HYOU1

Summary

HYOU1 (hypoxia up-regulated 1, HGNC:16931) is a protein-coding gene on chromosome 11q23.3, encoding Hypoxia up-regulated protein 1 (Q9Y4L1). Has a pivotal role in cytoprotective cellular mechanisms triggered by oxygen deprivation. It is a common-essential gene (DepMap: required in 97.8% of cancer cell lines).

The protein encoded by this gene belongs to the heat shock protein 70 family. This gene uses alternative transcription start sites. A cis-acting segment found in the 5’ UTR is involved in stress-dependent induction, resulting in the accumulation of this protein in the endoplasmic reticulum (ER) under hypoxic conditions. The protein encoded by this gene is thought to play an important role in protein folding and secretion in the ER. Since suppression of the protein is associated with accelerated apoptosis, it is also suggested to have an important cytoprotective role in hypoxia-induced cellular perturbation. This protein has been shown to be up-regulated in tumors, especially in breast tumors, and thus it is associated with tumor invasiveness. This gene also has an alternative translation initiation site, resulting in a protein that lacks the N-terminal signal peptide. This signal peptide-lacking protein, which is only 3 amino acids shorter than the mature protein in the ER, is thought to have a housekeeping function in the cytosol. In rat, this protein localizes to both the ER by a carboxy-terminal peptide sequence and to mitochondria by an amino-terminal targeting signal. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 10525 — RefSeq curated summary.

At a glance

• Gene–disease (curated): granulocytopenia with immunoglobulin abnormality (Strong, GenCC)
• GWAS associations: 2
• Clinical variants (ClinVar): 862 total — 1 pathogenic
• Phenotypes (HPO): 29
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 97.8% of screened cell lines (common-essential)
• MANE Select transcript: NM_006389

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16931
Approved symbol	HYOU1
Name	hypoxia up-regulated 1
Location	11q23.3
Locus type	gene with protein product
Status	Approved
Aliases	ORP150, HSP12A, Grp170
Ensembl gene	ENSG00000149428
Ensembl biotype	protein_coding
OMIM	601746
Entrez	10525

Gene structure

Transcript identifiers

Ensembl transcripts: 48 — 33 protein_coding, 9 retained_intron, 6 nonsense_mediated_decay

ENST00000526354, ENST00000527038, ENST00000527738, ENST00000529174, ENST00000530467, ENST00000530473, ENST00000531682, ENST00000531694, ENST00000531968, ENST00000532421, ENST00000532519, ENST00000533381, ENST00000534233, ENST00000543287, ENST00000610597, ENST00000612687, ENST00000614711, ENST00000617285, ENST00000621959, ENST00000622474, ENST00000652093, ENST00000694928, ENST00000694929, ENST00000694930, ENST00000694932, ENST00000694933, ENST00000694934, ENST00000694935, ENST00000694937, ENST00000860896, ENST00000860897, ENST00000860898, ENST00000860899, ENST00000860900, ENST00000860901, ENST00000860902, ENST00000860903, ENST00000860904, ENST00000860905, ENST00000860906, ENST00000860907, ENST00000860908, ENST00000914427, ENST00000914428, ENST00000914429, ENST00000914430, ENST00000964763, ENST00000964764

RefSeq mRNA: 3 — MANE Select: NM_006389 NM_001130991, NM_001411041, NM_006389

CCDS: CCDS8408, CCDS91604

Canonical transcript exons

ENST00000617285 — 26 exons

Exon	Start	End
ENSE00002144682	119054494	119054675
ENSE00002158938	119049018	119049203
ENSE00002873775	119054984	119055060
ENSE00003511401	119052637	119052829
ENSE00003513632	119054121	119054236
ENSE00003548013	119052090	119052172
ENSE00003571740	119051819	119051951
ENSE00003591080	119051035	119051173
ENSE00003597444	119052295	119052429
ENSE00003600576	119051438	119051625
ENSE00003600887	119049777	119049837
ENSE00003652093	119049556	119049635
ENSE00003712609	119048248	119048370
ENSE00003721677	119046562	119046802
ENSE00003725645	119045781	119045831
ENSE00003741565	119047947	119048080
ENSE00003741624	119047734	119047818
ENSE00003746107	119044188	119045654
ENSE00003746367	119055185	119055339
ENSE00003751075	119048476	119048563
ENSE00003752754	119048714	119048886
ENSE00003754739	119046417	119046467
ENSE00003849190	119057020	119057205
ENSE00003963361	119056070	119056167
ENSE00003963364	119055750	119055843
ENSE00003963370	119055493	119055571

