GRHL2

Summary

GRHL2 (grainyhead like transcription factor 2, HGNC:2799) is a protein-coding gene on chromosome 8q22.3, encoding Grainyhead-like protein 2 homolog (Q6ISB3). Transcription factor playing an important role in primary neurulation and in epithelial development.

The protein encoded by this gene is a transcription factor that can act as a homodimer or as a heterodimer with either GRHL1 or GRHL3. Defects in this gene are a cause of non-syndromic sensorineural deafness autosomal dominant type 28 (DFNA28).

Source: NCBI Gene 79977 — RefSeq curated summary.

At a glance

• Gene–disease (curated): nonsyndromic genetic hearing loss (Definitive, ClinGen) — +6 more curated relationships
• GWAS associations: 7
• Clinical variants (ClinVar): 344 total — 12 pathogenic, 13 likely-pathogenic
• Phenotypes (HPO): 37
• Transcription factor: yes — 10 downstream targets (CollecTRI)
• MANE Select transcript: NM_024915

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2799
Approved symbol	GRHL2
Name	grainyhead like transcription factor 2
Location	8q22.3
Locus type	gene with protein product
Status	Approved
Aliases	FLJ13782, BOM
Ensembl gene	ENSG00000083307
Ensembl biotype	protein_coding
OMIM	608576
Entrez	79977

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 4 protein_coding, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000395927, ENST00000472106, ENST00000474338, ENST00000517674, ENST00000521085, ENST00000646743, ENST00000907653

RefSeq mRNA: 2 — MANE Select: NM_024915 NM_001330593, NM_024915

CCDS: CCDS34931, CCDS83312

Canonical transcript exons

ENST00000646743 — 16 exons

Exon	Start	End
ENSE00000700645	101664454	101664518
ENSE00000700673	101631637	101631724
ENSE00000700676	101619539	101619697
ENSE00000700681	101577408	101577519
ENSE00000700683	101573668	101573824
ENSE00000700687	101570339	101570394
ENSE00000700696	101552715	101552782
ENSE00000819094	101558419	101558812
ENSE00000819095	101599057	101599151
ENSE00001161936	101666589	101669726
ENSE00003463184	101649414	101649499
ENSE00003508230	101644131	101644225
ENSE00003517471	101632226	101632365
ENSE00003542411	101543241	101543436
ENSE00003655169	101636897	101636928
ENSE00003823822	101492439	101492789

Expression profiles

Bgee: expression breadth ubiquitous, 200 present calls, max score 95.33.

FANTOM5 (CAGE): breadth broad, TPM avg 8.2586 / max 152.0737, expressed in 417 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
90026	4.9623	403
90030	1.7268	281
90027	1.5695	339

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	95.33	gold quality
oviduct epithelium	UBERON:0004804	93.64	gold quality
cervix squamous epithelium	UBERON:0006922	92.89	silver quality
corpus epididymis	UBERON:0004359	92.87	gold quality
bronchial epithelial cell	CL:0002328	92.33	gold quality
hair follicle	UBERON:0002073	91.14	gold quality
epithelium of bronchus	UBERON:0002031	90.69	gold quality
nasal cavity epithelium	UBERON:0005384	90.69	silver quality
bronchus	UBERON:0002185	90.03	gold quality
cervix epithelium	UBERON:0004801	89.40	silver quality
skin of abdomen	UBERON:0001416	87.50	gold quality
palpebral conjunctiva	UBERON:0001812	87.26	gold quality
oral cavity	UBERON:0000167	86.92	gold quality
esophagus mucosa	UBERON:0002469	86.70	gold quality
zone of skin	UBERON:0000014	86.57	gold quality
skin of leg	UBERON:0001511	86.48	gold quality
skin of hip	UBERON:0001554	86.28	gold quality
upper leg skin	UBERON:0004262	86.10	gold quality
lower esophagus mucosa	UBERON:0035834	86.00	gold quality
prostate gland	UBERON:0002367	85.93	gold quality
mammalian vulva	UBERON:0000997	85.49	gold quality
placenta	UBERON:0001987	85.38	gold quality
squamous epithelium	UBERON:0006914	85.20	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	85.19	gold quality
gingiva	UBERON:0001828	85.04	gold quality
mouth mucosa	UBERON:0003729	84.49	gold quality
upper arm skin	UBERON:0004263	84.47	silver quality
minor salivary gland	UBERON:0001830	84.32	gold quality
esophagus squamous epithelium	UBERON:0006920	84.31	gold quality
epithelium of esophagus	UBERON:0001976	84.28	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	12.81
E-GEOD-83139	yes	11.20
E-ENAD-27	yes	6.62

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

10 targets.

Target	Regulation
CDC42SE1
CDH1
CLDN3
CLDN4	Unknown
ERBB3
GRHL2
NKX2-1	Activation
RAB25
TERT
ZEB1	Repression

JASPAR motifs

Motif	Name	Family
MA1105.1	GRHL2	Grainyhead-related factors
MA1105.2	GRHL2	Grainyhead-related factors
MA1105.3	GRHL2	Grainyhead-related factors

JASPAR matrix evidence (PMIDs): PMID:20978075

Upstream regulators (CollecTRI, top): GLI1, GRHL2, ZEB1

miRNA regulators (miRDB)

150 targeting GRHL2, 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-656-3P	100.00	72.15	2788
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
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-493-5P	99.96	72.47	2382
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-3912-5P	99.95	66.11	925
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502

Literature-anchored findings (GeneRIF, showing 40)

