mi:“MI:0914”(association)	0.350
WDR5	PHF20L1	psi-mi:“MI:0914”(association)	0.350
WDR5	ZNF609	psi-mi:“MI:0914”(association)	0.350

BioGRID (224): ATN1 (Affinity Capture-MS), ATN1 (Affinity Capture-MS), ATN1 (Proximity Label-MS), ATN1 (Affinity Capture-MS), ATN1 (Affinity Capture-RNA), ATN1 (Affinity Capture-MS), ATN1 (Affinity Capture-MS), ATN1 (Affinity Capture-MS), ATN1 (Affinity Capture-Western), ATN1 (Two-hybrid), ATN1 (Two-hybrid), ATN1 (Two-hybrid), ATN1 (Two-hybrid), ATN1 (Two-hybrid), KAT7 (Two-hybrid)

ESM2 similar proteins: A1YFU7, A2AJK6, A2BH40, B2RWS6, D3YWE6, E9Q4N7, M9NEY8, O00512, O14497, O35126, O42368, O43365, O57401, P02831, P02833, P22810, P23441, P23512, P25822, P32182, P34545, P35582, P35583, P43698, P43699, P50220, P50901, P54258, P54259, P54269, P55317, Q06A37, Q08DG7, Q08E31, Q09472, Q0VCT9, Q10571, Q1KKX7, Q24248, Q24645

Diamond homologs: O35126, P54258, P54259, Q5IS70, Q62901, Q80TZ9, Q9P2R6, O94776, Q09228, Q13330, Q5REE1, Q5UAK0, Q62599, Q7T105, Q8K4B0, Q8N108, Q9R190

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
MAPK10	“down-regulates activity”	ATN1	phosphorylation
MAPK8	“down-regulates activity”	ATN1	phosphorylation
MAPK9	“down-regulates activity”	ATN1	phosphorylation
JNK	“down-regulates activity”	ATN1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 113 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Molecules associated with elastic fibres	7	30.4×	1e-06
Formation of WDR5-containing histone-modifying complexes	7	26.2×	1e-06
Deactivation of the beta-catenin transactivating complex	5	16.4×	1e-03
Epigenetic regulation of gene expression by MLL3 and MLL4 complexes	5	13.9×	2e-03
Epigenetic regulation by WDR5-containing histone modifying complexes	5	10.9×	6e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	4
Uncertain significance	243
Likely benign	66
Benign	19

Top pathogenic / likely-pathogenic (10)

Variant ID	HGVS	Classification
1012272	NM_001940.4(ATN1):c.3165_3176del (p.Ile1057_His1060del)	Pathogenic
37031	NM_001007026.1(ATN1):c.1462CAG[49_55] (p.Gln488[49_55])	Pathogenic
487496	NM_001940.4(ATN1):c.3160C>A (p.His1054Asn)	Pathogenic
487497	NM_001940.4(ATN1):c.3172C>T (p.His1058Tyr)	Pathogenic
487498	NM_001940.4(ATN1):c.3188T>G (p.Leu1063Arg)	Pathogenic
590267	NG_008047.1:g.17267CAG[(54-68)]	Pathogenic
1027367	NM_001940.4(ATN1):c.3167A>C (p.His1056Pro)	Likely pathogenic
1027369	NM_001940.4(ATN1):c.3182TGCACC[1] (p.1061LH[1])	Likely pathogenic
191276	NM_001940.4(ATN1):c.3178C>T (p.His1060Tyr)	Likely pathogenic
2229107	NM_001940.4(ATN1):c.3176C>G (p.Ser1059Trp)	Likely pathogenic

SpliceAI

1778 predictions. Top by Δscore:

Variant	Effect	Δscore
12:6934027:CGG:C	donor_loss	1.0000
12:6934028:GGT:G	donor_loss	1.0000
12:6934029:G:GG	donor_gain	1.0000
12:6934030:T:A	donor_loss	1.0000
12:6934172:GTAG:G	acceptor_loss	1.0000
12:6934173:TA:T	acceptor_loss	1.0000
12:6934174:A:AG	acceptor_gain	1.0000
12:6934175:G:GG	acceptor_gain	1.0000
12:6934175:GAT:G	acceptor_gain	1.0000
12:6934175:GATGT:G	acceptor_gain	1.0000
12:6934460:A:AG	acceptor_gain	1.0000
12:6934461:ACAG:A	acceptor_loss	1.0000
12:6934463:A:AG	acceptor_gain	1.0000
12:6934463:A:T	acceptor_loss	1.0000
12:6934464:G:C	acceptor_loss	1.0000
12:6934464:G:GA	acceptor_gain	1.0000
12:6934464:GAA:G	acceptor_gain	1.0000
12:6934574:CTGAG:C	donor_loss	1.0000
12:6934576:GAGGT:G	donor_loss	1.0000
12:6934578:GG:G	donor_loss	1.0000
12:6935683:G:GT	donor_gain	1.0000
12:6935683:G:T	donor_gain	1.0000
12:6938063:GCGTG:G	donor_gain	1.0000
12:6938065:GTG:G	donor_gain	1.0000
12:6938066:TG:T	donor_gain	1.0000
12:6938066:TGGTG:T	donor_loss	1.0000
12:6938067:GG:G	donor_gain	1.0000
12:6938068:G:GA	donor_loss	1.0000
12:6938068:G:GG	donor_gain	1.0000
12:6938069:T:G	donor_loss	1.0000