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 98.55.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 46.7106 / max 568.2557, expressed in 1822 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
122679	26.8283	1814
122681	13.8920	1791
122680	2.4371	1368
122676	1.7561	1110
122682	1.0324	732
122678	0.7648	399

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
islet of Langerhans	UBERON:0000006	98.55	gold quality
pancreas	UBERON:0001264	97.97	gold quality
body of pancreas	UBERON:0001150	97.77	gold quality
adenohypophysis	UBERON:0002196	97.55	gold quality
pituitary gland	UBERON:0000007	97.50	gold quality
right testis	UBERON:0004534	96.89	gold quality
left testis	UBERON:0004533	96.74	gold quality
right lobe of thyroid gland	UBERON:0001119	96.50	gold quality
stromal cell of endometrium	CL:0002255	96.47	gold quality
left lobe of thyroid gland	UBERON:0001120	96.31	gold quality
thyroid gland	UBERON:0002046	96.19	gold quality
vermiform appendix	UBERON:0001154	95.95	gold quality
right lobe of liver	UBERON:0001114	95.92	gold quality
testis	UBERON:0000473	95.85	gold quality
bone marrow cell	CL:0002092	95.76	gold quality
hypothalamus	UBERON:0001898	95.60	gold quality
mucosa of transverse colon	UBERON:0004991	95.49	gold quality
superior frontal gyrus	UBERON:0002661	95.46	gold quality
placenta	UBERON:0001987	94.89	gold quality
liver	UBERON:0002107	94.82	gold quality
nucleus accumbens	UBERON:0001882	94.65	gold quality
anterior cingulate cortex	UBERON:0009835	94.60	gold quality
tonsil	UBERON:0002372	94.52	gold quality
putamen	UBERON:0001874	94.48	gold quality
caudate nucleus	UBERON:0001873	94.34	gold quality
adult mammalian kidney	UBERON:0000082	94.29	gold quality
frontal cortex	UBERON:0001870	94.29	gold quality
prefrontal cortex	UBERON:0000451	94.26	gold quality
apex of heart	UBERON:0002098	94.15	gold quality
right frontal lobe	UBERON:0002810	94.15	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	12.96

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ATF6, ESR1, FOXO1, SIRT1

miRNA regulators (miRDB)

109 targeting HYOU1, 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-6798-5P	100.00	65.77	699
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-552-5P	99.93	68.56	1583
HSA-MIR-8062	99.88	68.43	995
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-4756-5P	99.84	64.98	1809
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-6756-5P	99.82	67.97	2466
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

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 97.8% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 30)