• Fine mapping demonstrated that the majority of the associated SNPs reside in intron 1 of GRHL2 gene; the causative variant may change the expression levels of a GRHL2 isoform. (PMID:17921507)
• a gain of GRHL2 in 8q22.3 was associated with early recurrence of hepatocellular carcinoma, controlling for clinical parameters (PMID:18752864)
• Regulation of the hTERT promoter activity by MSH2, the hnRNPs K and D, and GRHL2 in human oral squamous cell carcinoma cells. (PMID:19015635)
• GRHL2 regulates the hTERT expression through an epigenetic mechanism and controls the cellular life span. (PMID:20938050)
• Grhl2 expression in human tissue samples, including adult kidney, embryonic kidney, renal cell carcinomas and Wilms tumors was highly correlated with E-cadherin expression (PMID:20978075)
• No positive association was found between GRHL2 polymorphisms and age-related hearing impairment in Han Chinese individuals. (PMID:21557239)
• GRHL2 suppresses death-receptor expression. (PMID:21949371)
• Findings define a major role for GRHL2 in the suppression of oncogenic EMT in breast cancer cells. (PMID:22379025)
• GRHL2 impairs keratinocyte differentiation through transcriptional inhibition of the genes clustered at the epidermal differentiation complex. (PMID:23254293)
• Grhl2 plays an essential role in the determination of epithelial phenotype of breast cancers, EMT and tumor progression (PMID:23284647)
• GRHL2 plays a key role in regulating many physiological functions of human airway epithelium, including those involving cell morphogenesis, adhesion, and motility. (PMID:23690579)
• Frameshift mutation in GRHL2 is associated with autosomal-dominant deafness. (PMID:23813623)
• expression of GRHL2 is directly suppressed by the ZEB1, which in turn is a direct target for repression by GRHL2, suggesting that the EMT transcription factors GRHL2 and ZEB1 form a double negative regulatory feedback loop (PMID:23814079)
• Over-expression of Grhl2 decreased c-Myc and Bcl-2 protein expression level. (PMID:24068586)
• These findings indicate that GRHL2 may be a noise-induced hearing loss susceptibility gene and that polymorphisms of GRLH2 may contribute to the etiology of noise-induced hearing loss. (PMID:24131873)
• has identified ZEB1 as a target of GRHL2 and suggested a reciprocal GRHL2-ZEB1 repressive relationship, providing a novel mechanism through which proliferation may be modulated in colorectal cancer cells. (PMID:24756066)
• Mutations in GRHL2 result in an autosomal-recessive ectodermal Dysplasia syndrome. (PMID:25152456)
• A loss or strong reduction in GRHL2 expression appears to be a characteristic of cervical cancer, suggesting that GRHL2 down-regulation is a necessary step during cervical carcinogenesis. (PMID:25550776)
• A Grhl2-dependent gene network controls trophoblast branching morphogenesis. (PMID:25758223)
• GRHL1, GRHL2, and GRHL3 have roles in cellular proliferation, differentiation, adhesion, and polarity and may promote cancer or be tumor suppressors [review] (PMID:26069269)
• The p63 gene is regulated by GRHL2 through reciprocal feedback and determines the epithelial phenotype in human keratinocytes. (PMID:26085095)
• Genetic variations in the EYA4, GRHL2 and DFNA5 genes and their interactions with occupational noise exposure may play an important role in the incidence of noise-induced hearing loss (NIHL). (PMID:26400775)
• Taken together, our results demonstrate a role for miR-217 in the regulation of keratinocyte differentiation, partially through the regulation of GRHL2. (PMID:26826389)
• GRHL2 genetic polymorphisms, rs611419 and rs10955255, have a protective role against sudden sensorineural hearing loss (SSHL) and reduce the risk of SSHL. However, rs6989650 is not associated with SSHL. (PMID:26847018)
• study demonstrates that loss of GRHL2 increases the levels of histone mark H3K27me3 on promoters and GRHL2-binding sites at miR-200b/a and E-cadherin genes. These findings support GRHL2 as a pivotal gatekeeper of EMT in EOC via miR-200-ZEB1. (PMID:26887977)
• A novel connection between GRHL2 and miR-200 in oral cancer.Grainyhead-like 2 regulates epithelial plasticity and stemness in oral cancer cells. (PMID:26933170)
• Data indicate a ‘phenotypic stability factors’ (PSFs) such as GRHL2 that couple to the core epithelial-to-mesenchymal transition (EMT) decision-making circuit (miR-200/ZEB) and stabilize hybrid epithelial/mesenchymal (hybrid E/M) E/M phenotype. (PMID:27008704)
• This study showed that Mendelian sensorineural hearing loss exhibits vestibular dysfunction, including DFNA9, DFNA11, DFNA15 and DFNA28. (PMID:27083884)
• Results demonstrate a mechanistic role for GRHL2 in promoting anoikis through metabolic alterations. (PMID:27084311)
• results indicated GRHL2 might be a noise-induced hearing loss (NIHL) susceptibility gene, but the effect of POU4F3 on NIHL could only be detected when taking noise exposure into account and their effects were enhanced by higher levels of noise exposure (PMID:27271650)
• marked overlap of dyskeratosis congenita with four other genetic syndromes, confounding accurate diagnosis and subsequent management. Patients with clinical features of dyskeratosis congenita need to have genetic analysis of USB1, LIG4 and GRHL2 in addition to the classical dyskeratosis congenita genes and telomere length measurements. (PMID:27612988)
• In skin from psoriasis patients, the effect of miR-194 on cell proliferation and differentiation was significantly reversed by overexpression of GRHL2. Moreover, the expression of miR-194 and GRHL2 was inversely correlated in psoriasis lesional skin. Taken together, our results suggest that miR-194 inhibits the proliferation and promotes the differentiation of keratinocytes through targeting GRHL2. (PMID:28040329)
• data analysis and modeling results highlight the relationships among multiple crucial Epithelial-to-Mesenchymal Transition /Mesenchymal-to-Epithelial Transition drivers including ZEB1, GRHL2, CD24, and ESRP1, particularly in basal-like breast cancers, which are most similar to triple-negative breast cancer (TNBC) and are considered the most dangerous subtype (PMID:28266048)
• These data are indicative for a strong oncogenic potential of the GRHL2 gene in epithelial ovarian cancer cells displaying either epithelial (A2780s) or mesenchymal (SKOV3) phenotypes. (PMID:28278050)
• In this review, we summarized recent progress on grainyhead-like 2 in development and cancer in order to get an insight into the regulation network of grainyhead-like 2 and understand the roles of grainyhead-like 2 in various cancers. (PMID:28459369)
• GRHL2 maintained AR expression in multiple prostate cancer model systems, was required for cell proliferation, enhanced AR’s transcriptional activity, and colocated with AR at specific sites on chromatin to regulate genes relevant to disease progression. (PMID:28473532)
• Silencing of GRHL2 expression in non-tumorigenic kidney cell line results in increased cell proliferation, increased resistance to apoptosis, as well as changes in the levels of selected proteins involved in the pathogenesis of clear cell renal cell carcinoma (ccRCC). These changes support the potential role for GRHL2 as a suppressor of ccRCC. (PMID:28543713)
• Studies indicate that Grainyhead-like transcription factor 2 (GRHL2) controls the expression of E-cadherin (CDH1) required for adherens junctions and possibly regulates the expression of claudin-4 (CLDN4) in tight junctions. (PMID:28636799)
• All of these processes involve epithelial-mesencyhmal transition (EMT), MET or a sequence of both, suggesting that the GRHL factors((GRHL1, GRHL2 and GRHL3), could potentially affect tumor initiation and progression via EMT (PMID:28714958)
• In this study, we demonstrated for the first time that GRHL2 has a functional role in the regulation of epithelial plasticity of PDAC cells. (PMID:28960866)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	grhl2a	ENSDARG00000058342
danio_rerio	grhl2b	ENSDARG00000061974
mus_musculus	Grhl2	ENSMUSG00000022286
rattus_norvegicus	Grhl2	ENSRNOG00000007000
drosophila_melanogaster	gem	FBGN0050011
caenorhabditis_elegans	grh-1	WBGENE00001707

