HRNR

Summary

HRNR (hornerin, HGNC:20846) is a protein-coding gene on chromosome 1q21.3, encoding Hornerin (Q86YZ3). Component of the epidermal cornified cell envelopes.

Predicted to enable calcium ion binding activity and transition metal ion binding activity. Involved in cell envelope organization and establishment of skin barrier. Located in cornified envelope; keratohyalin granule; and perinuclear region of cytoplasm.

Source: NCBI Gene 388697 — RefSeq curated summary.

At a glance

• GWAS associations: 17
• Clinical variants (ClinVar): 3 total
• Druggable target: yes
• MANE Select transcript: NM_001009931

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20846
Approved symbol	HRNR
Name	hornerin
Location	1q21.3
Locus type	gene with protein product
Status	Approved
Aliases	S100a18, S100A16, FLG3
Ensembl gene	ENSG00000197915
Ensembl biotype	protein_coding
OMIM	616293
Entrez	388697

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000368801

RefSeq mRNA: 1 — MANE Select: NM_001009931 NM_001009931

CCDS: CCDS30859

Canonical transcript exons

ENST00000368801 — 3 exons

Exon	Start	End
ENSE00001447986	152212076	152221490
ENSE00001447987	152223116	152223278
ENSE00001447988	152224143	152224193

Expression profiles

Bgee: expression breadth broad, 100 present calls, max score 73.04.

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	73.04	gold quality
sural nerve	UBERON:0015488	69.83	gold quality
lower esophagus mucosa	UBERON:0035834	64.57	gold quality
cortical plate	UBERON:0005343	61.18	gold quality
ganglionic eminence	UBERON:0004023	56.86	gold quality
islet of Langerhans	UBERON:0000006	54.53	gold quality
colonic epithelium	UBERON:0000397	52.89	gold quality
bone marrow cell	CL:0002092	52.81	gold quality
esophagus mucosa	UBERON:0002469	51.89	gold quality
adrenal tissue	UBERON:0018303	51.82	gold quality
urinary bladder	UBERON:0001255	51.18	silver quality
pancreas	UBERON:0001264	50.55	gold quality
tonsil	UBERON:0002372	50.39	silver quality
corpus callosum	UBERON:0002336	50.32	silver quality
kidney	UBERON:0002113	50.05	gold quality
adult mammalian kidney	UBERON:0000082	49.44	gold quality
skeletal muscle tissue	UBERON:0001134	49.43	gold quality
mucosa of stomach	UBERON:0001199	49.12	gold quality
metanephros cortex	UBERON:0010533	48.68	gold quality
calcaneal tendon	UBERON:0003701	48.31	silver quality
uterine cervix	UBERON:0000002	48.21	gold quality
left ovary	UBERON:0002119	48.16	gold quality
hindlimb stylopod muscle	UBERON:0004252	48.07	gold quality
muscle tissue	UBERON:0002385	47.83	gold quality
esophagus	UBERON:0001043	47.66	gold quality
left uterine tube	UBERON:0001303	47.31	gold quality
ovary	UBERON:0000992	47.26	gold quality
body of pancreas	UBERON:0001150	47.01	gold quality
liver	UBERON:0002107	46.93	gold quality
skin of abdomen	UBERON:0001416	46.83	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.83

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

66 targeting HRNR, 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-3646	100.00	73.56	5283
HSA-MIR-33A-5P	99.99	68.62	1055
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-433-3P	99.98	69.37	1203
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-10395-5P	99.86	67.35	676
HSA-MIR-139-5P	99.80	69.50	1399
HSA-MIR-374C-5P	99.80	72.06	2910
HSA-MIR-655-3P	99.80	72.19	2909
HSA-MIR-2052	99.79	69.37	2031
HSA-MIR-6885-3P	99.75	70.36	3187
HSA-MIR-132-3P	99.73	70.56	1424
HSA-MIR-212-3P	99.73	70.65	1424
HSA-MIR-4524A-3P	99.72	66.85	2406
HSA-MIR-494-3P	99.70	71.45	2795
HSA-MIR-586	99.65	70.40	2051
HSA-MIR-5700	99.64	69.88	2280
HSA-MIR-9851-3P	99.63	69.68	1110
HSA-MIR-4452	99.50	68.45	1493
HSA-MIR-4519	99.48	66.10	859
HSA-MIR-582-5P	99.47	70.79	2635
HSA-MIR-1272	99.34	68.79	878
HSA-MIR-593-5P	99.34	69.50	965
HSA-MIR-548V	99.29	69.47	1157
HSA-MIR-4477B	99.23	70.49	1733
HSA-MIR-2054	99.20	68.89	1699

