MITF

Summary

MITF (melanocyte inducing transcription factor, HGNC:7105) is a protein-coding gene on chromosome 3p13, encoding Microphthalmia-associated transcription factor (O75030). Transcription factor that acts as a master regulator of melanocyte survival and differentiation as well as melanosome biogenesis. It is haploinsufficient (ClinGen: sufficient evidence).

The protein encoded by this gene is a transcription factor that contains both basic helix-loop-helix and leucine zipper structural features. The encoded protein regulates melanocyte development and is responsible for pigment cell-specific transcription of the melanogenesis enzyme genes. Heterozygous mutations in the this gene cause auditory-pigmentary syndromes, such as Waardenburg syndrome type 2 and Tietz syndrome.

Source: NCBI Gene 4286 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Waardenburg syndrome type 2 (Definitive, ClinGen) — +7 more curated relationships
• GWAS associations: 36
• Clinical variants (ClinVar): 1,330 total — 93 pathogenic, 43 likely-pathogenic
• Phenotypes (HPO): 74
• Druggable target: yes — 3 molecules with ChEMBL bioactivity
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• Transcription factor: yes — 120 downstream targets (CollecTRI)
• MANE Select transcript: NM_001354604

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7105
Approved symbol	MITF
Name	melanocyte inducing transcription factor
Location	3p13
Locus type	gene with protein product
Status	Approved
Aliases	MI, bHLHe32
Ensembl gene	ENSG00000187098
Ensembl biotype	protein_coding
OMIM	156845
Entrez	4286

Gene structure

Transcript identifiers

Ensembl transcripts: 32 — 27 protein_coding, 4 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000314557, ENST00000314589, ENST00000352241, ENST00000394348, ENST00000394351, ENST00000429090, ENST00000433517, ENST00000448226, ENST00000451708, ENST00000461014, ENST00000461511, ENST00000472437, ENST00000478490, ENST00000495741, ENST00000531774, ENST00000642352, ENST00000687384, ENST00000689390, ENST00000693031, ENST00000693549, ENST00000894496, ENST00000894497, ENST00000894498, ENST00000894499, ENST00000956040, ENST00000956041, ENST00000956042, ENST00000956043, ENST00000956044, ENST00000956045, ENST00000956046, ENST00000956047

RefSeq mRNA: 13 — MANE Select: NM_001354604 NM_000248, NM_001184967, NM_001184968, NM_001354604, NM_001354605, NM_001354606, NM_001354607, NM_001354608, NM_006722, NM_198158, NM_198159, NM_198177, NM_198178

CCDS: CCDS2913, CCDS43106, CCDS43107, CCDS46865, CCDS46866, CCDS54607, CCDS74962, CCDS87108, CCDS93308

Canonical transcript exons

ENST00000352241 — 10 exons

Exon	Start	End
ENSE00001514168	69964847	69968332
ENSE00001940141	69739464	69739701
ENSE00003489451	69949051	69949168
ENSE00003494149	69956455	69956530
ENSE00003520446	69939098	69939181
ENSE00003546862	69959273	69959420
ENSE00003569466	69941236	69941331
ENSE00003582013	69937822	69938049
ENSE00003615407	69951812	69951886
ENSE00003788342	69879134	69879383

Expression profiles

Bgee: expression breadth ubiquitous, 293 present calls, max score 99.16.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 18.3536 / max 1473.8337, expressed in 1496 samples.

FANTOM5 promoters (22 alternative TSS)

Promoter ID	TPM avg	Samples expressed
37231	12.1677	1420
37262	3.0292	59
37254	0.7030	260
37251	0.4761	37
37237	0.3851	169
37253	0.3812	156
37238	0.2833	131
37263	0.2801	44
37252	0.1075	5
37245	0.0714	21