Paralogs (5): TFCP2L1 (ENSG00000115112), GRHL1 (ENSG00000134317), TFCP2 (ENSG00000135457), UBP1 (ENSG00000153560), GRHL3 (ENSG00000158055)

Protein

Protein identifiers

Grainyhead-like protein 2 homolog — Q6ISB3 (reviewed: Q6ISB3)

Alternative names: Brother of mammalian grainyhead, Transcription factor CP2-like 3

All UniProt accessions (1): Q6ISB3

UniProt curated annotations — full annotation on UniProt →

Function. Transcription factor playing an important role in primary neurulation and in epithelial development. Binds directly to the consensus DNA sequence 5’-AACCGGTT-3’ acting as an activator and repressor on distinct target genes. During embryogenesis, plays unique and cooperative roles with GRHL3 in establishing distinct zones of primary neurulation. Essential for closure 3 (rostral end of the forebrain), functions cooperatively with GRHL3 in closure 2 (forebrain/midbrain boundary) and posterior neuropore closure. Regulates epithelial morphogenesis acting as a target gene-associated transcriptional activator of apical junctional complex components. Up-regulates of CLDN3 and CLDN4, as well as of RAB25, which increases the CLDN4 protein and its localization at tight junctions. Comprises an essential component of the transcriptional machinery that establishes appropriate expression levels of CLDN4 and CDH1 in different types of epithelia. Exhibits functional redundancy with GRHL3 in epidermal morphogenetic events and epidermal wound repair. In lung, forms a regulatory loop with NKX2-1 that coordinates lung epithelial cell morphogenesis and differentiation. In keratinocytes, plays a role in telomerase activation during cellular proliferation, regulates TERT expression by binding to TERT promoter region and inhibiting DNA methylation at the 5’-CpG island, possibly by interfering with DNMT1 enzyme activity. In addition, impairs keratinocyte differentiation and epidermal function by inhibiting the expression of genes clustered at the epidermal differentiation complex (EDC) as well as GRHL1 and GRHL3 through epigenetic mechanisms.

Subunit / interactions. Homodimer, also forms heterodimers with GRHL1 or GRHL3.

Subcellular location. Nucleus. Membrane.

Tissue specificity. Expressed in keratinocytes (at protein level). Highly expressed in placenta, prostate, brain and kidney. Lower-level expression in a variety of epithelial tissues such as thymus, lung, salivary gland, mammary gland and digestive tract. Expressed in the cochlear. Expressed in corneal epithelial cells, but not in the endothelium or stroma.

