HR

Summary

HR (HR lysine demethylase and nuclear receptor corepressor, HGNC:5172) is a protein-coding gene on chromosome 8p21.3, encoding Lysine-specific demethylase hairless (O43593). Histone demethylase that specifically demethylates both mono- and dimethylated ‘Lys-9’ of histone H3.

This gene encodes a protein that is involved in hair growth. This protein functions as a transcriptional corepressor of multiple nuclear receptors, including thyroid hormone receptor, the retinoic acid receptor-related orphan receptors and the vitamin D receptors, and it interacts with histone deacetylases. The translation of this protein is modulated by a regulatory open reading frame (ORF) that exists upstream of the primary ORF. Mutations in this upstream ORF cause Marie Unna hereditary hypotrichosis (MUHH), an autosomal dominant form of genetic hair loss. Mutations in this gene also cause autosomal recessive congenital alopecia and atrichia with papular lesions, other diseases resulting in hair loss. Two transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 55806 — RefSeq curated summary.

At a glance

• Gene–disease (curated): atrichia with papular lesions (Definitive, GenCC) — +3 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 531 total — 24 pathogenic, 8 likely-pathogenic
• Phenotypes (HPO): 24
• Transcription factor: yes — 102 downstream targets (CollecTRI)
• MANE Select transcript: NM_005144

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5172
Approved symbol	HR
Name	HR lysine demethylase and nuclear receptor corepressor
Location	8p21.3
Locus type	gene with protein product
Status	Approved
Aliases	KDM3D, AU
Ensembl gene	ENSG00000168453
Ensembl biotype	protein_coding
OMIM	602302
Entrez	55806

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 4 protein_coding, 4 retained_intron, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000312841, ENST00000381418, ENST00000517699, ENST00000518461, ENST00000519619, ENST00000522016, ENST00000522039, ENST00000522759, ENST00000680789, ENST00000902240

RefSeq mRNA: 2 — MANE Select: NM_005144 NM_005144, NM_018411

CCDS: CCDS6022, CCDS6023

Canonical transcript exons

ENST00000381418 — 19 exons

Exon	Start	End
ENSE00001158728	22116875	22117039
ENSE00001158734	22118950	22119065
ENSE00001158747	22119760	22119890
ENSE00001158760	22120104	22120173
ENSE00001158795	22122493	22122608
ENSE00001158802	22122790	22122879
ENSE00001158812	22123649	22123813
ENSE00001158821	22125311	22125504
ENSE00001158830	22125582	22125732
ENSE00001231488	22127037	22127829
ENSE00001384505	22128559	22129210
ENSE00001813128	22130428	22131010
ENSE00001848718	22114419	22115762
ENSE00003467324	22121065	22121228
ENSE00003468616	22119164	22119283
ENSE00003518317	22116300	22116428
ENSE00003548110	22121613	22121694
ENSE00003727671	22120342	22120507
ENSE00003734845	22120716	22120958

Expression profiles

Bgee: expression breadth ubiquitous, 235 present calls, max score 97.74.

FANTOM5 (CAGE): breadth broad, TPM avg 5.7589 / max 230.2003, expressed in 868 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
92195	3.3834	548
92201	1.4776	504
92198	0.3232	197
92197	0.2428	131
92196	0.1561	89
92199	0.1222	45
92200	0.0535	27

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
skin of abdomen	UBERON:0001416	97.74	gold quality
skin of leg	UBERON:0001511	97.38	gold quality
zone of skin	UBERON:0000014	95.39	gold quality
right hemisphere of cerebellum	UBERON:0014890	94.52	gold quality
cerebellar hemisphere	UBERON:0002245	93.79	gold quality
cerebellar cortex	UBERON:0002129	93.75	gold quality
mucosa of transverse colon	UBERON:0004991	93.30	gold quality
mammalian vulva	UBERON:0000997	93.21	gold quality
cerebellum	UBERON:0002037	92.36	gold quality
lower esophagus mucosa	UBERON:0035834	91.65	gold quality
esophagus mucosa	UBERON:0002469	91.31	gold quality
right frontal lobe	UBERON:0002810	91.15	gold quality
nipple	UBERON:0002030	90.99	gold quality
sural nerve	UBERON:0015488	90.31	gold quality
prefrontal cortex	UBERON:0000451	90.25	gold quality
parotid gland	UBERON:0001831	90.07	silver quality
gingival epithelium	UBERON:0001949	89.27	gold quality
buccal mucosa cell	CL:0002336	89.19	silver quality
hair follicle	UBERON:0002073	88.42	silver quality
gingiva	UBERON:0001828	88.21	gold quality
Brodmann (1909) area 9	UBERON:0013540	87.31	gold quality
upper arm skin	UBERON:0004263	87.12	gold quality
transverse colon	UBERON:0001157	87.00	gold quality
tibial nerve	UBERON:0001323	86.92	gold quality
frontal cortex	UBERON:0001870	86.59	gold quality
upper leg skin	UBERON:0004262	86.31	gold quality
left ventricle myocardium	UBERON:0006566	86.28	gold quality
Brodmann (1909) area 10	UBERON:0013541	85.92	gold quality
cardiac muscle of right atrium	UBERON:0003379	85.64	gold quality
neocortex	UBERON:0001950	85.47	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.17