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pigmented layer of retina	UBERON:0001782	99.16	gold quality
retina	UBERON:0000966	99.13	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	97.32	gold quality
heart right ventricle	UBERON:0002080	97.29	gold quality
biceps brachii	UBERON:0001507	97.22	gold quality
gluteal muscle	UBERON:0002000	96.79	gold quality
myocardium	UBERON:0002349	96.71	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	96.65	gold quality
vastus lateralis	UBERON:0001379	96.59	gold quality
quadriceps femoris	UBERON:0001377	96.56	gold quality
left ventricle myocardium	UBERON:0006566	96.55	gold quality
deltoid	UBERON:0001476	96.31	gold quality
urethra	UBERON:0000057	96.23	gold quality
renal medulla	UBERON:0000362	96.16	gold quality
cardiac muscle of right atrium	UBERON:0003379	95.86	gold quality
skeletal muscle tissue	UBERON:0001134	95.79	gold quality
visceral pleura	UBERON:0002401	95.78	gold quality
muscle tissue	UBERON:0002385	95.37	gold quality
saphenous vein	UBERON:0007318	95.35	gold quality
secondary oocyte	CL:0000655	95.17	gold quality
body of tongue	UBERON:0011876	95.16	gold quality
diaphragm	UBERON:0001103	95.11	gold quality
upper leg skin	UBERON:0004262	95.05	gold quality
cauda epididymis	UBERON:0004360	94.99	gold quality
tibialis anterior	UBERON:0001385	94.92	gold quality
triceps brachii	UBERON:0001509	94.85	gold quality
buccal mucosa cell	CL:0002336	94.55	gold quality
seminal vesicle	UBERON:0000998	94.24	gold quality
vena cava	UBERON:0004087	94.10	gold quality
muscle organ	UBERON:0001630	94.00	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 7.

Experiment	Marker?	Max mean expression
E-CURD-119	yes	53.21
E-GEOD-135922	yes	31.89
E-HCAD-10	yes	18.24
E-MTAB-8142	yes	17.59
E-CURD-112	yes	15.31
E-MTAB-9801	yes	6.31
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

120 targets.

Target	Regulation
ACP5	Activation
AKT1
APEX1	Activation
ATP6V0D2
ATP6V1B2
BAD	Unknown
BCL2	Activation
BCL2A1	Repression
BEST1	Activation
BIRC7	Unknown
BRAF
CADM1	Unknown
CD40
CD40LG	Activation
CDH1	Activation
CDK2	Unknown
CDK6
CDKN1A	Repression
CDKN1B	Repression
CDKN2A	Repression
CLCN7	Activation
CMA1	Unknown
CSF1
CTSK	Activation
CXCL8	Activation
DCSTAMP	Activation
DCT	Activation
DIAPH1	Activation
DICER1
DIO2

JASPAR motifs

Motif	Name	Family
MA0620.2	MITF	bHLH-ZIP
MA0620.3	MITF	bHLH-ZIP
MA0620.4	MITF	bHLH-ZIP

JASPAR matrix evidence (PMIDs): PMID:12086670

Upstream regulators (CollecTRI, top): ATF1, CDH3, CREB1, DIDO1, EWSR1, FOXD3, GLI2, HOXA1, IRF6, JUN, LEF1, MITF, ONECUT1, ONECUT2, OTX2, PAX2, PAX3, PAX6, POU3F2, SOX10, SOX9, SSRP1, TBX2, TCF4, TRRAP, ZEB2, ZNF382

miRNA regulators (miRDB)

155 targeting MITF, 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-3163	100.00	77.23	8605
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-3162-3P	100.00	65.37	363
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-9-3P	99.96	70.88	2068
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-3910	99.95	71.13	2227