Disease relevance. Deafness, autosomal dominant, 28 (DFNA28) [MIM:608641] A form of non-syndromic sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. DFNA28 is characterized by mild to moderate hearing loss across most frequencies that progresses to severe loss in the higher frequencies by the fifth decade. The disease is caused by variants affecting the gene represented in this entry. Ectodermal dysplasia/short stature syndrome (ECTDS) [MIM:616029] An autosomal recessive ectodermal dysplasia syndrome characterized by nail dystrophy and/or loss, oral mucosa and/or tongue pigmentation, abnormal dentition, keratoderma affecting the margins of the palms and soles, focal hyperkeratosis of the dorsal aspects of the hands and feet, and short stature. The disease is caused by variants affecting the gene represented in this entry. Corneal dystrophy, posterior polymorphous, 4 (PPCD4) [MIM:618031] A subtype of posterior corneal dystrophy, a disease characterized by alterations of Descemet membrane presenting as vesicles, opacities or band-like lesions on slit-lamp examination and specular microscopy. In severe cases, corneal endothelial failure may occur and corneal transplantation is required to restore vision. Secondary complications are common and include corneal edema, glaucoma, iris adherence to the cornea, and corectopia. PPCD4 transmission pattern is consistent with autosomal dominant inheritance. The disease is caused by variants affecting the gene represented in this entry.

Induction. Expressed in proliferating cells, the expression decreases during senescence. In keratinocytes, expression levels decrease upon calcium exposure.

Miscellaneous. GRHL genes (GRHL1, GRHL2 and GRHL3) show a paradoxal lack of redundancy despite their extensive sequence identity in the DNA-binding and protein dimerization domains and the fact that the core consensus DNA binding sites are identical. They have related but remarkably different functions during embryogenesis because of their differential spatiotemporal expression patterns during development.

Similarity. Belongs to the grh/CP2 family. Grainyhead subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q6ISB3-1	1	yes
Q6ISB3-2	2

RefSeq proteins (2): NP_001317522, NP_079191* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007604	CP2	Domain
IPR040167	TF_CP2-like	Family
IPR057520	GRHL1/CP2_C	Domain

Pfam: PF04516, PF25416

UniProt features (34 total): strand 12, sequence conflict 4, region of interest 4, sequence variant 3, helix 3, compositionally biased region 2, chain 1, domain 1, mutagenesis site 1, turn 1, site 1, splice variant 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
5MR7	X-RAY DIFFRACTION	2.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6ISB3-F1	67.46	0.39

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): 423 (important for activation of transcription)

Mutagenesis-validated functional residues (1):

Position	Phenotype
423	loss of activity as transcriptional activator.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 318 (showing top): GOBP_CARDIAC_CHAMBER_DEVELOPMENT, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GCACCTT_MIR18A_MIR18B, GOBP_LABYRINTHINE_LAYER_DEVELOPMENT, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_LUNG_EPITHELIUM_DEVELOPMENT, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_CARDIAC_CHAMBER_MORPHOGENESIS, GOBP_EPITHELIAL_CELL_DEVELOPMENT, JAEGER_METASTASIS_DN, GOBP_EMBRYONIC_DIGIT_MORPHOGENESIS, GOBP_EMBRYONIC_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_LUNG_CELL_DIFFERENTIATION, ATACCTC_MIR202

GO Biological Process (27): neural tube closure (GO:0001843), cardiac ventricle morphogenesis (GO:0003208), epithelial cell morphogenesis (GO:0003382), regulation of transcription by RNA polymerase II (GO:0006357), cell adhesion (GO:0007155), brain development (GO:0007420), neural tube development (GO:0021915), keratinocyte differentiation (GO:0030216), cell junction assembly (GO:0034329), multicellular organism growth (GO:0035264), embryonic digit morphogenesis (GO:0042733), camera-type eye development (GO:0043010), positive regulation of transcription by RNA polymerase II (GO:0045944), embryonic cranial skeleton morphogenesis (GO:0048701), face development (GO:0060324), lung lobe morphogenesis (GO:0060463), lung epithelial cell differentiation (GO:0060487), epithelial cell morphogenesis involved in placental branching (GO:0060672), anterior neural tube closure (GO:0061713), bicellular tight junction assembly (GO:0070830), epithelium migration (GO:0090132), in utero embryonic development (GO:0001701), epidermis development (GO:0008544), regulation of gene expression (GO:0010468), respiratory tube development (GO:0030323), positive regulation of DNA-templated transcription (GO:0045893), embryonic organ development (GO:0048568)

GO Molecular Function (13): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), intronic transcription regulatory region sequence-specific DNA binding (GO:0001161), DNA-binding transcription activator activity (GO:0001216), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), DNA-binding transcription factor activity (GO:0003700), chromatin DNA binding (GO:0031490), identical protein binding (GO:0042802), sequence-specific DNA binding (GO:0043565), DNA-binding transcription factor binding (GO:0140297), DNA binding (GO:0003677), chromatin binding (GO:0003682), protein binding (GO:0005515)

GO Cellular Component (5): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), cell-cell junction (GO:0005911), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
transcription cis-regulatory region binding	3
cellular anatomical structure	3
tube closure	2
regulation of DNA-templated transcription	2
transcription by RNA polymerase II	2
head development	2
embryonic morphogenesis	2
regulation of transcription by RNA polymerase II	2
positive regulation of DNA-templated transcription	2
DNA-binding transcription factor activity	2
DNA binding	2
binding	2
primary neural tube formation	1
cardiac chamber morphogenesis	1
cardiac ventricle development	1
cell morphogenesis	1
epithelial cell development	1
cellular process	1
central nervous system development	1
animal organ development	1
nervous system development	1
tube development	1
chordate embryonic development	1
epithelium development	1
epidermal cell differentiation	1
skin development	1
cellular component assembly	1
cell junction organization	1
multicellular organismal process	1
developmental growth	1
embryonic limb morphogenesis	1
eye development	1
embryonic skeletal system morphogenesis	1
cranial skeletal system development	1
anatomical structure development	1
anatomical structure morphogenesis	1
lung morphogenesis	1
lung lobe development	1
epithelial cell differentiation	1