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

102 targets.

Target	Regulation
ABCB1
ABL1
ACHE
ADAMTS7
APOA1
BGLAP
BRCA1
CAMP
CASP14
CAT
CCL2
CCL7
CCND1
CCND3
CCNE1
CD74
CDH1
CDK4
CDKN1A
CHRM4
CHRNA7
CIITA
CISH
CRHR1
CYP21A1P
CYP24A1
CYP2B6
CYP3A4
DIO3
DLD

Upstream regulators (CollecTRI, top): DNMT1, TP53, VDR

miRNA regulators (miRDB)

54 targeting HR, 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-4481	100.00	66.42	1669
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-4745-5P	99.98	65.95	1028
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-374A-5P	99.90	71.34	2923
HSA-MIR-374B-5P	99.90	69.98	2734
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-6844	99.82	70.69	2423
HSA-MIR-1296-3P	99.72	64.04	636
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-486-3P	99.51	66.82	1901
HSA-MIR-6165	99.44	67.12	1389
HSA-MIR-593-3P	99.22	67.28	1327
HSA-MIR-4279	99.19	66.70	2437
HSA-MIR-3619-5P	99.00	68.87	2308
HSA-MIR-6770-5P	98.97	66.76	1853
HSA-MIR-3196	98.96	63.91	326
HSA-MIR-873-5P	98.84	66.90	1348
HSA-MIR-331-3P	98.76	64.91	793
HSA-MIR-214-3P	98.71	68.12	2128
HSA-MIR-761	98.71	68.07	2051
HSA-MIR-6818-3P	98.56	68.23	1307
HSA-MIR-3180	98.46	64.68	348
HSA-MIR-3180-3P	98.46	64.68	348
HSA-MIR-6816-5P	98.46	64.35	364

Literature-anchored findings (GeneRIF, showing 39)