Literature-anchored findings (GeneRIF, showing 13)

• hornerin is expressed in regenerating and psoriatic skin (PMID:15507446)
• HRNR is expressed in healthy skin and contributes to its barrier function (PMID:19020553)
• The data demonstrate that HRNR is a component of cornified cell envelopes of human epidermis. Its reduced expression in AD may contribute to the epidermal barrier defect observed in the disease. (PMID:21282207)
• Our data opens new possibilities for hornerin and its proteolytic fragments in the control of mammary cell function and breast cancer. (PMID:22727333)
• Analysis of the rs877776 single nucleotide polymorphism in HRNR revealed neither a significant difference in genotype distribution between patients and controls nor a significant association of the variant with any atopic dermatitis-related phenotype. (PMID:23557745)
• Human hornerin is a protein whose expression is changed by UVB irradiation. (PMID:23751202)
• HRNR gene function is a target of FLG adaptive sweep, and the functional FLG variants that involve susceptibility to atopic dermatitis, seem to hitchhike the selective sweep on HRNR. (PMID:27678121)
• HRNR deimination improves its cross-linking by TGases and its proteolytic processing by calpain-1. (PMID:27742573)
• These results indicate that hornerin is highly expressed in pancreatic tumor endothelium and alters tumor vessel parameters through a VEGF-independent mechanism. Angiogenesis is essential for solid tumor progression. (PMID:28916756)
• HRNR promotes tumor progression and is correlated with a poor hepatocellular carcinoma (HCC)prognosis. HRNR may contribute to HCC progression via the regulation of the AKT pathway. (PMID:30103712)
• high order repeat formation conserved in apes (PMID:30256937)
• PROK2, HRNR, and FIG4 as potential genetic biomarkers of high bleeding propensity in East Asian patients with acute coronary syndrome using ticagrelor. (PMID:36263704)
• Expression of hornerin in skin lesions of atopic dermatitis and skin diseases. (PMID:38123340)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Hrnr	ENSMUSG00000041991
rattus_norvegicus		ENSRNOG00000064486

Paralogs (3): FLG2 (ENSG00000143520), FLG (ENSG00000143631), RPTN (ENSG00000215853)

Protein

Protein identifiers

Hornerin — Q86YZ3 (reviewed: Q86YZ3)

All UniProt accessions (1): Q86YZ3

UniProt curated annotations — full annotation on UniProt →

Function. Component of the epidermal cornified cell envelopes.

Subcellular location. Cytoplasmic granule.

Tissue specificity. Expressed in cornified epidermis, psoriatic and regenerating skin after wounding. Found in the upper granular layer and in the entire cornified layer of epidermis.

Post-translational modifications. Processed during the process of epidermal differentiation. Forms covalent cross-links mediated by transglutaminase TGM3, between glutamine and the epsilon-amino group of lysine residues (in vitro).

Induction. By UV-B irradiation.

Similarity. Belongs to the S100-fused protein family. In the N-terminal section; belongs to the S-100 family.

RefSeq proteins (1): NP_001009931* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001751	S100/CaBP7/8-like_CS	Conserved_site
IPR002048	EF_hand_dom	Domain
IPR011992	EF-hand-dom_pair	Homologous_superfamily
IPR013787	S100_Ca-bd_sub	Domain
IPR018247	EF_Hand_1_Ca_BS	Binding_site
IPR034325	S-100_dom	Domain
IPR052503	S100-fused_Epidermal_Struct	Family

Pfam: PF01023

UniProt features (152 total): compositionally biased region 71, repeat 30, modified residue 20, sequence variant 13, binding site 7, sequence conflict 5, region of interest 3, domain 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

No AlphaFold model available for Q86YZ3 — AlphaFold DB does not currently provide models for proteins above ~3000 aa.