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• MAZR and MITF synergistically transactivated the mMCP-6 gene. MAZR appeared to play important roles in the normal phenotypic expression of mast cells in association with MITF (PMID:11751862)
• Microphthalmia-associated transcription factor (MITF) regulates the differentiation and development of melanocytes and retinal pigment epithelium and is also responsible for pigment cell-specific transcription of the melanogenesis enzyme genes. Review. (PMID:11764295)
• Microphthalmia-associated transcription factor interacts with LEF-1, a mediator of Wnt signaling (PMID:12032083)
• MITF-M transactivates its own promoter (M promoter) by interacting with LEF-1 (PMID:12048204)
• Bcl2 regulation by the melanocyte master regulator Mitf modulates lineage survival and melanoma cell viability (PMID:12086670)
• MITF regulates not only the expression of enzymes involved in melanin synthesis, but also the expression of a receptor which plays an essential role in melanocyte functions (PMID:12204775)
• Beta catenin induced human melanoma growth requires the downstream target MITF (PMID:12235125)
• MITF gene may be implicated in Waardenburg syndrome. (PMID:12666593)
• MITF-M plays dual roles in the Wnt signaling pathway; MITF-M represents a downstream target and a nuclear mediator of Wnt signals in melanocytes (PMID:12753399)
• Data show that MITF appears to regulate the expression of the SILV and MLANA genes. (PMID:12819038)
• MITF expression in melanocytes is regulated by alpha-melanocyte-stimulating hormone modulated by SOX10 (PMID:12944398)
• MITF and STAT3 cooperatively induce c-fos, resulting in cellular transformation (PMID:14737107)
• MITF as a major transcriptional regulator of studies identify MITF as a major transcriptional regulator of TRPM1 and suggest that its prognostic value may be linked to MITF-mediated regulation of cellular differentiation (PMID:14744763)
• Mitf might play a role in the multinucleation process of giant cells and giant cell lesions. (PMID:15205688)
• the functional consequences of MITF sumoylation depend on promoter context. Sumoylation provides a possible mechanism for altering the effects of MITF by affecting the target genes that it activates (PMID:15507434)
• MITF regulates p16INK4A expression in melanocytes. (PMID:15623583)
• The majority of isoforms were found to be broadly expressed, with the M- and Mc-isoforms being tissue-restricted to melanocytes and mast cells, respectively. (PMID:15715979)
• Simultaneous expression of the EWSR1-ATF1 and MITF-M transcripts in clear cell carcinoma has led to the proposal that the MITF-M promoter is transactivated by EWSR1-ATF1. (PMID:15884099)
• We therefore conclude that the alpha-MSH/cAMP pathway, using MITF as a signal transducer and HIF1alpha as a target, might contribute to melanoma progression. (PMID:15983061)
• MITF represents a distinct class of ’lineage survival’ or ’lineage addiction’ oncogenes required for both tissue-specific cancer development and tumour progression (PMID:16001072)
• These data suggest that MITF is an anti-proliferation factor that is down-regulated by B-RAF signaling and that this is a crucial event for the progression of melanomas that harbor oncogenic B-RAF. (PMID:16129781)
• identified MITF as a new substrate of caspases and we characterized the cleavage site after Asp 345 in the C-terminal domain (PMID:16140982)
• MITF, specifically MITF-M, is a key transcription factor for protein kinase C-beta (PKC-beta), linking the PKC- and cAMP-dependent pathways in regulation of melanogenesis (PMID:16411896)
• The results of this study demonstrate a role for glutamate in MiTF regulation that may have implications in melanocyte associated disorders. (PMID:16420247)
• c-Met expression is regulated by Mitf in the melanocyte lineage (PMID:16455654)
• Mitf detection in blood can indicate subclinical metastatic disease and predict treatment outcome in melanoma patients. (PMID:16489066)
• The transcription factor MITF is an amplified oncogene in melanoma that is critical for anchoring lineage dependence and malignant character. (PMID:16510564)
• Sphingosylphosphorylcholine reduces melanin synthesis via MITF downregulation. (PMID:16524430)
• Tacrolimus or cyclosporine A act on human osteoclast precursors in rheumatoid arthritis patients by targeting the calcineurin-dependent NFAT pathway and activation pathway for c-Jun or MITF. (PMID:16586042)
• MITF and TFE3 reciprocally rescue one another in lines derived from CCS or pediatric renal carcinoma. (PMID:16766266)
• Of special interest was the rapid decrease in expression of MITF in melanocytes treated with DKK1, which is concurrent with the decreased activities of beta-catenin and of glucose-synthase kinase 3beta. (PMID:17159916)
• findings show that in melanomas invasiveness can be regulated epigenetically by Mitf, via regulation of the DIAPH1 gene; Mitf, via regulation of Dia1, can both inhibit invasiveness & promote proliferation (PMID:17182868)
• MITF evokes transcription of a paradigmatic MITF target tyrosinase and show that the adenoviral E1A protein represses the MITF-driven transcription in these cells. (PMID:17250547)
• analysis of the Mitf gene reveals novel conserved domains in human, mouse and Drosophila (PMID:17516926)
• Detection of both partial and whole gene deletions of MITF increase mutation detection in Waardenburg syndrome. (PMID:17627390)
• Microphthalmia-associated transcription factor gene amplification in metastatic melanoma may have a role in patient survival (PMID:17975146)
• link between microphthalmia-associated transcription factor haploinsufficiency and endothelin signaling (PMID:18039926)
• These results show that RAB27A is a new direct transcriptional target of MITF and link MITF to melanosome transport, another key parameter of melanocyte differentiation and skin pigmentation. (PMID:18281284)
• a novel MITF isoform, MITF-CM, which possesses a unique amino terminus was identified. (PMID:18284417)
• expression of mature miR-137 in melanoma cell lines down-regulates MITF expression (PMID:18316599)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	mitfa	ENSDARG00000003732
mus_musculus	Mitf	ENSMUSG00000035158
rattus_norvegicus	Mitf	ENSRNOG00000008658
drosophila_melanogaster	Mitf	FBGN0263112
caenorhabditis_elegans		WBGENE00020930