Protein interactions and networks

STRING

1300 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GRHL2	OVOL2	Q9BRP0	735
GRHL2	GATA3	P23771	597
GRHL2	KMT2C	Q8NEZ4	589
GRHL2	HOXB13	Q92826	584
GRHL2	ZEB1	P37275	584
GRHL2	OVOL1	O14753	583
GRHL2	ESRP1	Q6NXG1	533
GRHL2	SNAI1	O95863	494
GRHL2	FOXA1	P55317	487
GRHL2	CDH1	P12830	482
GRHL2	TFAP2C	Q92754	462
GRHL2	HDAC1	Q13547	460
GRHL2	SNAI2	O43623	448
GRHL2	KCNQ4	P56696	448
GRHL2	ELF5	Q9UKW6	447

IntAct

39 interactions, top by confidence:

A	B	Type	Score
GRHL2	GRHL1	psi-mi:“MI:0915”(physical association)	0.800
GRHL1	GRHL2	psi-mi:“MI:0915”(physical association)	0.800
GRHL2	LMO4	psi-mi:“MI:0915”(physical association)	0.780
LMO4	GRHL2	psi-mi:“MI:0915”(physical association)	0.780
ESR1	PGR	psi-mi:“MI:0915”(physical association)	0.770
PAX5	GRHL2	psi-mi:“MI:0915”(physical association)	0.560
PAX6	GRHL2	psi-mi:“MI:0915”(physical association)	0.560
PIAS2	GRHL2	psi-mi:“MI:0915”(physical association)	0.560
GRHL2	GRHL2	psi-mi:“MI:0915”(physical association)	0.510
C4A	ESR1	psi-mi:“MI:0915”(physical association)	0.400
	GRHL2	psi-mi:“MI:0915”(physical association)	0.370
CXCL13	GRHL2	psi-mi:“MI:0915”(physical association)	0.370
IFNA14	GRHL2	psi-mi:“MI:0915”(physical association)	0.370
IFNL1	GRHL2	psi-mi:“MI:0915”(physical association)	0.370
IL21	GRHL2	psi-mi:“MI:0915”(physical association)	0.370
TNFSF4	GRHL2	psi-mi:“MI:0915”(physical association)	0.370
GRHL1	POLRMT	psi-mi:“MI:0914”(association)	0.350
AR	MED6	psi-mi:“MI:2364”(proximity)	0.270
RAVER1	KDM6A	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (26): GRHL2 (Two-hybrid), GRHL1 (Affinity Capture-MS), GRHL2 (Affinity Capture-MS), GRHL2 (Affinity Capture-RNA), GRHL2 (Affinity Capture-MS), GRHL2 (Synthetic Lethality), GRHL2 (Two-hybrid), GRHL2 (Two-hybrid), LMO4 (Two-hybrid), PAX5 (Two-hybrid), GRHL2 (Affinity Capture-MS), GRHL2 (Two-hybrid), GRHL2 (Reconstituted Complex), GRHL1 (Affinity Capture-MS), GRHL2 (Proximity Label-MS)

ESM2 similar proteins: A1L1C7, O08873, O42611, O60716, O94776, O94967, P83094, Q01826, Q0P5J8, Q15542, Q3UHE1, Q3UVG3, Q4R8N2, Q58A45, Q5EY87, Q5JSJ4, Q5M7R9, Q5R7S4, Q5RAR8, Q5TKA1, Q60611, Q640Q5, Q658Y4, Q68FH0, Q6ISB3, Q6NT76, Q6TEP1, Q80U28, Q8BIE6, Q8BJA3, Q8C092, Q8C0V0, Q8C735, Q8C8N2, Q8CGF6, Q8K5C0, Q8N9R8, Q8VI24, Q8WXG6, Q90ZY6

Diamond homologs: G5EDF0, P13002, Q12800, Q3UNW5, Q4V860, Q5EY87, Q5FWH3, Q5M7R9, Q5PPL8, Q5RAR8, Q5RB16, Q6GL65, Q6ISB3, Q6NZH6, Q7T2U9, Q811S7, Q8K5C0, Q8TE85, Q921D9, Q9ERA0, Q9NZI5, Q9NZI6, Q9NZI7

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
ZEB1	“down-regulates quantity by repression”	GRHL2	“transcriptional regulation”
GRHL2	“down-regulates quantity by repression”	ZEB1	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	12
Likely pathogenic	13
Uncertain significance	141
Likely benign	95
Benign	51

Top pathogenic / likely-pathogenic (25)