• Mutations in the human hairless gene have been reported in families with recessive universal congenital alopecia. (PMID:11966690)
• first demonstration of compound heterozygous mutations underlying atrichia with papular lesions (APL). (PMID:12271294)
• Hairless protein functions as a corepressor of vitamin D receptor to block calcitriol action on keratinocytes. (PMID:16269453)
• In the present report of two families with congenital atrichia, the second exonic insertion mutation in the human HR gene and the first mutation in exon 12 are described. (PMID:17372750)
• all of the pathogenic HR mutants bound VDR but exhibited reduced binding to histone deacetylase 1 (HDAC1), suggesting that the impaired corepressor activity is due in part to defective interactions with HDACs (PMID:17609203)
• Three novel nonsense mutations in the hairless (HR) gene in atrichia with papular lesions are reported. (PMID:17869066)
• two novel heterozygous mutations in exons 3 and 8 of the hairless gene (PMID:17958788)
• Two mutations identified in this study are novel mutations in the HR gene and extend the body of evidence implicating the hairless gene family in the pathogenesis of human skin disorders. (PMID:18164595)
• Mutations in the human hairless gene on chromosome 8p12 have been implicated in atrichia with papular lesions. Here, we report two novel heterozygous mutations in an Australian family and a novel homozygous mutation in 2 Arab siblings. (PMID:18709303)
• A pathogenic initiation codon mutation in U2HR, an inhibitory upstream ORF in the 5’ UTR of the gene encoding the human hairless homolog (HR). (PMID:19122663)
• Case Report: A novel U2HR non-synonymous mutation in a Chinese patient with Marie Unna Hereditary Hypotrichosis. (PMID:19540091)
• study reports an Iranian family with atrichia with papular lesions due to 3-bp deletion (c.1839-1841delATG) mutations in the HR gene (PMID:19747330)
• The full-length HR repressed VDR-mediated transactivation, but HRDelta1072-1126 failed to suppress VDR-mediated transactivation. (PMID:19819974)
• A mutation in the 5’-UTR of HR as identified in patients with Marie Unna hereditary hypotrichosis. (PMID:19897589)
• the first time that a mutation in U2HR has been identified in families from the Middle East (PMID:20055871)
• Mutation of the Hr gene results in congenital hair loss in both mice and men (PMID:20087431)
• Marie Unna hereditary hypotrichosis is caused by a novel mutation (U2HR) in the human hairless transcript. (PMID:20163456)
• Hr and VDR interact via multiple protein-protein interfaces, catalyzing histone demethylation to effect chromatin remodeling and repress the transcription of VDR target genes that control the hair cycle. (PMID:20512927)
• The index patient displayed the typical pattern of hair loss and was found to carry the disease-causing c.3G>A (p.M1I) U2HR mutation (PMID:20659777)
• study reports a family with Marie Unna hereditary hypotrichosis (MUHH) from Turkey; identified the mutation c.2T > C (M1T) in all affected family members; concluded that there may be considerable clinical variations in MUHH (PMID:20814945)
• Mutations in the gene HR coding for the hairless protein are associated with an autosomal recessive form of alopecia universalis (PMID:21272494)
• DNA sequence analysis of the HR gene revealed three novel mutations including two nonsense (p.Cys690X, p.Arg819X) and a missense (p.Pro1157Arg) in four families with congenital atrichia with papular lesions. (PMID:21919222)
• deletion mutants of hairless indicate that the JmjC domain contributes to the co-repressor activity (PMID:21982945)
• We have identified a novel heterozygous missense mutation in a Chinese patient with Marie Unna hereditary hypotrichosis. (PMID:22155146)
• data demonstrates an acceleration of HR sequence evolution in human branch and suggests that the ability of HR protein to mediate postnatal hair-cycling has been altered in the course of human evolution. (PMID:22355551)
• novel heterozygous mutation in the first Japanese case of Marie Unna hereditary hypotrichosis (PMID:23293922)
• mutation responsible for atrichia with papular lesions in a Pakistani family (PMID:24111842)
• Unliganded VDR upregulates the expression of hairless, the gene product of which acts as a downstream comodulator to feedback-repress DKKL1 and SOSTDC1. (PMID:24190897)
• study reports two cases of Marie Unna hereditary hypotrichosis; a novel nonsense mutation of U2HR was identified in the second case, but no causative mutation in U2HR or EPS8L3 was found in the first case (PMID:24236410)
• we have identified a mutation, c.74C>T, in a Chinese family with MUHH, which has been previously described in a family from Hungary. Our findings therefore indicate the prevalence of this mutation in diverse populations. (PMID:24261346)
• Findings indicate that hairless (HR) is a H3K9 demethylase that regulates epidermal homeostasis via direct control of its target genes. (PMID:24334705)
• we report the first Korean case of Marie Unna hereditary hypotrichosis with a novel heterozygous missense mutation (c.80C>T) in U2HR that has not been documented to date. (PMID:24961381)
• We have identified two recurrent missense mutations in U2HR c.1A>T (p. Met1?) and c.104A>G (p.*35Wext1263*) in two Chinese Han families with Marie Unna Hereditary Hypotrichosis. (PMID:26269244)
• Mutations identified extend the spectrum of mutations in the HR gene resulting in Atrichia with papular lesions. (PMID:26680117)
• mammalian Hr is a phosphoprotein which can exert cross-talk with the p53 pathway with important implications for the regulation of cell proliferation and differentiation in tissues such as skin and brain where Hr is highly expressed. (PMID:27355563)
• summary of the current knowledge of hairless protein (HR) bioactions, how HR mutations may be contributing to alopecia as well as to cancer (PMID:28543886)
• These results suggest that transcriptional repression or mutation of HR may contribute to glioblastoma pathogenesis, which uncovers a role of HR in brain and suggests that modulating HR activity in glioblastoma may be a therapeutic strategy. (PMID:30191601)
• Study in a large, five-generation Han Chinese family with several patients presenting with Marie Unna hereditary hypotrichosis (MUHH) and multiple familial trichoepithelioma (MFT) revealed that the c.1A>G mutation in HR (U2HR) was present in all MUHH patients. No pathogenic variants were found in EPS8L3 or CYLD in any family members but FABP12 (rs536105592 G>A) was identified in the patients with both MUHH and MFT. (PMID:30809827)
• Impact of a High Coverage Vaccination Rate on Human Papillomavirus Infection Prevalence in Young Women: A Cross-sectional Study. (PMID:32796265)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
mus_musculus	Hr	ENSMUSG00000022096
rattus_norvegicus	Hr	ENSRNOG00000011427
drosophila_melanogaster	Kdm3	FBGN0037703