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 (7): 27; 32; 62; 64; 66; 68; 73

Post-translational modifications (20): 659, 661, 890, 993, 1008, 1205, 1463, 1478, 1712, 1714, 1829, 1831, 1933, 1948, 2299, 2301, 2403, 2418, 2652, 2654

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-6798695	Neutrophil degranulation

MSigDB gene sets: 172 (showing top): GOBP_EPITHELIUM_DEVELOPMENT, REACTOME_INNATE_IMMUNE_SYSTEM, GOCC_SECRETORY_GRANULE, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_DN, GGGTGGRR_PAX4_03, GOBP_RESPONSE_TO_METAL_ION, GOBP_EPIDERMAL_CELL_DIFFERENTIATION, RICKMAN_METASTASIS_DN, GOBP_EPIDERMIS_DEVELOPMENT, P300_01, GOBP_KERATINIZATION, GOBP_SKIN_DEVELOPMENT, ACEVEDO_METHYLATED_IN_LIVER_CANCER_DN, GOBP_RESPONSE_TO_CALCIUM_ION, GOCC_SECRETORY_VESICLE

GO Biological Process (3): keratinization (GO:0031424), cell envelope organization (GO:0043163), establishment of skin barrier (GO:0061436)

GO Molecular Function (3): calcium ion binding (GO:0005509), transition metal ion binding (GO:0046914), metal ion binding (GO:0046872)

GO Cellular Component (9): cornified envelope (GO:0001533), extracellular region (GO:0005576), nucleus (GO:0005634), cytoplasm (GO:0005737), extracellular matrix (GO:0031012), azurophil granule lumen (GO:0035578), keratohyalin granule (GO:0036457), perinuclear region of cytoplasm (GO:0048471), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Innate Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
metal ion binding	2
cytoplasm	2
keratinocyte differentiation	1
multicellular organismal process	1
external encapsulating structure organization	1
skin epidermis development	1
cation binding	1
plasma membrane	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
external encapsulating structure	1
vacuolar lumen	1
secretory granule lumen	1
azurophil granule	1
extracellular vesicle	1

Protein interactions and networks

STRING

1744 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HRNR	S100A14	Q9HCY8	777
HRNR	S100A3	P33764	762
HRNR	S100A2	P29034	738
HRNR	S100A1	P23297	733
HRNR	S100A5	P33763	732
HRNR	S100Z	Q8WXG8	697
HRNR	S100A4	P26447	679
HRNR	S100A7	P31151	672
HRNR	S100A6	P06703	643
HRNR	S100A13	Q99584	643
HRNR	S100A11	P31949	592
HRNR	LORICRIN	P23490	576
HRNR	S100A10	P08206	576
HRNR	S100G	P29377	576
HRNR	S100A7A	Q86SG5	507

IntAct

113 interactions, top by confidence:

A	B	Type	Score
POT1	TERF2	psi-mi:“MI:0914”(association)	0.890
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
ERBB2	HAX1	psi-mi:“MI:0914”(association)	0.530
PPP1R16B	USP11	psi-mi:“MI:0914”(association)	0.420
PPP1R16B	USP11	psi-mi:“MI:2364”(proximity)	0.420
HRNR	rep	psi-mi:“MI:0915”(physical association)	0.400
YWHAZ	HRNR	psi-mi:“MI:0915”(physical association)	0.400
Ddb1	COPS6	psi-mi:“MI:0914”(association)	0.350
FOXN3	FOXN3	psi-mi:“MI:0914”(association)	0.350
	TBKBP1	psi-mi:“MI:0914”(association)	0.350
	AHRR	psi-mi:“MI:0914”(association)	0.350
	AURKA	psi-mi:“MI:0914”(association)	0.350
CDKN3	STMN1	psi-mi:“MI:0914”(association)	0.350
CDK1	RBMXL2	psi-mi:“MI:0914”(association)	0.350
COQ2	SNRPGP15	psi-mi:“MI:0914”(association)	0.350
PARK7	SAP18	psi-mi:“MI:0914”(association)	0.350
PDHA1		psi-mi:“MI:0914”(association)	0.350
SOAT1	SNRPGP15	psi-mi:“MI:0914”(association)	0.350
SOD1	NPEPPSL1	psi-mi:“MI:0914”(association)	0.350
VDAC1	SNRPGP15	psi-mi:“MI:0914”(association)	0.350
METTL3	TUBAL3	psi-mi:“MI:0914”(association)	0.350