Variant ID	HGVS	Classification
156217	NM_024915.4(GRHL2):c.1445T>A (p.Ile482Lys)	Pathogenic
1710810	NM_024915.4(GRHL2):c.223C>T (p.Arg75Ter)	Pathogenic
2195	NM_024915.4(GRHL2):c.1609dup (p.Arg537fs)	Pathogenic
2778996	NM_024915.4(GRHL2):c.1011C>G (p.Tyr337Ter)	Pathogenic
2818855	NM_024915.4(GRHL2):c.936_945dup (p.Tyr316fs)	Pathogenic
2982279	NM_024915.4(GRHL2):c.1276C>T (p.Arg426Ter)	Pathogenic
3662386	NM_024915.4(GRHL2):c.925_926del (p.Asn309fs)	Pathogenic
3702148	NM_024915.4(GRHL2):c.1609C>T (p.Arg537Ter)	Pathogenic
4056875	NM_024915.4(GRHL2):c.412C>T (p.Gln138Ter)	Pathogenic
4525864	NM_024915.4(GRHL2):c.759del (p.Ala254fs)	Pathogenic
4528931	NM_024915.4(GRHL2):c.284+2039_678+217del	Pathogenic
92126	NM_024915.4(GRHL2):c.1258-1G>A	Pathogenic
156216	NM_024915.4(GRHL2):c.1192T>C (p.Tyr398His)	Likely pathogenic
2440600	NM_024915.4(GRHL2):c.1518-2del	Likely pathogenic
2584500	NM_024915.4(GRHL2):c.1004-2A>C	Likely pathogenic
2635445	NM_024915.4(GRHL2):c.21-1G>A	Likely pathogenic
289923	NM_024915.4(GRHL2):c.1098+1G>A	Likely pathogenic
3354517	NM_024915.4(GRHL2):c.868C>T (p.Arg290Ter)	Likely pathogenic
3600504	NM_024915.4(GRHL2):c.1099-1G>A	Likely pathogenic
3601162	NM_024915.4(GRHL2):c.1318C>T (p.Gln440Ter)	Likely pathogenic
3601163	NM_024915.4(GRHL2):c.1698+1G>A	Likely pathogenic
425447	NM_024915.4(GRHL2):c.801del (p.Met267fs)	Likely pathogenic
4813842	NM_024915.4(GRHL2):c.310C>T (p.Gln104Ter)	Likely pathogenic
489404	NM_024915.4(GRHL2):c.20+257del	Likely pathogenic
620467	NM_024915.4(GRHL2):c.1264G>T (p.Glu422Ter)	Likely pathogenic

SpliceAI

3583 predictions. Top by Δscore:

Variant	Effect	Δscore
8:101492790:G:GG	donor_gain	1.0000
8:101543236:TACA:T	acceptor_loss	1.0000
8:101543239:A:AG	acceptor_gain	1.0000
8:101543239:A:AT	acceptor_loss	1.0000
8:101543240:G:GA	acceptor_gain	1.0000
8:101543240:GT:G	acceptor_gain	1.0000
8:101543240:GTA:G	acceptor_gain	1.0000
8:101543240:GTAA:G	acceptor_gain	1.0000
8:101543240:GTAAT:G	acceptor_gain	1.0000
8:101543433:CAAGG:C	donor_loss	1.0000
8:101543434:AAGGT:A	donor_loss	1.0000
8:101543435:AGG:A	donor_loss	1.0000
8:101543437:GTAG:G	donor_loss	1.0000
8:101543438:T:A	donor_loss	1.0000
8:101558400:G:A	acceptor_gain	1.0000
8:101573663:CACA:C	acceptor_loss	1.0000
8:101573664:A:AG	acceptor_gain	1.0000
8:101573664:ACAGT:A	acceptor_gain	1.0000
8:101573665:C:G	acceptor_gain	1.0000
8:101573665:CA:C	acceptor_loss	1.0000
8:101573666:A:AG	acceptor_gain	1.0000
8:101573666:A:G	acceptor_loss	1.0000
8:101573666:AGT:A	acceptor_gain	1.0000
8:101573666:AGTG:A	acceptor_gain	1.0000
8:101573667:G:GA	acceptor_gain	1.0000
8:101573667:GT:G	acceptor_gain	1.0000
8:101573667:GTG:G	acceptor_gain	1.0000
8:101573667:GTGG:G	acceptor_gain	1.0000
8:101573667:GTGGC:G	acceptor_gain	1.0000
8:101573823:GG:G	donor_gain	1.0000

AlphaMissense

4186 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:101543317:G:C	D33H	1.000
8:101543326:T:A	W36R	1.000
8:101543326:T:C	W36R	1.000
8:101543328:G:C	W36C	1.000
8:101543328:G:T	W36C	1.000
8:101543339:T:C	L40S	1.000
8:101543351:T:A	L44Q	1.000
8:101543351:T:C	L44P	1.000
8:101543360:C:A	A47D	1.000
8:101543363:C:T	T48I	1.000
8:101543368:G:C	A50P	1.000
8:101543369:C:A	A50D	1.000
8:101543372:T:A	M51K	1.000
8:101543372:T:C	M51T	1.000
8:101543372:T:G	M51R	1.000
8:101543373:G:A	M51I	1.000
8:101543373:G:C	M51I	1.000
8:101543373:G:T	M51I	1.000
8:101543375:T:C	M52T	1.000
8:101543411:T:A	L64H	1.000
8:101543420:T:A	L67H	1.000
8:101543420:T:C	L67P	1.000
8:101573688:T:C	L252P	1.000
8:101573738:T:A	Y269N	1.000
8:101573738:T:C	Y269H	1.000
8:101573738:T:G	Y269D	1.000
8:101573739:A:G	Y269C	1.000
8:101573742:T:A	L270H	1.000
8:101573742:T:C	L270P	1.000
8:101573744:A:G	N271D	1.000

dbSNP variants (sampled 300 via entrez): RS1000008418 (8:101645376 C>T), RS1000037477 (8:101516138 G>A,C,T), RS1000040264 (8:101603292 A>G), RS1000086251 (8:101670422 A>C,G), RS1000097079 (8:101500208 G>A), RS1000099872 (8:101583864 A>C,T), RS1000106883 (8:101666780 A>G), RS1000111347 (8:101631175 T>A), RS1000124254 (8:101499287 C>T), RS1000137697 (8:101639486 T>C), RS1000146232 (8:101500594 C>T), RS1000162999 (8:101675963 G>T), RS1000165762 (8:101508314 C>T), RS1000168843 (8:101639723 G>A), RS1000216952 (8:101514778 C>T)