Paralogs (3): KDM3A (ENSG00000115548), KDM3B (ENSG00000120733), JMJD1C (ENSG00000171988)

Protein

Protein identifiers

Lysine-specific demethylase hairless — O43593 (reviewed: O43593)

Alternative names: [histone H3]-dimethyl-L-lysine(9) demethylase hairless

All UniProt accessions (2): O43593, E5RK80

UniProt curated annotations — full annotation on UniProt →

Function. Histone demethylase that specifically demethylates both mono- and dimethylated ‘Lys-9’ of histone H3. May act as a transcription regulator controlling hair biology (via targeting of collagens), neural activity, and cell cycle.

Subcellular location. Nucleus.

Tissue specificity. Strongest expression of isoforms 1 and 2 is seen in the small intestine, weaker expression in brain and colon, and trace expression is found in liver, pancreas, spleen, thymus, stomach, salivary gland, appendix and trachea. Isoform 1 is always the most abundant. Isoform 1 is exclusively expressed at low levels in kidney and testis. Isoform 2 is exclusively expressed at high levels in the skin.

Disease relevance. Alopecia universalis congenita (ALUNC) [MIM:203655] A rare disorder characterized by loss of hair from the entire body. No hair are present in hair follicles on skin biopsy. The disease is caused by variants affecting the gene represented in this entry. Atrichia with papular lesions (APL) [MIM:209500] An autosomal recessive disease characterized by papillary lesions over most of the body and almost complete absence of hair. The disease is caused by variants affecting the gene represented in this entry. Hypotrichosis 4 (HYPT4) [MIM:146550] An autosomal dominant condition characterized by reduced amount of hair, alopecia, little or no eyebrows, eyelashes or body hair, and coarse, wiry, twisted hair in early childhood. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Binds 1 Fe(2+) ion per subunit.

Domain organisation. Contains two Leu-Xaa-Xaa-Leu-Leu (LXXLL) motifs. The LXXLL motifs are essential for the association with nuclear receptors. The JmjC domain and the C6-type zinc-finger are required for the demethylation activity.

Isoforms (2)

UniProt ID	Names	Canonical?
O43593-1	1, Long	yes
O43593-2	2, Short

RefSeq proteins (2): NP_005135, NP_060881 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003347	JmjC_dom	Domain
IPR045109	LSDs-like	Family

Pfam: PF02373

Enzyme classification (BRENDA):

• EC 1.14.11.65 — [histone H3]-dimethyl-L-lysine9 demethylase (BRENDA: 9 organisms, 67 substrates, 84 inhibitors, 4 Km, 4 kcat entries)

Substrate kinetics (BRENDA)

2 substrates with measured Km, best-characterized 2. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
[HISTONE H3]-N6,N6-DIMETHYL-L-LYSINE9	0.106–0.1061	2
[HISTONE H3]-N6-METHYL-L-LYSINE9	0.095–0.0952	2

Catalyzed reactions (Rhea), 1 shown:

• N(6),N(6)-dimethyl-L-lysyl(9)-[histone H3] + 2 2-oxoglutarate + 2 O2 = L-lysyl(9)-[histone H3] + 2 formaldehyde + 2 succinate + 2 CO2 (RHEA:60188)

UniProt features (27 total): sequence variant 8, region of interest 6, compositionally biased region 3, binding site 3, short sequence motif 2, chain 1, domain 1, splice variant 1, zinc finger region 1, mutagenesis site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43593-F1	55.65	0.19

Functional residue map

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

Ligand- & substrate-binding residues (3): 1007; 1009; 1125

Mutagenesis-validated functional residues (1):

Position	Phenotype
1056	markedly diminishes histone demethylase activity.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 226 (showing top): FREAC2_01, BENPORATH_ES_WITH_H3K27ME3, TGCGCANK_UNKNOWN, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_PAIRED_DONORS_WITH_INCORPORATION_OR_REDUCTION_OF_MOLECULAR_OXYGEN, PEREZ_TP63_TARGETS, CMYB_01, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, TATTATA_MIR374, FOXO4_01, GGGTGGRR_PAX4_03, PAX8_B, MARTINEZ_RB1_TARGETS_UP, chr8p21, GATA1_01, HFH8_01