• ORP150 exerts cytoprotective effects in renal tubular epithelia subjected to I/R injury and suggest a key role for ER stress in the renal tubular response to acute renal failure (PMID:15240565)
• Hypoxia results in an enhancement of ORP 150 expression in several tumour cell lines. (PMID:16543725)
• These findings suggest that ORP150 is structurally and functionally well conserved in distant species (PMID:17131193)
• Our observations led to the hypothesis that ORP150 protects against MPTP/MPP(+)-induced neurotoxicity, and indicate the importance of the ER environment in maintaining the nigrostriatal pathways. (PMID:17330988)
• data indicate ORP150 inhibits oxLDL-induced apoptosis by blocking calcium signaling & apoptosis; calcium released from ER stores is inhibited by ORP150; ORP150 is expressed in advanced atherosclerotic lesions (PMID:18404158)
• The forced expression of ORP150 highlights its new protective role against oxLDL-induced ER stress and subsequent apoptosis (PMID:19106412)
• the increased expression of ORP150 is a factor which protects collagen against intracellular degradation induced by glucose deprivation. (PMID:19225868)
• The ORP150-precursor peptide complex can elicit a cytotoxic T-lymphocyte response through cross-presentation, as well as the CD4-positive T cell response by dendritic cells. (PMID:19812200)
• Report ORP-150 levels in autopsy tissue after hypoxia/ischemia events in term neonates. (PMID:20626887)
• AICAR infusion enhanced ORP150 expression, resulting in the marked amelioration of hepatic ER stress and apoptosis (PMID:21296878)
• Data indicate that Grp170 (Lhs1 ortholog) coprecipitate with alphaENaC. (PMID:23645669)
• inducible overexpression of ORP150, in ER stress conditions, exerts inhibitory effect on apoptosis and senescence in human breast carcinoma cells but not in normal fibroblasts (PMID:23757447)
• Here we show that Grp170 can bind directly to a variety of incompletely folded protein substrates in the endoplasmic reticulum, and as expected for a bona fide chaperone, it does not interact with folded secretory proteins. (PMID:24327659)
• HYOU1 also modulates vIL-6’s ability to induce CCL2. (PMID:24920810)
• Grp170 induces nucleotide exchange of BiP and releases SV40 virus from BiP, promoting SV40 ER-to-cytosol transport and infection. (PMID:25653441)
• Two NEFs, Grp170 and Sil1, trigger toxin release from BiP to enable successful retrotranslocation and clarify the fate of the toxin after it disengages from BiP. (PMID:25877869)
• High ORP150 expression is associated with thyroid cancer. (PMID:26700459)
• Findings establish a general function of Grp170 during ERAD and suggest that positioning this client-release factor at the retrotranslocation site may afford a mechanism to couple client release from BiP and retrotranslocation. (PMID:27030672)
• Data reveal that Grp170 participates in preparing mutant proinsulin for degradation while enabling wild-type proinsulin escape from the endoplasmic reticulum. (PMID:28028074)
• ORP150 and CHIP demonstrate antagonism under normal and stress conditions wherein they inversely regulate each other thus affecting BACE1 level. (PMID:29266373)
• These results strongly suggest that AMPK can activate ORP150 through FOXO1 pathway and confer protection against endoplasmic reticulum stress - induced apoptosis of airway epithelial cells following exposure to cigarette smoke extract. (PMID:29448096)
• Serum level of ORP150 was significantly up-regulated in the diabetic nephropathy patients.ORP150 levels were positively correlated with proteinuria burden via mediating VEGF in the diabetic nephropathy. (PMID:31028725)
• Study found that the expression levels of HYOU1 were significantly upregulated in both EOC tissues and cell lines, and associated with advanced FIGO stage, LN metastasis, and shorter overall survival. In addition, high HYOU1 expression as an unfavorable factor for overall survival. Its inhibition of HYOU1 suppressed tumor proliferation and colony formation, as well as the migratory and invasive capacity. (PMID:31173282)
• we demonstrate that in the ER,Akita forms detergent-insoluble protein aggregates that entrap WT proinsulin. Strikingly, we find that two distinct ER quality-control pathways are deployed to limit the levels of these aggregates. First, Grp170 acts to prevent formation of detergent-insoluble Akita aggregates, which otherwise recruit and capture WT proinsulin. (PMID:31176671)
• Long non-coding antisense RNA HYOU1-AS is essential to human breast cancer development through competitive binding hnRNPA1 to promote HYOU1 expression. (PMID:33422616)
• Expression of HYOU1 via Reciprocal Crosstalk between NSCLC Cells and HUVECs Control Cancer Progression and Chemoresistance in Tumor Spheroids. (PMID:33455947)
• HYOU1 facilitates proliferation, invasion and glycolysis of papillary thyroid cancer via stabilizing LDHB mRNA. (PMID:33792181)
• Long non-coding RNA KCNQ1OT1 facilitates the progression of cervical cancer and tumor growth through modulating miR-296-5p/HYOU1 axis. (PMID:34704918)
• The Clinical and Molecular Assessment of Iranian Families with Severe Congenital Neutropenia, Identification of HYOU1 and SHOC2 as Potential Novel Gene Defects. (PMID:35822684)
• HYOU1 promotes cell proliferation, migration, and invasion via the PI3K/AKT/FOXO1 feedback loop in bladder cancer. (PMID:36348197)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	hyou1	ENSDARG00000013670
mus_musculus	Hyou1	ENSMUSG00000032115
rattus_norvegicus	Hyou1	ENSRNOG00000010944
drosophila_melanogaster	Grp170	FBGN0023529
caenorhabditis_elegans		WBGENE00011771