BioGRID (175): HRNR (Affinity Capture-MS), HRNR (Affinity Capture-MS), HRNR (Affinity Capture-MS), HRNR (Proximity Label-MS), HRNR (Proximity Label-MS), HRNR (Affinity Capture-MS), HRNR (Affinity Capture-Western), HRNR (Affinity Capture-MS), HRNR (Affinity Capture-MS), HRNR (Affinity Capture-MS), HRNR (Affinity Capture-MS), HRNR (Affinity Capture-MS), HRNR (Affinity Capture-MS), HRNR (Affinity Capture-MS), HRNR (Affinity Capture-MS)

ESM2 similar proteins: A0A087WUL8, A0A0J9YWL9, A0A0U1RQI7, A0A494C071, A6NJU9, A6NNC1, A6QL64, A7XUY5, A7XUZ6, A8MRT5, B4DH59, C9JG80, E5RHQ5, E9Q6E9, F1LWT0, F8W0I5, O14686, O60732, P06916, P0DPF3, P18751, P36042, P53353, P83060, Q02496, Q13117, Q2EG98, Q3BBV0, Q3BBV2, Q4ZJY7, Q4ZJZ0, Q5HY64, Q5JPF3, Q5TAG4, Q5TI25, Q60528, Q63661, Q6P3W6, Q6P902, Q86T75

Diamond homologs: A7K6Y8, A7K6Y9, O77691, O77791, P02632, P02633, P02634, P02638, P02639, P04271, P04631, P05109, P05942, P05943, P05964, P06702, P06703, P07091, P14069, P20930, P22793, P23297, P24479, P24480, P25815, P27004, P27005, P28318, P28782, P28783, P29377, P30801, P31725, P31949, P31950, P33763, P35467, P50114, P50115, P50116

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 129 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.

GO biological processes:

GO term	Partners	Fold	FDR
response to ethanol	8	11.5×	5e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	2
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

286 predictions. Top by Δscore:

Variant	Effect	Δscore
1:152221488:ATTC:A	acceptor_loss	1.0000
1:152221489:TT:T	acceptor_gain	1.0000
1:152221490:TCTG:T	acceptor_loss	1.0000
1:152221491:C:CC	acceptor_gain	1.0000
1:152221492:T:A	acceptor_loss	1.0000
1:152223111:CTTA:C	donor_loss	1.0000
1:152223112:TTAC:T	donor_loss	1.0000
1:152223113:TACC:T	donor_loss	1.0000
1:152223114:A:AC	donor_gain	1.0000
1:152223115:C:CC	donor_gain	1.0000
1:152223115:C:G	donor_loss	1.0000
1:152223115:CCTT:C	donor_gain	1.0000
1:152223274:GTAAC:G	acceptor_gain	1.0000
1:152223275:TAAC:T	acceptor_gain	1.0000
1:152223276:AAC:A	acceptor_gain	1.0000
1:152223277:AC:A	acceptor_gain	1.0000
1:152223278:CC:C	acceptor_gain	1.0000
1:152223278:CCTA:C	acceptor_loss	1.0000
1:152223279:C:CA	acceptor_loss	1.0000
1:152223279:C:CC	acceptor_gain	1.0000
1:152221486:GGATT:G	acceptor_gain	0.9900
1:152221487:GATT:G	acceptor_gain	0.9900
1:152221488:ATT:A	acceptor_gain	0.9900
1:152221493:G:C	acceptor_gain	0.9900
1:152221493:G:GC	acceptor_gain	0.9900
1:152221495:A:C	acceptor_gain	0.9900
1:152223114:AC:A	donor_gain	0.9900
1:152223115:CC:C	donor_gain	0.9900
1:152223115:CCT:C	donor_gain	0.9900
1:152223114:ACCTT:A	donor_gain	0.9800