GO Biological Process (3): regulation of transcription by RNA polymerase II (GO:0006357), chromatin remodeling (GO:0006338), negative regulation of DNA-templated transcription (GO:0045892)

GO Molecular Function (10): transcription coregulator activity (GO:0003712), transcription corepressor activity (GO:0003714), zinc ion binding (GO:0008270), chromatin DNA binding (GO:0031490), histone H3K9 demethylase activity (GO:0032454), histone H3K9me/H3K9me2 demethylase activity (GO:0140683), DNA binding (GO:0003677), protein binding (GO:0005515), oxidoreductase activity (GO:0016491), metal ion binding (GO:0046872)

GO Cellular Component (5): histone deacetylase complex (GO:0000118), chromatin (GO:0000785), nucleoplasm (GO:0005654), nuclear body (GO:0016604), nucleus (GO:0005634)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of DNA-templated transcription	2
nucleoplasm	2
cellular anatomical structure	2
transcription by RNA polymerase II	1
chromatin organization	1
DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
transcription regulator activity	1
transcription coregulator activity	1
negative regulation of DNA-templated transcription	1
transition metal ion binding	1
DNA binding	1
chromatin binding	1
histone H3 demethylase activity	1
2-oxoglutarate-dependent dioxygenase activity	1
histone H3K9 demethylase activity	1
nucleic acid binding	1
binding	1
catalytic activity	1
cation binding	1
nuclear protein-containing complex	1
catalytic complex	1
chromosome	1
nuclear lumen	1
intracellular membraneless organelle	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

422 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HR	FAM131C	Q96AQ9	477
HR	JMJD7	P0C870	444
HR	HSPBAP1	Q96EW2	399
HR	GPN3	Q9UHW5	393
HR	JMJD4	Q9H9V9	392
HR	JMJD8	Q96S16	391
HR	TYW5	A2RUC4	381
HR	FAM110C	Q1W6H9	349
HR	WASHC1	A8K0Z3	348
HR	FOXI3	A8MTJ6	346
HR	POLR2F	P41584	343
HR	PHF2	O75151	330
HR	KDM2A	Q9Y2K7	328
HR	BRI3	O95415	325
HR	RIOX2	Q8IUF8	325

IntAct

86 interactions, top by confidence:

A	B	Type	Score
HR	ABHD11	psi-mi:“MI:0915”(physical association)	0.560
	HR	psi-mi:“MI:0915”(physical association)	0.560
KRTAP6-3	HR	psi-mi:“MI:0915”(physical association)	0.560
CYSRT1	HR	psi-mi:“MI:0915”(physical association)	0.560
HR	ACTMAP	psi-mi:“MI:0915”(physical association)	0.560
HR	ATP23	psi-mi:“MI:0915”(physical association)	0.560
HR	KLHL20	psi-mi:“MI:0915”(physical association)	0.560
HR	KRTAP11-1	psi-mi:“MI:0915”(physical association)	0.560
HR	CNFN	psi-mi:“MI:0915”(physical association)	0.560
HR	RBP3	psi-mi:“MI:0915”(physical association)	0.560
HR	TSC1	psi-mi:“MI:0915”(physical association)	0.560
HR	ZMYND12	psi-mi:“MI:0915”(physical association)	0.560
HR	SPAG8	psi-mi:“MI:0915”(physical association)	0.560
HR	CFAP68	psi-mi:“MI:0915”(physical association)	0.560
HR	KRTAP3-3	psi-mi:“MI:0915”(physical association)	0.560
HR	FAM168A	psi-mi:“MI:0915”(physical association)	0.560
PLA2G10	HR	psi-mi:“MI:0915”(physical association)	0.560
HR	KRTAP3-1	psi-mi:“MI:0915”(physical association)	0.560
HR	AMMECR1	psi-mi:“MI:0915”(physical association)	0.560
HR	KRTAP15-1	psi-mi:“MI:0915”(physical association)	0.560
HR	HOXA1	psi-mi:“MI:0915”(physical association)	0.560
HR	INCA1	psi-mi:“MI:0915”(physical association)	0.560
HR	KRTAP13-2	psi-mi:“MI:0915”(physical association)	0.560
HR	SPRY3	psi-mi:“MI:0915”(physical association)	0.560
HR	GEMIN4	psi-mi:“MI:0915”(physical association)	0.560
HR	VDR	psi-mi:“MI:0407”(direct interaction)	0.440
RARA	HR	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (51): TP53 (Affinity Capture-Western), HR (Affinity Capture-Western), HR (Biochemical Activity), HR (Two-hybrid), HR (Two-hybrid), HR (Two-hybrid), HR (Two-hybrid), HR (Two-hybrid), HR (Two-hybrid), HR (Two-hybrid), HR (Two-hybrid), HR (Two-hybrid), HR (Two-hybrid), HR (Two-hybrid), HR (Two-hybrid)