Paralogs (13): HSPA5 (ENSG00000044574), HSPA8 (ENSG00000109971), HSPA9 (ENSG00000113013), HSPH1 (ENSG00000120694), HSPA2 (ENSG00000126803), HSPA13 (ENSG00000155304), HSPA4L (ENSG00000164070), HSPA4 (ENSG00000170606), HSPA6 (ENSG00000173110), HSPA14 (ENSG00000187522), HSPA1B (ENSG00000204388), HSPA1A (ENSG00000204389), HSPA1L (ENSG00000204390)

Protein

Protein identifiers

Hypoxia up-regulated protein 1 — Q9Y4L1 (reviewed: Q9Y4L1)

Alternative names: 150 kDa oxygen-regulated protein, 170 kDa glucose-regulated protein, Heat shock protein family H member 4

All UniProt accessions (14): Q9Y4L1, A0A087WWI4, A0A087X054, A0A384P5T6, A0A494C039, A0A8Q3SHG4, A0A8Q3SHL4, A0A8Q3SHP7, E9PJ21, J3KSR2, J3KTF1, J3QLE9, J3QQH7, K7EQK2

UniProt curated annotations — full annotation on UniProt →

Function. Has a pivotal role in cytoprotective cellular mechanisms triggered by oxygen deprivation. Promotes HSPA5/BiP-mediated ATP nucleotide exchange and thereby activates the unfolded protein response (UPR) pathway in the presence of endoplasmic reticulum stress. May play a role as a molecular chaperone and participate in protein folding.

Subunit / interactions. Part of a large chaperone multiprotein complex comprising DNAJB11, HSP90B1, HSPA5, HYOU, PDIA2, PDIA4, PDIA6, PPIB, SDF2L1, UGGT1 and very small amounts of ERP29, but not, or at very low levels, CALR nor CANX.

Subcellular location. Endoplasmic reticulum lumen.

Tissue specificity. Highly expressed in tissues that contain well-developed endoplasmic reticulum and synthesize large amounts of secretory proteins. Highly expressed in liver and pancreas and lower expression in brain and kidney. Also expressed in macrophages within aortic atherosclerotic plaques, and in breast cancers.

Disease relevance. Immunodeficiency 59 and hypoglycemia (IMD59) [MIM:233600] An autosomal recessive primary immunologic disorder characterized by combined immunodeficiency, granulocytopenia, B-cell and dendritic cell deficiency, recurrent septic infections of the respiratory tract, skin and mucous membranes, and disturbed glucose metabolism. The disease may be caused by variants affecting the gene represented in this entry.

Induction. By hypoxia and also by 2-deoxyglucose or tunicamycin.

Similarity. Belongs to the heat shock protein 70 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9Y4L1-1	1	yes
Q9Y4L1-2	2

RefSeq proteins (3): NP_001124463, NP_001397970, NP_006380* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR013126	Hsp_70_fam	Family
IPR018181	Heat_shock_70_CS	Conserved_site
IPR029047	HSP70_peptide-bd_sf	Homologous_superfamily
IPR029048	HSP70_C_sf	Homologous_superfamily
IPR043129	ATPase_NBD	Homologous_superfamily

Pfam: PF00012

UniProt features (27 total): glycosylation site 9, sequence conflict 4, splice variant 3, region of interest 2, sequence variant 2, compositionally biased region 2, modified residue 2, signal peptide 1, chain 1, short sequence motif 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y4L1-F1	81.96	0.68

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 (2): 567, 883

Glycosylation sites (9): 222, 515, 596, 830, 862, 869, 922, 931, 155

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-3000484	Scavenging by Class F Receptors
R-HSA-381038	XBP1(S) activates chaperone genes
R-HSA-9918432	Maturation of DENV proteins

MSigDB gene sets: 342 (showing top): GOBP_NEGATIVE_REGULATION_OF_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GOBP_NEGATIVE_REGULATION_OF_NEURON_APOPTOTIC_PROCESS, REACTOME_UNFOLDED_PROTEIN_RESPONSE_UPR, GRUETZMANN_PANCREATIC_CANCER_DN, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, KAAB_HEART_ATRIUM_VS_VENTRICLE_UP, GOBP_VESICLE_MEDIATED_TRANSPORT, MODULE_503, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, GOBP_PROTEIN_MATURATION, GOBP_NEGATIVE_REGULATION_OF_INTRINSIC_APOPTOTIC_SIGNALING_PATHWAY, GOBP_ENDOPLASMIC_RETICULUM_TO_GOLGI_VESICLE_MEDIATED_TRANSPORT, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_LEVELS, MODULE_195, GOBP_APOPTOTIC_SIGNALING_PATHWAY