Disease associations

OMIM: gene MIM:608576 | disease phenotypes: MIM:608641, MIM:616029, MIM:618031

GenCC curated gene-disease

Disease	Classification	Inheritance
nonsyndromic genetic hearing loss	Definitive	Autosomal dominant
autosomal dominant nonsyndromic hearing loss 28	Strong	Autosomal dominant
nail and teeth abnormalities-marginal palmoplantar keratoderma-oral hyperpigmentation syndrome	Strong	Autosomal recessive
posterior polymorphous corneal dystrophy	Strong	Autosomal dominant
corneal dystrophy, posterior polymorphous, 4	Strong	Autosomal dominant
autosomal dominant nonsyndromic hearing loss	Supportive	Autosomal dominant
congenital fibrosis of extraocular muscles	Limited	Unknown

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
nonsyndromic genetic hearing loss	Definitive	AD

Mondo (9): hearing loss disorder (MONDO:0005365), autosomal dominant nonsyndromic hearing loss 28 (MONDO:0012083), nail and teeth abnormalities-marginal palmoplantar keratoderma-oral hyperpigmentation syndrome (MONDO:0014460), corneal dystrophy, posterior polymorphous, 4 (MONDO:0054832), corneal dystrophy (MONDO:0018102), nonsyndromic genetic hearing loss (MONDO:0019497), congenital fibrosis of extraocular muscles (MONDO:0007614), autosomal dominant nonsyndromic hearing loss (MONDO:0019587), posterior polymorphous corneal dystrophy (MONDO:0020364)

Orphanet (3): Nail and teeth abnormalities-marginal palmoplantar keratoderma-oral hyperpigmentation syndrome (Orphanet:423454), Rare autosomal dominant non-syndromic sensorineural deafness type DFNA (Orphanet:90635), Corneal dystrophy (Orphanet:34533)

HPO phenotypes

37 total (30 of 37 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000407	Sensorineural hearing impairment
HP:0000483	Astigmatism
HP:0000501	Glaucoma
HP:0000533	Chorioretinal atrophy
HP:0000565	Esotropia
HP:0000613	Photophobia
HP:0000622	Blurred vision
HP:0000632	Lacrimation abnormality
HP:0000646	Amblyopia
HP:0000668	Hypodontia
HP:0000684	Delayed eruption of teeth
HP:0000962	Hyperkeratosis
HP:0000982	Palmoplantar keratoderma
HP:0001798	Anonychia
HP:0002015	Dysphagia
HP:0002043	Esophageal stricture
HP:0002099	Asthma
HP:0003593	Infantile onset
HP:0003676	Progressive
HP:0004322	Short stature
HP:0006297	Enamel hypoplasia
HP:0007663	Reduced visual acuity
HP:0007906	Ocular hypertension
HP:0007957	Corneal opacity
HP:0008404	Nail dystrophy
HP:0009918	Ectopia pupillae
HP:0011483	Anterior synechiae of the anterior chamber
HP:0011490	Abnormal Descemet membrane morphology

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST002104_6	Bronchopulmonary dysplasia	3.000000e-06
GCST002318_112	Rheumatoid arthritis	7.000000e-09
GCST002318_113	Rheumatoid arthritis	2.000000e-08
GCST006959_125	Rheumatoid arthritis	2.000000e-06
GCST006959_66	Rheumatoid arthritis	1.000000e-07
GCST012288_1	Chronic hepatitis B infection vs asymptomatic persistence	2.000000e-06
GCST012319_2	LDL levels x SSRI levels (escitalopram or citalopram) interaction in schizophrenia or bipolar disorder	3.000000e-07

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004611	low density lipoprotein cholesterol measurement

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D003317	Corneal Dystrophies, Hereditary	C11.204.236; C11.270.162; C16.320.290.162
D034381	Hearing Loss	C09.218.458.341; C10.597.751.418.341; C23.888.592.763.393.341
C563890	Deafness, Autosomal Dominant 28 (supp.)
C580334	Nonsyndromic Deafness (supp.)
C580012	congenital fibrosis of the extraocular muscles (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

22 total (human), top 22 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	6
trichostatin A	increases expression, affects cotreatment	3
sodium arsenite	increases expression, affects expression	2
mercuric bromide	increases expression, affects cotreatment	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
S-(1,2-dichlorovinyl)cysteine	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	increases expression, affects cotreatment	1
Panobinostat	increases expression, affects cotreatment	1
Air Pollutants	increases abundance, decreases expression	1
Benzo(a)pyrene	decreases methylation, increases methylation	1
Calcitriol	increases expression	1
Carbamazepine	affects expression	1
Diethylhexyl Phthalate	increases expression	1
Endosulfan	decreases expression	1
Estradiol	affects cotreatment, decreases expression	1
Silicon Dioxide	decreases expression	1
Smoke	decreases expression	1
Dihydrotestosterone	increases expression	1
Silver Compounds	decreases expression	1
Lactic Acid	decreases expression	1
Particulate Matter	decreases expression, increases abundance	1