ESM2 similar proteins: A0A5F9ZHS7, A1YGK1, A2T7E6, A8MZG2, O08574, O43593, O60393, O75593, O88621, O95231, P0C1T1, P0CG20, P20428, P97609, Q04667, Q17QR5, Q2KIS6, Q2M1V0, Q2T9Q7, Q32LE6, Q497V6, Q5JUK2, Q5M844, Q5RJB0, Q5TGS1, Q61645, Q61657, Q6ZMY3, Q6ZN32, Q6ZNG2, Q7RTU1, Q8BZW2, Q8CGW9, Q8IWN7, Q8IXT2, Q8IZ20, Q8N1L9, Q8N7G0, Q8N944, Q8N9Y4

Diamond homologs: C0SUU8, C0SV12, F4HZD1, O43593, P97609, Q32PH1, Q4G059, Q4KM91, Q61645, Q8VYB9, Q922M5, Q96GN5, Q9BWT1, Q9D0M2, Q9SSE9, Q15652, Q8H1S7

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
TP53	“down-regulates quantity by repression”	HR	“transcriptional regulation”
2-oxoglutarate(2-)	“up-regulates activity”	HR	“chemical activation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 31 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
Keratinization	6	17.6×	9e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	24
Likely pathogenic	8
Uncertain significance	324
Likely benign	60
Benign	67

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1075245	NM_005144.5(HR):c.2147del (p.Pro716fs)	Pathogenic
1687272	NM_005144.5(HR):c.2541G>A (p.Trp847Ter)	Pathogenic
2111487	NM_005144.5(HR):c.2545C>T (p.Gln849Ter)	Pathogenic
2136646	NM_005144.5(HR):c.2455C>T (p.Arg819Ter)	Pathogenic
2136647	NM_005144.5(HR):c.1864T>G (p.Cys622Gly)	Pathogenic
2136648	NM_005144.5(HR):c.1146_1161dup (p.Ser388fs)	Pathogenic
2696995	NM_005144.5(HR):c.-248C>T	Pathogenic
2755530	NM_005144.5(HR):c.3287_3291dup (p.Leu1098fs)	Pathogenic
3646769	NM_005144.5(HR):c.-321A>G	Pathogenic
4709573	NM_005144.5(HR):c.2818C>T (p.Arg940Ter)	Pathogenic
4726510	NM_005144.5(HR):c.2416G>T (p.Glu806Ter)	Pathogenic
623309	NM_005144.5(HR):c.2776+1G>A	Pathogenic
667396	NM_005144.5(HR):c.2001_2004del (p.Ser667fs)	Pathogenic
7331	NM_005144.5(HR):c.3407T>A (p.Val1136Asp)	Pathogenic
7334	NM_005144.5(HR):c.1258del (p.Gln420fs)	Pathogenic
7335	NM_005144.5(HR):c.1837C>T (p.Arg613Ter)	Pathogenic
7338	NM_005144.5(HR):c.2847-2_2847-1del	Pathogenic
7339	NM_005144.5(HR):c.3526C>T (p.Gln1176Ter)	Pathogenic
7340	NM_005144.5(HR):c.3034G>A (p.Asp1012Asn)	Pathogenic
7341	NC_000008.11:g.22130707A>G	Pathogenic
7342	NC_000008.11:g.22130702G>A	Pathogenic
7343	NC_000008.11:g.22130636G>C	Pathogenic
7344	NC_000008.11:g.22130605T>C	Pathogenic
830233	NC_000008.11:g.22130706C>T	Pathogenic
2001115	NM_005144.5(HR):c.-248C>G	Likely pathogenic
2633428	NM_005144.5(HR):c.1595_1596del (p.Thr532fs)	Likely pathogenic
3064835	NM_005144.5(HR):c.1915+1G>A	Likely pathogenic
3393165	NM_005144.5(HR):c.1987_1988del (p.Gln663fs)	Likely pathogenic
3393319	NM_005144.5(HR):c.3199del (p.Arg1067fs)	Likely pathogenic
3777057	NM_005144.5(HR):c.3428_3429del (p.Pro1143fs)	Likely pathogenic