Paralogs (3): TFE3 (ENSG00000068323), TFEC (ENSG00000105967), TFEB (ENSG00000112561)

Protein

Protein identifiers

Microphthalmia-associated transcription factor — O75030 (reviewed: O75030)

Alternative names: Class E basic helix-loop-helix protein 32

All UniProt accessions (9): A0A087WXU1, A0A8I5KRZ6, A0A8I5KSZ4, A0A8I5KTU3, C9J845, C9JBI8, C9K0S7, E9PKJ8, O75030

UniProt curated annotations — full annotation on UniProt →

Function. Transcription factor that acts as a master regulator of melanocyte survival and differentiation as well as melanosome biogenesis. Binds to M-boxes (5’-TCATGTG-3’) and symmetrical DNA sequences (E-boxes) (5’-CACGTG-3’) found in the promoter of pigmentation genes, such as tyrosinase (TYR). Involved in the cellular response to amino acid availability by acting downstream of MTOR: in the presence of nutrients, MITF phosphorylation by MTOR promotes its inactivation. Upon starvation or lysosomal stress, inhibition of MTOR induces MITF dephosphorylation, resulting in transcription factor activity. Plays an important role in melanocyte development by regulating the expression of tyrosinase (TYR) and tyrosinase-related protein 1 (TYRP1). Plays a critical role in the differentiation of various cell types, such as neural crest-derived melanocytes, mast cells, osteoclasts and optic cup-derived retinal pigment epithelium.

Subunit / interactions. Homodimer or heterodimer; dimerization is mediated via the coiled coil region. Efficient DNA binding requires dimerization with another bHLH protein. Binds DNA in the form of homodimer or heterodimer with either TFE3, TFEB or TFEC. Interacts with small GTPases Rag (RagA/RRAGA, RagB/RRAGB, RagC/RRAGC and/or RagD/RRAGD); promoting its recruitment to lysosomal membrane in the presence of nutrients. Interacts with KARS1. Identified in a complex with HINT1 and CTNNB1. Interacts with VSX2.

Subcellular location. Nucleus. Cytoplasm. Lysosome membrane.

Tissue specificity. Expressed in melanocytes (at protein level). Expressed in the retinal pigment epithelium, brain, and placenta. Expressed in the kidney. Expressed in the kidney and retinal pigment epithelium. Expressed in the kidney. Expressed in the kidney. Expressed in melanocytes. Expressed in melanocytes.

Post-translational modifications. When nutrients are present, phosphorylation by MTOR at Ser-5 via non-canonical mTORC1 pathway promotes ubiquitination by the SCF(BTRC) complex, followed by degradation. Phosphorylation at Ser-405 significantly enhances the ability to bind the tyrosinase promoter. Phosphorylation by MARK3/cTAK1 at Ser-280 promotes association with 14-3-3/YWHA adapters and retention in the cytosol. Phosphorylated at Ser-180 and Ser-516 following KIT signaling, triggering a short live activation: Phosphorylation at Ser-180 and Ser-516 by MAPK and RPS6KA1, respectively, activate the transcription factor activity but also promote ubiquitination and subsequent degradation by the proteasome. Phosphorylated in response to blue light (415nm). Ubiquitinated by the SCF(BTRC) and SCF(FBXW11) complexes following phosphorylation ar Ser-5 by MTOR, leading to its degradation by the proteasome. Ubiquitinated following phosphorylation at Ser-180, leading to subsequent degradation by the proteasome. Deubiquitinated by USP13, preventing its degradation.