AlphaMissense

18035 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:152223209:G:C	F15L	0.986
1:152223209:G:T	F15L	0.986
1:152223211:A:G	F15L	0.986
1:152223147:A:G	L36P	0.982
1:152221416:A:C	F71L	0.981
1:152221416:A:T	F71L	0.981
1:152221418:A:G	F71L	0.981
1:152221387:A:G	L81P	0.979
1:152221405:A:G	L75P	0.978
1:152221417:A:G	F71S	0.977
1:152223156:A:G	L33P	0.973
1:152221409:A:G	Y74H	0.971
1:152223131:A:C	F41L	0.970
1:152223131:A:T	F41L	0.970
1:152223133:A:G	F41L	0.970
1:152221379:C:G	A84P	0.969
1:152223132:A:G	F41S	0.969
1:152223171:A:G	L28S	0.969
1:152221409:A:C	Y74D	0.968
1:152223144:A:G	L37P	0.966
1:152221396:A:T	I78K	0.964
1:152221408:T:G	Y74S	0.961
1:152223120:A:G	L45P	0.955
1:152223210:A:G	F15S	0.955
1:152221459:A:C	I57S	0.953
1:152221396:A:C	I78R	0.950
1:152221459:A:T	I57N	0.946
1:152223222:A:T	V11D	0.946
1:152221402:A:G	L76P	0.945
1:152221417:A:C	F71C	0.942

dbSNP variants (sampled 300 via entrez): RS1000278058 (1:152212429 C>A), RS1001911398 (1:152225031 C>A,G), RS1001961756 (1:152226123 C>G), RS1001963642 (1:152212875 C>A,G,T), RS1002067854 (1:152225875 A>G), RS1002186169 (1:152224470 A>G), RS1002519095 (1:152223384 A>G), RS1002980177 (1:152223101 G>A), RS1003045052 (1:152221827 T>A,C), RS1004881250 (1:152222264 A>G), RS1005551622 (1:152212999 T>C), RS1005697320 (1:152225461 A>T), RS1005749730 (1:152225098 T>G), RS1005863218 (1:152220866 A>G,T), RS1005867840 (1:152211690 T>G)

Disease associations

OMIM: gene MIM:616293 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

17 associations (top):

Study	Trait	p-value
GCST004861_28	Itch intensity from mosquito bite	3.000000e-08
GCST005038_8	Allergic disease (asthma, hay fever or eczema)	7.000000e-17
GCST006661_183	Male-pattern baldness	1.000000e-10
GCST007563_33	Allergic disease (asthma, hay fever or eczema)	3.000000e-11
GCST007564_24	Asthma or allergic disease (pleiotropy)	5.000000e-12
GCST007797_16	Asthma onset (childhood vs adult)	8.000000e-24
GCST007798_7	Asthma	4.000000e-24
GCST007800_52	Asthma (childhood onset)	8.000000e-48
GCST007994_25	Asthma (age of onset)	8.000000e-27
GCST007995_26	Asthma (childhood onset)	2.000000e-65
GCST008916_75	Asthma	2.000000e-08
GCST008916_82	Asthma	5.000000e-27
GCST008916_88	Asthma	1.000000e-25
GCST009798_26	Asthma	2.000000e-21
GCST009798_76	Asthma	1.000000e-22
GCST010984_48	Allergic disease (asthma, hay fever and/or eczema) (multivariate analysis)	6.000000e-19
GCST010985_2	Allergic disease (asthma, hay fever and/or eczema) (age of onset)	3.000000e-48

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0008377	mosquito bite reaction itch intensity measurement
EFO:0004847	age at onset

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5724652 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

18 total (human), top 18 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Tetrachlorodibenzodioxin	increases expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
2,3,5-(triglutathion-S-yl)hydroquinone	decreases ADP-ribosylation	1
jinfukang	increases expression, affects cotreatment	1
Resveratrol	decreases expression, affects cotreatment	1
Benzo(a)pyrene	increases methylation	1
Cadmium	affects binding	1
Cisplatin	affects cotreatment, increases expression	1
Coal Tar	affects cotreatment, decreases expression, decreases reaction, increases expression	1
Copper	affects cotreatment, decreases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Ivermectin	decreases expression	1
Lead	affects binding	1
Nickel	affects binding	1
Potassium Dichromate	increases expression	1
Smoke	increases expression	1
Zinc	affects binding	1
Lactic Acid	decreases expression	1

ChEMBL screening assays

6 unique, capped per target: 6 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5697749	Binding	Inhibition of HRNR (unknown origin) assessed as fold change at 10 uM incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. — Nature

Clinical trials (associated diseases)

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