GO Biological Process (11): response to ischemia (GO:0002931), endoplasmic reticulum to Golgi vesicle-mediated transport (GO:0006888), response to endoplasmic reticulum stress (GO:0034976), cellular response to hypoxia (GO:0071456), negative regulation of hypoxia-induced intrinsic apoptotic signaling pathway (GO:1903298), negative regulation of endoplasmic reticulum stress-induced neuron intrinsic apoptotic signaling pathway (GO:1903382), protein folding (GO:0006457), response to stress (GO:0006950), negative regulation of apoptotic process (GO:0043066), regulation of cellular response to stress (GO:0080135), negative regulation of intrinsic apoptotic signaling pathway (GO:2001243)

GO Molecular Function (7): adenyl-nucleotide exchange factor activity (GO:0000774), ATP binding (GO:0005524), obsolete unfolded protein binding (GO:0051082), protein-folding chaperone binding (GO:0051087), ATP-dependent protein folding chaperone (GO:0140662), nucleotide binding (GO:0000166), protein binding (GO:0005515)

GO Cellular Component (10): extracellular region (GO:0005576), mitochondrion (GO:0005739), endoplasmic reticulum (GO:0005783), endoplasmic reticulum lumen (GO:0005788), smooth endoplasmic reticulum (GO:0005790), focal adhesion (GO:0005925), membrane (GO:0016020), endoplasmic reticulum chaperone complex (GO:0034663), extracellular exosome (GO:0070062), endocytic vesicle lumen (GO:0071682)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Binding and Uptake of Ligands by Scavenger Receptors	1
IRE1alpha activates chaperones	1
Dengue Virus Genome Translation and Replication	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	3
cellular response to stress	3
cellular anatomical structure	2
intracellular membrane-bounded organelle	2
endoplasmic reticulum	2
intracellular organelle lumen	2
response to stress	1
intercellular transport	1
intracellular transport	1
Golgi vesicle transport	1
response to hypoxia	1
cellular response to decreased oxygen levels	1
negative regulation of cellular response to hypoxia	1
regulation of hypoxia-induced intrinsic apoptotic signaling pathway	1
intrinsic apoptotic signaling pathway in response to hypoxia	1
negative regulation of intrinsic apoptotic signaling pathway	1
neuron intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress	1
negative regulation of neuron apoptotic process	1
negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway	1
regulation of endoplasmic reticulum stress-induced neuron intrinsic apoptotic signaling pathway	1
cellular process	1
protein maturation	1
response to stimulus	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
regulation of cellular process	1
regulation of response to stress	1
intrinsic apoptotic signaling pathway	1
negative regulation of intracellular signal transduction	1
negative regulation of apoptotic signaling pathway	1
regulation of intrinsic apoptotic signaling pathway	1
ATP binding	1
ADP binding	1
ATPase regulator activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
protein binding	1
protein folding chaperone	1
ATP-dependent activity	1

Protein interactions and networks

STRING

3962 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HYOU1	HSP90B1	P14625	995
HYOU1	PDIA4	P13667	988
HYOU1	SIL1	Q9H173	959
HYOU1	HSPA5	P11021	913
HYOU1	DNAJB9	Q9UBS3	892
HYOU1	DNAJB11	Q9UBS4	890
HYOU1	PPIB	P23284	875
HYOU1	SCARF1	Q14162	855
HYOU1	CALR	P27797	840
HYOU1	SDF2L1	Q9HCN8	829
HYOU1	PDIA3	P30101	816
HYOU1	DNAJC3	Q13217	813
HYOU1	OS9	Q13438	793
HYOU1	CANX	P27824	791
HYOU1	DNAJC10	Q8IXB1	786