Disease relevance. Waardenburg syndrome 2A (WS2A) [MIM:193510] WS2 is a genetically heterogeneous, autosomal dominant disorder characterized by sensorineural deafness, pigmentary disturbances, and absence of dystopia canthorum. The frequency of deafness is higher in WS2 than in WS1. The disease is caused by variants affecting the gene represented in this entry. Tietz albinism-deafness syndrome (TADS) [MIM:103500] An autosomal dominant disorder characterized by generalized hypopigmentation and congenital, bilateral, profound sensorineural deafness. The disease is caused by variants affecting the gene represented in this entry. Melanoma, cutaneous malignant 8 (CMM8) [MIM:614456] A malignant neoplasm of melanocytes, arising de novo or from a pre-existing benign nevus, which occurs most often in the skin but may also involve other sites. Disease susceptibility is associated with variants affecting the gene represented in this entry. Coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness (COMMAD) [MIM:617306] An autosomal recessive syndrome characterized by severe microphthalmia, profound congenital sensorineural hearing loss, lack of pigment in the hair, skin, and eyes, macrocephaly, facial dysmorphism, and osteopetrosis. The disease is caused by variants affecting the gene represented in this entry. An allelic combination involving at least one dominant-negative mutation, inherited in a recessive manner, represents the underlying molecular mechanism leading to COMMAD syndrome. Variations affecting this gene are associated with susceptibility to pheochromocytomas and paragangliomas, rare neural crest-derived tumors with an approximate incidence of 1:300,000/year.

Domain organisation. The leucine zipper region is part of a larger coiled coil.

Similarity. Belongs to the MiT/TFE family.

Isoforms (12)

UniProt ID	Names	Canonical?
O75030-1	A1	yes
O75030-2	A2
O75030-3	B1
O75030-4	B2
O75030-5	C1
O75030-6	C2
O75030-7	H1
O75030-8	H2
O75030-9	M1
O75030-10	M2
O75030-11	Mdel
O75030-12	12

RefSeq proteins (13): NP_000239, NP_001171896, NP_001171897, NP_001341533, NP_001341534, NP_001341535, NP_001341536, NP_001341537, NP_006713, NP_937801, NP_937802, NP_937820, NP_937821 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011598	bHLH_dom	Domain
IPR021802	MiT/TFE_C	Domain
IPR031867	MiT/TFE_N	Domain
IPR036638	HLH_DNA-bd_sf	Homologous_superfamily

Pfam: PF00010, PF11851, PF15951

UniProt features (52 total): sequence variant 10, splice variant 8, modified residue 7, mutagenesis site 7, helix 6, region of interest 5, compositionally biased region 3, cross-link 2, chain 1, domain 1, sequence conflict 1, coiled-coil region 1

Structure

Experimental structures (PDB)

12 structures.

PDB	Method	Resolution (Å)
9H7Q	X-RAY DIFFRACTION	1.72
9H5H	X-RAY DIFFRACTION	1.74
9H7T	X-RAY DIFFRACTION	1.85
7EOD	X-RAY DIFFRACTION	1.9
9H7S	X-RAY DIFFRACTION	1.99
4C7N	X-RAY DIFFRACTION	2.1
7D8S	X-RAY DIFFRACTION	2.28
9H5F	X-RAY DIFFRACTION	2.3
9H7R	X-RAY DIFFRACTION	2.52
7D8R	X-RAY DIFFRACTION	3
7D8T	X-RAY DIFFRACTION	3.2
8E1D	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75030-F1	62.25	0.21

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 (9): 5, 180, 280, 405, 414, 491, 516, 289, 423

Mutagenesis-validated functional residues (7):

Position	Phenotype
5	impaired phosphorylation by mtor, leading to abolished ubiquitination and degradation by the scf(btrc) complex.
180	abolishes both transcription factor activity and ubiquitination, leading to an inert and stable protein; when associated
280	accumulates in the nucleus due to impaired phosphorylation.
289	loss of sumoylation; when associated with r-423.
405	loss of phosphorylation and function.
423	loss of sumoylation; when associated with r-289.
516	abolishes both transcription factor activity and ubiquitination, leading to an inert and stable protein; when associated