SpliceAI

3100 predictions. Top by Δscore:

Variant	Effect	Δscore
8:22119157:GACCT:G	donor_loss	1.0000
8:22119162:A:G	donor_loss	1.0000
8:22119163:C:CG	donor_loss	1.0000
8:22119163:CCTTT:C	donor_gain	1.0000
8:22119279:CACAC:C	acceptor_gain	1.0000
8:22119280:ACAC:A	acceptor_gain	1.0000
8:22119281:CAC:C	acceptor_gain	1.0000
8:22119281:CACC:C	acceptor_gain	1.0000
8:22119282:AC:A	acceptor_gain	1.0000
8:22119282:ACCTG:A	acceptor_loss	1.0000
8:22119283:CC:C	acceptor_gain	1.0000
8:22119284:C:CC	acceptor_gain	1.0000
8:22119284:CT:C	acceptor_loss	1.0000
8:22119287:C:CT	acceptor_gain	1.0000
8:22119288:A:AC	acceptor_gain	1.0000
8:22119288:A:C	acceptor_gain	1.0000
8:22119292:C:CT	acceptor_gain	1.0000
8:22119293:A:T	acceptor_gain	1.0000
8:22119294:A:AC	acceptor_gain	1.0000
8:22119294:A:C	acceptor_gain	1.0000
8:22120100:ACAC:A	donor_loss	1.0000
8:22120102:A:T	donor_loss	1.0000
8:22120103:CCTGC:C	donor_loss	1.0000
8:22120170:CGAA:C	acceptor_gain	1.0000
8:22120174:C:CC	acceptor_gain	1.0000
8:22120904:T:TA	donor_gain	1.0000
8:22120954:TCATC:T	acceptor_gain	1.0000
8:22120955:CATC:C	acceptor_gain	1.0000
8:22120955:CATCC:C	acceptor_gain	1.0000
8:22120956:ATC:A	acceptor_gain	1.0000

AlphaMissense

7641 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:22120924:A:T	I801N	0.999
8:22121092:G:C	F780L	0.998
8:22121092:G:T	F780L	0.998
8:22121094:A:G	F780L	0.998
8:22116960:A:G	L1098P	0.996
8:22118960:A:G	F1068S	0.996
8:22120924:A:C	I801S	0.996
8:22120927:A:T	I800N	0.994
8:22118993:A:G	F1057S	0.993
8:22121093:A:C	F780C	0.993
8:22127295:A:G	W383R	0.993
8:22127295:A:T	W383R	0.993
8:22127302:C:A	K380N	0.993
8:22127302:C:G	K380N	0.993
8:22119003:A:G	W1054R	0.992
8:22119003:A:T	W1054R	0.992
8:22120927:A:G	I800T	0.992
8:22120933:T:A	D798V	0.992
8:22121093:A:G	F780S	0.991
8:22127293:C:A	W383C	0.991
8:22127293:C:G	W383C	0.991
8:22116960:A:T	L1098Q	0.990
8:22118992:G:C	F1057L	0.990
8:22118992:G:T	F1057L	0.990
8:22118994:A:G	F1057L	0.990
8:22120900:A:G	I809T	0.990
8:22120922:C:G	A802P	0.990
8:22120924:A:G	I801T	0.990
8:22120927:A:C	I800S	0.990
8:22121150:A:G	L761P	0.990

dbSNP variants (sampled 300 via entrez): RS1000054480 (8:22131275 C>A,G,T), RS1000089838 (8:22116412 C>T), RS1000104685 (8:22130966 G>A), RS1000507763 (8:22122003 A>G), RS1000691998 (8:22117514 A>G,T), RS1000788001 (8:22118767 C>A,T), RS1000832928 (8:22132946 T>G), RS1001058916 (8:22132323 C>A,G,T), RS1001125936 (8:22126361 G>A), RS1001146810 (8:22117291 T>C), RS1001160697 (8:22123933 G>C,T), RS1001280146 (8:22131594 C>G,T), RS1001608044 (8:22123403 C>A), RS1001626743 (8:22131796 C>G), RS1001709867 (8:22128060 G>A,C)

Disease associations

OMIM: gene MIM:602302 | disease phenotypes: MIM:209500, MIM:203655, MIM:614607, MIM:146550