IntAct

221 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
GABARAPL2	IPO5	psi-mi:“MI:0914”(association)	0.690
HSPA5	HYOU1	psi-mi:“MI:0915”(physical association)	0.670
IGF1R	PIK3R2	psi-mi:“MI:2364”(proximity)	0.590
AURKB	SEC16A	psi-mi:“MI:2364”(proximity)	0.570
CANX	PGRMC1	psi-mi:“MI:0914”(association)	0.570
INSR	PIK3R2	psi-mi:“MI:2364”(proximity)	0.570
COL1A1	PDIA4	psi-mi:“MI:0914”(association)	0.560
GRB2	ARHGEF35	psi-mi:“MI:0914”(association)	0.530
	PLOD2	psi-mi:“MI:0914”(association)	0.530
EGFR	NDUFA4	psi-mi:“MI:0914”(association)	0.530
FBXO2	TMEM131L	psi-mi:“MI:0914”(association)	0.530
OS9	AGRN	psi-mi:“MI:0914”(association)	0.530
COL1A1	GOLIM4	psi-mi:“MI:0914”(association)	0.500
COL1A1	GOLIM4	psi-mi:“MI:0915”(physical association)	0.500
TUBA1A	TUBAL3	psi-mi:“MI:0914”(association)	0.420
ALK	PIK3R2	psi-mi:“MI:0914”(association)	0.420

BioGRID (427): HYOU1 (Affinity Capture-RNA), HYOU1 (Affinity Capture-RNA), HYOU1 (Affinity Capture-MS), HYOU1 (Affinity Capture-MS), HYOU1 (Affinity Capture-MS), HYOU1 (Affinity Capture-MS), HYOU1 (Affinity Capture-Western), HYOU1 (Affinity Capture-MS), DNAJB11 (Co-fractionation), DNAJC7 (Co-fractionation), ETF1 (Co-fractionation), HK1 (Co-fractionation), HK2 (Co-fractionation), HYOU1 (Co-fractionation), HYOU1 (Co-fractionation)

ESM2 similar proteins: A2QCJ2, A6SL49, C5P635, E9CS37, F1QR43, F4HQD4, F4HTM3, F4JMJ1, O18756, O47881, O82491, O94874, O94923, P07153, P32621, P78586, Q01217, Q01317, Q0UVK7, Q0VA61, Q2UPI1, Q4R4T0, Q4X0Z7, Q566I3, Q5AZT7, Q5ZLK7, Q60432, Q63617, Q6CNR9, Q6FPE6, Q6GNG3, Q7DMA9, Q7S8C4, Q7X923, Q7ZUW2, Q8H6B1, Q8LDU1, Q8LPF0, Q8TGG8, Q8TGH6

Diamond homologs: A0A0D1CD96, A1BET8, A1UUC3, A2Q0Z1, A5CM86, A9ILH7, B0RBI1, B2IBR4, B3Q972, B5YH59, B6JCI3, B8EIP9, F4JMJ1, G3I8R9, O05700, O65719, O73885, O97125, P02825, P02827, P06761, P07823, P0DMW0, P0DMW1, P11021, P11142, P11145, P11146, P11484, P14834, P16474, P17804, P17879, P18694, P19120, P19378, P20029, P22010, P22623, P22954

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
ATF6	“up-regulates quantity by expression”	HYOU1	“transcriptional regulation”
SIRT1	“up-regulates quantity by expression”	HYOU1	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 217 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
PI3K Cascade	6	10.8×	3e-03
Transcriptional Regulation by MECP2	5	10.5×	9e-03
Dengue Virus Attachment and Entry	6	10.3×	3e-03
Constitutive Signaling by Aberrant PI3K in Cancer	11	9.2×	8e-06
Defective CFTR causes cystic fibrosis	6	8.7×	7e-03
Hedgehog ligand biogenesis	6	8.4×	7e-03
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	13	8.3×	3e-06
Anchoring of the basal body to the plasma membrane	11	8.2×	2e-05

GO biological processes:

GO term	Partners	Fold	FDR
peptidyl-tyrosine phosphorylation	10	22.4×	8e-09
positive regulation of MAP kinase activity	6	20.7×	8e-05
cell surface receptor protein tyrosine kinase signaling pathway	19	17.6×	2e-15
protein autophosphorylation	13	10.1×	2e-07
positive regulation of protein localization to plasma membrane	6	8.7×	8e-03
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	20	8.3×	3e-10
response to endoplasmic reticulum stress	8	7.1×	3e-03
ERAD pathway	7	6.8×	1e-02

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	519
Likely benign	277
Benign	26