AlphaMissense

7579 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:6937542:C:G	H759D	1.000
12:6937543:A:G	H759R	1.000
12:6937544:T:A	H759Q	1.000
12:6937544:T:G	H759Q	1.000
12:6937548:A:C	S761R	1.000
12:6937549:G:A	S761N	1.000
12:6937550:T:A	S761R	1.000
12:6937550:T:G	S761R	1.000
12:6937558:C:A	A764D	1.000
12:6937846:T:C	F766L	1.000
12:6937847:T:C	F766S	1.000
12:6937847:T:G	F766C	1.000
12:6937848:C:A	F766L	1.000
12:6937848:C:G	F766L	1.000
12:6937854:A:C	K768N	1.000
12:6937854:A:T	K768N	1.000
12:6937859:T:C	L770P	1.000
12:6937864:C:A	R772S	1.000
12:6937875:C:A	N775K	1.000
12:6937875:C:G	N775K	1.000
12:6937879:T:C	C777R	1.000
12:6937880:G:A	C777Y	1.000
12:6937881:C:G	C777W	1.000
12:6937895:T:C	L782P	1.000
12:6937900:T:C	F784L	1.000
12:6937901:T:C	F784S	1.000
12:6937902:C:A	F784L	1.000
12:6937902:C:G	F784L	1.000
12:6937907:C:A	P786Q	1.000
12:6937907:C:G	P786R	1.000

dbSNP variants (sampled 300 via entrez): RS1000062722 (12:6942517 C>A,T), RS1001012705 (12:6929211 T>C), RS1001107126 (12:6929497 C>A,T), RS1001276024 (12:6923220 C>T), RS1001989739 (12:6942775 C>T), RS1002345369 (12:6923375 T>C), RS1003055749 (12:6926093 A>G), RS1003340638 (12:6924499 G>C), RS1003392732 (12:6924714 A>G), RS1003521274 (12:6931163 C>A,T), RS1004022607 (12:6932163 T>C), RS1004369240 (12:6939332 C>G), RS1004945648 (12:6925195 G>A,T), RS1005075298 (12:6932671 C>T), RS1005167390 (12:6933036 C>T)

Disease associations

OMIM: gene MIM:607462 | disease phenotypes: MIM:218340, MIM:613702, MIM:615833, MIM:618494, MIM:125370, MIM:307000

GenCC curated gene-disease

Disease	Classification	Inheritance
congenital hypotonia, epilepsy, developmental delay, and digital anomalies	Strong	Autosomal dominant
dentatorubral-pallidoluysian atrophy	Strong	Autosomal dominant

Mondo (7): temtamy syndrome (MONDO:0009033), Klippel-Feil syndrome 3, autosomal dominant (MONDO:0013375), developmental and epileptic encephalopathy, 21 (MONDO:0014360), congenital hypotonia, epilepsy, developmental delay, and digital anomalies (MONDO:0032781), dentatorubral-pallidoluysian atrophy (MONDO:0007435), X-linked hydrocephalus with stenosis of the aqueduct of Sylvius (MONDO:0010611), intellectual disability (MONDO:0001071)

Orphanet (6): Temtamy syndrome (Orphanet:1777), Isolated Klippel-Feil syndrome (Orphanet:2345), Non-specific early-onset epileptic encephalopathy (Orphanet:442835), Dentatorubral pallidoluysian atrophy (Orphanet:101), Hydrocephalus with stenosis of the aqueduct of Sylvius (Orphanet:2182), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