Function

Pathways and Gene Ontology

Reactome pathways

16 pathways

ID	Pathway
R-HSA-3232118	SUMOylation of transcription factors
R-HSA-9856649	Transcriptional and post-translational regulation of MITF-M expression and activity
R-HSA-9824585	Regulation of MITF-M-dependent genes involved in pigmentation
R-HSA-9824594	Regulation of MITF-M-dependent genes involved in apoptosis
R-HSA-9825892	Regulation of MITF-M-dependent genes involved in cell cycle and proliferation
R-HSA-9825895	Regulation of MITF-M-dependent genes involved in DNA replication, damage repair and senescence
R-HSA-9854907	Regulation of MITF-M dependent genes involved in metabolism
R-HSA-9854909	Regulation of MITF-M dependent genes involved in invasion
R-HSA-9857377	Regulation of MITF-M-dependent genes involved in lysosome biogenesis and autophagy
R-HSA-9926550	Regulation of MITF-M-dependent genes involved in extracellular matrix, focal adhesion and epithelial-to-mesenchymal transition
R-HSA-1266738	Developmental Biology
R-HSA-2990846	SUMOylation
R-HSA-3108232	SUMO E3 ligases SUMOylate target proteins
R-HSA-392499	Metabolism of proteins
R-HSA-597592	Post-translational protein modification
R-HSA-9730414	MITF-M-regulated melanocyte development

MSigDB gene sets: 0 (showing top):

GO Biological Process (23): negative regulation of transcription by RNA polymerase II (GO:0000122), regulation of DNA-templated transcription (GO:0006355), regulation of transcription by RNA polymerase II (GO:0006357), positive regulation of gene expression (GO:0010628), Wnt signaling pathway (GO:0016055), osteoclast differentiation (GO:0030316), melanocyte differentiation (GO:0030318), negative regulation of cell migration (GO:0030336), regulation of cell population proliferation (GO:0042127), camera-type eye development (GO:0043010), negative regulation of apoptotic process (GO:0043066), cell fate commitment (GO:0045165), regulation of osteoclast differentiation (GO:0045670), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), bone remodeling (GO:0046849), protein-containing complex assembly (GO:0065003), melanocyte apoptotic process (GO:1902362), positive regulation of DNA-templated transcription initiation (GO:2000144), regulation of RNA biosynthetic process (GO:2001141), regulation of gene expression (GO:0010468), cell differentiation (GO:0030154), pigmentation (GO:0043473)

GO Molecular Function (10): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription repressor activity, RNA polymerase II-specific (GO:0001227), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), chromatin binding (GO:0003682), protein dimerization activity (GO:0046983), E-box binding (GO:0070888), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), protein binding (GO:0005515)

GO Cellular Component (9): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), lysosomal membrane (GO:0005765), cytosol (GO:0005829), protein-containing complex (GO:0032991), lysosome (GO:0005764), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
MITF-M-dependent gene expression	8
SUMO E3 ligases SUMOylate target proteins	1
MITF-M-regulated melanocyte development	1
Post-translational protein modification	1
SUMOylation	1
Metabolism of proteins	1
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
RNA polymerase II transcription regulatory region sequence-specific DNA binding	4
regulation of transcription by RNA polymerase II	3
transcription by RNA polymerase II	3
regulation of DNA-templated transcription	3
DNA-templated transcription	2
regulation of gene expression	2
apoptotic process	2
positive regulation of DNA-templated transcription	2
DNA-binding transcription factor activity, RNA polymerase II-specific	2
binding	2
negative regulation of DNA-templated transcription	1
regulation of RNA biosynthetic process	1
gene expression	1
positive regulation of macromolecule biosynthetic process	1
cell surface receptor signaling pathway	1
myeloid leukocyte differentiation	1
pigment cell differentiation	1
cell migration	1
regulation of cell migration	1
negative regulation of cell motility	1
cell population proliferation	1
regulation of cellular process	1
eye development	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
cell differentiation	1
cellular developmental process	1
regulation of myeloid leukocyte differentiation	1
osteoclast differentiation	1
positive regulation of RNA biosynthetic process	1
tissue remodeling	1
cellular component assembly	1
protein-containing complex organization	1
DNA-templated transcription initiation	1
regulation of DNA-templated transcription initiation	1
regulation of macromolecule biosynthetic process	1
RNA biosynthetic process	1
regulation of RNA metabolic process	1
cis-regulatory region sequence-specific DNA binding	1

Protein interactions and networks

STRING

2778 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MITF	TYR	P14679	978
MITF	SPI1	P17947	957
MITF	DCT	P40126	951
MITF	SOX10	P56693	938
MITF	TYRP1	P17643	927
MITF	JUN	P05412	923
MITF	TFE3	P19532	905
MITF	FOS	P01100	886
MITF	PAX6	P26367	880
MITF	PAX3	P23760	873
MITF	MC1R	Q01726	844
MITF	KARS1	Q15046	843
MITF	EP300	Q09472	834
MITF	CTNNB1	P35222	812
MITF	POMC	P01189	799