GenCC curated gene-disease

Disease	Classification	Inheritance
atrichia with papular lesions	Definitive	Autosomal recessive
hypotrichosis 4	Strong	Autosomal dominant
alopecia universalis congenita	Strong	Autosomal recessive
Marie Unna hereditary hypotrichosis	Supportive	Autosomal dominant

Mondo (5): atrichia with papular lesions (MONDO:0008847), alopecia universalis congenita (MONDO:0008757), intellectual disability, autosomal dominant 14 (MONDO:0013819), hypotrichosis 4 (MONDO:0100522), Marie Unna hereditary hypotrichosis (MONDO:0018631)

Orphanet (4): Atrichia with papular lesions (Orphanet:86819), Alopecia universalis (Orphanet:701), Coffin-Siris syndrome (Orphanet:1465), Marie Unna hereditary hypotrichosis (Orphanet:444)

HPO phenotypes

24 total (24 of 24 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000561	Absent eyelashes
HP:0000820	Abnormality of the thyroid gland
HP:0000822	Hypertension
HP:0001045	Vitiligo
HP:0001047	Atopic dermatitis
HP:0001596	Alopecia
HP:0001597	Abnormal nail morphology
HP:0002208	Coarse hair
HP:0002209	Sparse scalp hair
HP:0002221	Absent axillary hair
HP:0002223	Absent eyebrow
HP:0002232	Patchy alopecia
HP:0002289	Alopecia universalis
HP:0002555	Absent pubic hair
HP:0002960	Autoimmunity
HP:0003119	Abnormal circulating lipid concentration
HP:0003623	Neonatal onset
HP:0003765	Psoriasiform dermatitis
HP:0007482	Generalized papillary lesions
HP:0008070	Sparse hair
HP:0100651	Type I diabetes mellitus
HP:0100840	Aplasia/Hypoplasia of the eyebrow
HP:0200102	Sparse or absent eyelashes

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST001762_946	Obesity-related traits	5.000000e-06

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
C537055	Alopecia universalis (supp.)
C565924	Atrichia with Papular Lesions (supp.)
C567718	Marie Unna Hereditary Hypotrichosis 1 (supp.)
C535912	Marie Unna congenital hypotrichosis (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Estradiol	decreases reaction, increases expression, affects binding, affects reaction	4
bisphenol A	affects binding, affects folding, increases reaction, decreases reaction, decreases methylation	3
sodium arsenite	decreases expression, increases expression	3
Calcitriol	increases expression, decreases reaction, increases activity, increases reaction	3
trichostatin A	decreases reaction, increases activity, decreases expression	2
bisphenol AF	increases reaction, decreases reaction, affects binding, affects folding	2
Resveratrol	decreases expression, increases expression, affects cotreatment	2
Acetaminophen	decreases expression, increases expression	2
Doxorubicin	decreases expression	2
Tretinoin	decreases expression	2
GSK-J4	increases expression	1
TAK-243	increases sumoylation	1
beta-lapachone	decreases expression, increases expression	1
sulforaphane	decreases expression	1
butyraldehyde	decreases expression	1
aflatoxin B2	increases methylation	1
cupric chloride	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, decreases expression	1
abrine	decreases expression	1
bisphenol S	affects binding, decreases reaction	1
Sunitinib	decreases expression	1
Leflunomide	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Benzo(a)pyrene	increases methylation	1
Cisplatin	decreases expression	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Formaldehyde	increases expression	1
Lead	increases expression	1
Lipopolysaccharides	affects cotreatment, decreases expression	1
Lithocholic Acid	decreases reaction, increases activity, increases expression, increases reaction, affects binding	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1TX	Abcam HeLa HR KO	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02020161	PHASE4	UNKNOWN	Clinical Guidelines for APL Treatment
NCT07296445	PHASE3	NOT_YET_RECRUITING	A Trial to Investigate Whether Oral Arsenic Trioxide Is Similar to Intravenous Arsenic Trioxide in Pharmacokinetics, Safety, and Efficacy (LATITUDE/SDKARS-301)
NCT07503730	PHASE3	RECRUITING	Early Use of Realgar-Indigo Naturalis Formula (RIF) Combined With All-trans Retinoic Acid (ATRA) for Treating Acute Promyelocytic Leukemia (APL).
NCT05881265	PHASE2	RECRUITING	Treatment of Chidamide and Venetoclax for Retinoic Acid and Arsenic Resistant Acute Promyelocytic Leukemia