95 total (30 of 95 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000028	Cryptorchidism
HP:0000089	Renal hypoplasia
HP:0000122	Unilateral renal agenesis
HP:0000126	Hydronephrosis
HP:0000175	Cleft palate
HP:0000194	Open mouth
HP:0000219	Thin upper lip vermilion
HP:0000286	Epicanthus
HP:0000341	Narrow forehead
HP:0000343	Long philtrum
HP:0000348	High forehead
HP:0000358	Posteriorly rotated ears
HP:0000365	Hearing impairment
HP:0000369	Low-set ears
HP:0000403	Recurrent otitis media
HP:0000414	Bulbous nose
HP:0000490	Deeply set eye
HP:0000568	Microphthalmia
HP:0000597	Ophthalmoparesis
HP:0000639	Nystagmus
HP:0000643	Blepharospasm
HP:0000726	Dementia
HP:0001138	Optic neuropathy
HP:0001152	Saccadic smooth pursuit interruptions
HP:0001212	Prominent fingertip pads
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST010002_206	Refractive error	3.000000e-62

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
C536078	Hydrocephalus, X-linked (supp.)
C536959	Temtamy syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6193764 (PROTEIN-PROTEIN INTERACTION)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Cadmium Chloride	decreases expression, increases abundance, increases expression	3
sodium arsenite	increases expression	2
Genistein	decreases expression	2
6,7-dimethoxy-2-(pyrrolidin-1-yl)-N-(5-(pyrrolidin-1-yl)pentyl)quinazolin-4-amine	decreases expression	1
FR900359	affects phosphorylation	1
bisphenol F	affects cotreatment, decreases methylation	1
dicrotophos	increases expression	1
bisphenol A	affects cotreatment, increases methylation	1
nickel subsulfide	decreases expression	1
butyraldehyde	decreases expression	1
tetrabromobisphenol A	decreases expression	1
potassium chromate(VI)	affects cotreatment, increases expression	1
coumarin	affects phosphorylation	1
epigallocatechin gallate	increases expression, affects cotreatment	1
CGP 52608	affects binding, increases reaction	1
monomethylarsonous acid	decreases expression	1
abrine	increases expression	1
(+)-JQ1 compound	decreases expression	1
Arsenic Trioxide	increases sumoylation	1
Fulvestrant	affects cotreatment, increases methylation, decreases methylation	1
Air Pollutants	increases abundance, increases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Cadmium	decreases expression, increases abundance	1
Caffeine	increases phosphorylation	1
Cytarabine	increases expression	1
Doxorubicin	decreases expression	1
Lipopolysaccharides	affects response to substance, affects expression	1
Smoke	decreases expression	1
Thiram	increases expression	1
Valproic Acid	decreases expression	1

ChEMBL screening assays

5 unique, capped per target: 5 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4610591	Binding	Protac activity at C-IAP1/atrophin-1 mutant in fibroblasts derived from DRPLA patient assessed as reduction in mutant atrophin-1 expression after 24 to 48 hrs by Western blot analysis	Application of protein knockdown strategy targeting β-sheet structure to multiple disease-associated polyglutamine proteins. — Bioorg Med Chem

Cellosaurus cell lines

9 cell lines: 5 induced pluripotent stem cell, 2 cancer cell line, 2 finite cell line

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

Cellosaurus	Name	Category	Sex
CVCL_E1RH	HAP1 ATN1 (-) 1	Cancer cell line	Male
CVCL_E1RI	HAP1 ATN1 (-) 2	Cancer cell line	Male
CVCL_T902	GM13716	Finite cell line	Male
CVCL_T905	GM13717	Finite cell line	Male
CVCL_WK22	CSSi008-A	Induced pluripotent stem cell	Male
CVCL_WP63	CENSOi054-A	Induced pluripotent stem cell	Male
CVCL_WP64	CENSOi055-A	Induced pluripotent stem cell	Male
CVCL_XC40	IBCHi001-A	Induced pluripotent stem cell	Male
CVCL_YC23	CENSOi054-B	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT06706388	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Personalized Antisense Oligonucleotide Therapy for A Single Participant With ATN1 Gene Mutation
NCT07084311	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Personalized Antisense Oligonucleotide for A Single Participant With ATN1 Gene Mutation
NCT07221760	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Personalized Antisense Oligonucleotide for A Single Participant (nL62541) With ATN1 Gene Mutation
NCT05489393	Not specified	RECRUITING	CureDRPLA Global Patient Registry
NCT06273150	Not specified	RECRUITING	Dentatorubral-pallidoluysian Atrophy Natural History and Biomarkers Study
NCT06147414	Not specified	RECRUITING	Development of Non-Invasive Prenatal Diagnosis for Single Gene Disorders
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population
NCT02504502	Not specified	COMPLETED	Enhancing Genomic Laboratory Reports to Enhance Communication and Empower Patients
NCT02513277	Not specified	COMPLETED	Diabetes Screening & Prevention for People With Learning (Intellectual) Disabilities:STOP Diabetes Study