IntAct

45 interactions, top by confidence:

A	B	Type	Score
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
MITF	TFEB	psi-mi:“MI:0915”(physical association)	0.560
MITF	TFE3	psi-mi:“MI:0915”(physical association)	0.560
MITF	TFEB	psi-mi:“MI:0914”(association)	0.560
TFEB	MITF	psi-mi:“MI:0914”(association)	0.560
FHL2	CNOT1	psi-mi:“MI:0914”(association)	0.530
CLTC	MITF	psi-mi:“MI:0407”(direct interaction)	0.440
MITF	RBPJ	psi-mi:“MI:0915”(physical association)	0.400
MITF	SUMO1	psi-mi:“MI:0915”(physical association)	0.400
MITF	ADRB2	psi-mi:“MI:0915”(physical association)	0.370
	MITF	psi-mi:“MI:0915”(physical association)	0.370
XCL1	MITF	psi-mi:“MI:0915”(physical association)	0.370
MITF	HK3	psi-mi:“MI:0915”(physical association)	0.370
STUB1	MITF	psi-mi:“MI:0915”(physical association)	0.370
EBP	MITF	psi-mi:“MI:0915”(physical association)	0.370
Xpo1	IFT56	psi-mi:“MI:0914”(association)	0.350
YWHAB	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
YWHAG	C1orf226	psi-mi:“MI:0914”(association)	0.350
YWHAB	FOXO6	psi-mi:“MI:0914”(association)	0.350
YWHAG	FOXO6	psi-mi:“MI:0914”(association)	0.350
MITF	YWHAZ	psi-mi:“MI:0914”(association)	0.350
ERG	BCL9	psi-mi:“MI:2364”(proximity)	0.270
SOX2	SMCHD1	psi-mi:“MI:2364”(proximity)	0.270
SP7	IGF2BP3	psi-mi:“MI:2364”(proximity)	0.270
YWHAG	RPSA2	psi-mi:“MI:2364”(proximity)	0.270
FBXW7	MITF	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (85): MITF (Affinity Capture-Western), MITF (Affinity Capture-MS), MITF (Affinity Capture-MS), TFEB (Affinity Capture-MS), TFE3 (Affinity Capture-MS), RBM6 (Affinity Capture-MS), KLHL20 (Affinity Capture-MS), MITF (Affinity Capture-RNA), MITF (Biochemical Activity), MITF (Affinity Capture-Western), MITF (Affinity Capture-RNA), MITF (Affinity Capture-MS), MITF (Phenotypic Enhancement), PIAS3 (Reconstituted Complex), PIAS3 (Affinity Capture-Western)

ESM2 similar proteins: A0A0G2JTZ2, A2BEA6, A4IFD2, B1H349, B3DM43, B3DM47, F1M8W4, O15409, O75030, P0CF24, P23899, P27889, P35680, P35710, P35711, P35712, P40645, P40647, P58463, P70062, P70063, P70064, Q23045, Q2LE08, Q4VYR7, Q4VYS1, Q58NQ4, Q5QL03, Q5RCU4, Q5RER5, Q5W1J5, Q6GL68, Q800Q5, Q86MD3, Q8HZ00, Q8MJ97, Q8MJ98, Q8MJ99, Q8MJA0, Q8STF6

Diamond homologs: A0A286LEZ9, A2T713, A2T7L8, A4IFU7, O02818, O14948, O75030, O88368, P0DPB0, P17106, P19484, P19532, P22415, P49379, Q05B92, Q07957, Q08874, Q10186, Q5A1E3, Q5XFQ6, Q61069, Q63302, Q64092, Q6XBT4, Q9R210, Q9WTW4, H2KZZ2, P38165, A3KNA7, O43019, O97676, P36956, P56720, Q12772, Q3T1I5, Q3U1N2, Q4WIN1, Q59RL7, Q60416, Q60429

SIGNOR signaling

35 interactions.