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
599200	NM_006389.5(HYOU1):c.691T>C (p.Tyr231His)	Pathogenic

SpliceAI

3661 predictions. Top by Δscore:

Variant	Effect	Δscore
11:119046413:TCA:T	donor_loss	1.0000
11:119046414:CACCA:C	donor_loss	1.0000
11:119046416:CCAGT:C	donor_gain	1.0000
11:119046463:CTGGC:C	acceptor_gain	1.0000
11:119046467:CCT:C	acceptor_loss	1.0000
11:119046468:C:CA	acceptor_loss	1.0000
11:119046468:C:CC	acceptor_gain	1.0000
11:119046469:T:A	acceptor_loss	1.0000
11:119046557:CTCA:C	donor_loss	1.0000
11:119046559:CA:C	donor_loss	1.0000
11:119046560:ACCTG:A	donor_loss	1.0000
11:119046561:C:T	donor_loss	1.0000
11:119046561:CCTG:C	donor_gain	1.0000
11:119047730:TTACC:T	donor_loss	1.0000
11:119047732:A:AC	donor_gain	1.0000
11:119047732:AC:A	donor_gain	1.0000
11:119047733:C:CC	donor_gain	1.0000
11:119047733:CC:C	donor_gain	1.0000
11:119047737:G:C	donor_gain	1.0000
11:119047754:T:A	donor_gain	1.0000
11:119047814:CCCCC:C	acceptor_gain	1.0000
11:119047815:CCCC:C	acceptor_gain	1.0000
11:119047815:CCCCC:C	acceptor_gain	1.0000
11:119047816:CCC:C	acceptor_gain	1.0000
11:119047816:CCCC:C	acceptor_gain	1.0000
11:119047817:CC:C	acceptor_gain	1.0000
11:119047817:CCC:C	acceptor_gain	1.0000
11:119047818:CC:C	acceptor_gain	1.0000
11:119047818:CCTG:C	acceptor_loss	1.0000
11:119047819:C:CC	acceptor_gain	1.0000

AlphaMissense

6561 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:119049620:A:G	I581T	1.000
11:119049620:A:T	I581N	1.000
11:119046674:C:A	K908N	0.999
11:119046674:C:G	K908N	0.999
11:119046684:A:G	L905P	0.999
11:119046699:C:G	R900P	0.999
11:119049620:A:C	I581S	0.999
11:119051072:A:G	F543S	0.999
11:119051078:G:T	A541D	0.999
11:119051080:C:A	K540N	0.999
11:119051080:C:G	K540N	0.999
11:119051082:T:C	K540E	0.999
11:119051617:G:C	F449L	0.999
11:119051617:G:T	F449L	0.999
11:119051619:A:G	F449L	0.999
11:119051867:A:C	F430L	0.999
11:119051867:A:T	F430L	0.999
11:119051869:A:G	F430L	0.999
11:119051886:G:T	A424D	0.999
11:119051890:C:G	A423P	0.999
11:119051905:C:A	G418W	0.999
11:119052680:C:G	R315P	0.999
11:119055560:C:A	R66M	0.999
11:119055786:A:T	V50D	0.999
11:119049607:A:C	F585L	0.998
11:119049607:A:T	F585L	0.998
11:119049608:A:C	F585C	0.998
11:119049609:A:G	F585L	0.998
11:119049632:A:T	L577H	0.998
11:119051079:C:G	A541P	0.998

dbSNP variants (sampled 300 via entrez): RS1000010527 (11:119058378 A>T), RS1000069607 (11:119045393 C>A,T), RS1000239980 (11:119053387 T>C,G), RS1000253955 (11:119058710 A>G), RS1000373735 (11:119047352 C>T), RS1000590490 (11:119053642 C>A), RS1000708936 (11:119055363 C>A,T), RS1001013130 (11:119057215 G>A,C), RS1001066650 (11:119043786 A>G), RS1001478537 (11:119058963 G>A), RS1001550988 (11:119054305 C>A,T), RS1001824856 (11:119059144 G>A,C), RS1001915569 (11:119044199 A>G), RS1002020570 (11:119050338 G>A,T), RS1002424482 (11:119057954 C>G,T)