Cellosaurus cell lines

3 cell lines: 3 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A2H8	SEES3-1V human GRHL2, clone1	Embryonic stem cell	Male
CVCL_A2H9	SEES3-1V human GRHL2, clone2	Embryonic stem cell	Male
CVCL_A2I0	SEES3-1V human GRHL2, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00205881	PHASE4	COMPLETED	Bilateral Benefit in Adult Users of the HiRes 90K Bionic Ear System
NCT00331539	PHASE4	UNKNOWN	Relationship Between Auto NRT and Behavioural T & C Levels With the Nucleus Freedom Cochlear Implant
NCT00424307	PHASE4	UNKNOWN	Bilateral Cochlear Implant Benefit in Young Children
NCT00765635	PHASE4	COMPLETED	Chlorobutanol, Potassium Carbonate, and Irrigation in Cerumen Removal
NCT03321006	PHASE4	COMPLETED	Treating Hearing Loss to Improve Mood and Cognition in Older Adults
NCT01499901	PHASE3	WITHDRAWN	Comparison of the Bilateral Sequential and Simultaneous Cochlear Implantation in the Deaf Children
NCT02561091	PHASE3	COMPLETED	AM-111 in the Treatment of Acute Inner Ear Hearing Loss
NCT03331627	PHASE3	COMPLETED	Safety and Efficacy of STR001-IT and STR001-ER in Patients With SSHL
NCT05532657	PHASE3	ACTIVE_NOT_RECRUITING	ACHIEVE Brain Health Follow-Up Study
NCT00013455	PHASE2	COMPLETED	Quantifying Auditory Perceptual Learning Following Hearing Aid Fitting
NCT00323427	PHASE2	COMPLETED	Clinical Trial of the Living Well With Hearing Loss Workshop
NCT00552786	PHASE2	COMPLETED	Antioxidation Medication for Noise-induced Hearing Loss
NCT00802425	PHASE2	COMPLETED	Efficacy of AM-111 in Patients With Acute Sensorineural Hearing Loss
NCT01139281	PHASE2	COMPLETED	The Protective Effect of Ginkgo Biloba Extract on Cisplatin-induced Ototoxicity in Humans
NCT01451853	PHASE2	UNKNOWN	SPI-1005 for Prevention and Treatment of Chemotherapy Induced Hearing Loss
NCT01588925	PHASE2	COMPLETED	Hearing Preservation Using Dexamethasone and Hyaluronic Acid for Cochlear Implantation
NCT01773278	PHASE2	RECRUITING	Cholesterol and Antioxidant Treatment in Patients With Smith-Lemli-Opitz Syndrome (SLOS)
NCT02832128	PHASE2	COMPLETED	Evaluating Possible Improvement in Speech and Hearing Tests After 28 Days of Dosing of the Study Drug AUT00063 Compared to Placebo (QuicKfire)
NCT04915183	PHASE2	RECRUITING	Atorvastatin to Reduce Cisplatin-Induced Hearing Loss Among Individuals With Head and Neck Cancer
NCT05258773	PHASE2	COMPLETED	Evaluation of the Presence of SENS-401 in the Perilymph
NCT06340633	PHASE2	RECRUITING	SPI-1005 in Adults Receiving Cochlear Implant
NCT00582946	PHASE1	COMPLETED	Wide-Bandwidth Open Canal Hearing Aid For Better Multitalker Speech Understanding
NCT00584155	PHASE1	WITHDRAWN	Protection From Cisplatin Ototoxicity by Lactated Ringers
NCT01206829	PHASE1	UNKNOWN	Hearing Impairment, Cognitive Therapy and Coping
NCT01256229	PHASE1	COMPLETED	Outcomes In Children With Developmental Delay And Deafness
NCT01343394	PHASE1	WITHDRAWN	Safety of Autologous Human Umbilical Cord Blood Mononuclear Fraction to Treat Acquired Hearing Loss in Children
NCT01452607	PHASE1	COMPLETED	Study to Evaluate the Safety and Pharmacokinetics of SPI-1005
NCT02259595	PHASE1	COMPLETED	Study to Determine the Safety, Tolerability, and Pharmacokinetic Profile of HPN-07 and HPN-07 Plus NAC
NCT04041440	PHASE1	COMPLETED	Speech Recognition Training in Children With Hearing Loss
NCT07218913	PHASE1	RECRUITING	Testing the Addition of Pedmark to Cisplatin Chemotherapy for Reducing Drug-Induced Ear Damage in Men With Stage II-III Metastatic Testicular Germ Cell Tumors
NCT01802190	Not specified	TERMINATED	Prevalence of POU4F3 and SLC17A8 Mutations
NCT03059420	Not specified	RECRUITING	Genetic Studies of Strabismus, Congenital Cranial Dysinnervation Disorders (CCDDs), and Their Associated Anomalies
NCT00800111	Not specified	COMPLETED	Study of Endothelial Keratoplasty Outcomes
NCT02020044	Not specified	UNKNOWN	Outcome After Descemet Membrane Endothelial Keratoplasty (DMEK) and Ultra-thin Descemet Stripping Automated Endothelial Keratoplasty (DSAEK)
NCT04387331	Not specified	UNKNOWN	The Postoperative Head Position as a Predictor of the Surgical Outcome After DMEK
NCT00486577	PHASE2/PHASE3	COMPLETED	Chronic Electrical Stimulation of the Auditory Cortex for Intractable Tinnitus
NCT00789061	PHASE2/PHASE3	UNKNOWN	Applying Proton Pump Inhibitor to Prevent and Treat Acute Fluctuating Hearing Loss in Patients With SLC26A4 Mutation
NCT01423409	PHASE2/PHASE3	COMPLETED	Multicenter Trial Assessing an Innovative VAS of Pain Among Deaf People
NCT05786378	PHASE2/PHASE3	UNKNOWN	Assessment of The Efficacy of Intratympanic Platelet Rich Plasma for Treatment of Sensorineural Hearing Loss.
NCT01108601	PHASE1/PHASE2	UNKNOWN	Transtympanic Ringer’s Lactate for the Prevention of Cisplatin Ototoxicity