Disease associations

OMIM: gene MIM:601746 | disease phenotypes: MIM:618218, MIM:233600

GenCC curated gene-disease

Disease	Classification	Inheritance
granulocytopenia with immunoglobulin abnormality	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
granulocytopenia with immunoglobulin abnormality	Limited	AR

Mondo (2): infantile hypotonia-oculomotor anomalies-hyperkinetic movements-developmental delay syndrome (MONDO:0033864), granulocytopenia with immunoglobulin abnormality (MONDO:0009305)

Orphanet (1): Infantile hypotonia-oculomotor anomalies-hyperkinetic movements-developmental delay syndrome (Orphanet:522077)

HPO phenotypes

29 total (29 of 29 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000218	High palate
HP:0000275	Narrow face
HP:0000300	Oval face
HP:0000347	Micrognathia
HP:0000431	Wide nasal bridge
HP:0000460	Narrow nose
HP:0000768	Pectus carinatum
HP:0001238	Slender finger
HP:0001581	Recurrent skin infections
HP:0001943	Hypoglycemia
HP:0002024	Malabsorption
HP:0002028	Chronic diarrhea
HP:0002240	Hepatomegaly
HP:0002721	Immunodeficiency
HP:0002783	Recurrent lower respiratory tract infections
HP:0002788	Recurrent upper respiratory tract infections
HP:0003623	Neonatal onset
HP:0004313	Decreased circulating immunoglobulin concentration
HP:0004322	Short stature
HP:0006579	Prolonged neonatal jaundice
HP:0009890	High anterior hairline
HP:0011107	Recurrent aphthous stomatitis
HP:0012089	Arteritis
HP:0012302	Herpes simplex encephalitis
HP:0030388	Decreased class-switched memory B cell proportion
HP:0040154	Acne inversa
HP:0100806	Sepsis
HP:0410300	Complete or near-complete absence of specific antibody response to unconjugated pneumococcus vaccine

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST003264_865	Post bronchodilator FEV1/FVC ratio	1.000000e-06
GCST011800_6	Post-bronchodilator lung function in asthma (FVC)	9.000000e-09

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004713	FEV/FVC ratio
EFO:0004312	vital capacity

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C565535	Granulocytopenia with Immunoglobulin Abnormality (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2216741 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 4 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.28	Kd	52.36	nM	CHEMBL5653589
7.28	ED50	52.36	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 7 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148563: Binding affinity to human HYOU1 incubated for 45 mins by Kinobead based pull down assay	kd	0.0524	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Cyclosporine	increases expression	6
bisphenol A	increases expression, increases methylation, affects expression, decreases expression	5
sodium arsenite	affects cotreatment, increases abundance, increases expression, decreases expression	5
Tunicamycin	increases expression	5
Air Pollutants	affects cotreatment, increases abundance, increases oxidation, increases expression	2
Arsenic	increases expression, affects cotreatment, decreases expression, increases abundance	2
Nickel	increases expression	2
Ozone	affects cotreatment, increases oxidation, increases abundance, decreases expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
Cadmium Chloride	decreases expression, increases abundance, increases expression	2
Thapsigargin	increases expression	2
bisphenol F	increases expression	1
dicrotophos	increases expression	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	increases abundance, affects cotreatment, increases oxidation	1
titanium dioxide	decreases methylation	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
cobaltous chloride	decreases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
diallyl trisulfide	decreases expression	1
bicalutamide	increases expression	1
perfluorooctane sulfonic acid	increases expression	1
deguelin	increases expression	1
2-palmitoylglycerol	increases expression	1
dimethylarsinous acid	increases expression	1
ICG 001	decreases expression	1
bisphenol B	increases expression	1
thifluzamide	increases expression	1
(4-amino-1,4-dihydro-3-(2-pyridyl)-5-thioxo-1,2,4-triazole)copper(II)	increases expression	1

ChEMBL screening assays

4 unique, capped per target: 4 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2217167	Binding	Binding affinity to HYOU1 in human HepG2 cell lysate after 1 hr by capture compound based LC/MS analysis	Dabigatran and dabigatran ethyl ester: potent inhibitors of ribosyldihydronicotinamide dehydrogenase (NQO2). — J Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT07329257	Not specified	RECRUITING	Investigating Phenotypic, Epigenetic, and NeuroGenetic Traits in Rare and Ultra-rare Neurodevelopmental Disorders (Project PENGUIN)