A	Effect	B	Mechanism
RPS6KA1	down-regulates	MITF	phosphorylation
ERK1/2	down-regulates	MITF	phosphorylation
MITF	“up-regulates quantity by expression”	TPSAB1	“transcriptional regulation”
RPS6K	down-regulates	MITF	phosphorylation
MITF	“up-regulates quantity by expression”	OCA2	“transcriptional regulation”
MITF	“up-regulates quantity by expression”	BEST1	“transcriptional regulation”
MITF	“up-regulates quantity by expression”	SERPINF1	“transcriptional regulation”
MITF	“up-regulates quantity by expression”	PMEL	“transcriptional regulation”
MITF	“up-regulates quantity by expression”	MLANA	“transcriptional regulation”
MITF	“up-regulates quantity by expression”	TYRP1	“transcriptional regulation”
MITF	“up-regulates quantity by expression”	DCT	“transcriptional regulation”
MITF	“up-regulates quantity by expression”	TYR	“transcriptional regulation”
CLK4	“down-regulates quantity by destabilization”	MITF	phosphorylation
GSK3B	“up-regulates activity”	MITF	phosphorylation
GSK3B	“up-regulates quantity by stabilization”	MITF	phosphorylation
AKT1	“down-regulates quantity by destabilization”	MITF	phosphorylation
PRKDC	“up-regulates activity”	MITF	phosphorylation
GSK3B	“down-regulates quantity by destabilization”	MITF	phosphorylation
GSK3A	up-regulates	MITF	phosphorylation
MAPK1	down-regulates	MITF	phosphorylation
UBE2I	down-regulates	MITF	ubiquitination
MITF	“up-regulates quantity by expression”	ACP5	“transcriptional regulation”
MITF	“up-regulates quantity by expression”	TRPM1	“transcriptional regulation”
SOX9	“up-regulates activity”	MITF	binding
POU3F2	“up-regulates quantity by expression”	MITF	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 36 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
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	5	108.3×	9e-08
Transcriptional and post-translational regulation of MITF-M expression and activity	8	46.0×	1e-09
MITF-M-regulated melanocyte development	9	33.1×	1e-09
SARS-CoV-1-host interactions	5	28.3×	3e-05
SARS-CoV-1 Infection	6	27.6×	4e-06
TP53 Regulates Metabolic Genes	6	25.1×	5e-06
G2/M Checkpoints	5	21.7×	9e-05
G2/M DNA damage checkpoint	5	19.4×	1e-04

GO biological processes:

GO term	Partners	Fold	FDR
osteoblast differentiation	5	17.8×	1e-03
intracellular protein localization	5	15.4×	2e-03
protein stabilization	5	9.8×	7e-03

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

1330 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	93
Likely pathogenic	43
Uncertain significance	705
Likely benign	357
Benign	43

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1013483	NM_001354604.2(MITF):c.915dup (p.Leu306fs)	Pathogenic
1048557	NM_001354604.2(MITF):c.1291dup (p.Cys431fs)	Pathogenic
1202631	NM_001354604.2(MITF):c.644dup (p.His215fs)	Pathogenic
1202636	Single allele	Pathogenic
1297077	NM_001354604.2(MITF):c.955+1G>C	Pathogenic
1324720	NM_001354604.2(MITF):c.1061T>G (p.Leu354Ter)	Pathogenic
14270	NM_000248.4(MITF):c.33+1G>A	Pathogenic
14271	NM_001354604.2(MITF):c.763-2A>C	Pathogenic
14272	NM_001354604.2(MITF):c.964AGA[2] (p.Arg324del)	Pathogenic
14273	NM_001354604.2(MITF):c.1069T>C (p.Ser357Pro)	Pathogenic
14274	NM_001354604.2(MITF):c.1145del (p.Glu382fs)	Pathogenic
14275	NM_001354604.2(MITF):c.951C>G (p.Asn317Lys)	Pathogenic
14276	NM_001354604.2(MITF):c.961C>T (p.Arg321Ter)	Pathogenic
2020473	NM_001354604.2(MITF):c.764T>A (p.Leu255Ter)	Pathogenic
2024980	NM_001354604.2(MITF):c.643_644dup (p.Ser216fs)	Pathogenic
2203401	NM_001354604.2(MITF):c.815del (p.Pro272fs)	Pathogenic
228361	NM_198159.2(MITF):c.(?938)-102*(78_?)del	Pathogenic
228362	NM_001354604.2(MITF):c.1043G>A (p.Trp348Ter)	Pathogenic
228364	NM_001354604.2(MITF):c.704C>G (p.Ser235Ter)	Pathogenic
236050	NM_001354604.2(MITF):c.1208del (p.Gly403fs)	Pathogenic
2422628	NC_000003.11:g.(?69985874)(70014399_?)del	Pathogenic
2422629	NC_000003.11:g.(?70013978)(70014399_?)del	Pathogenic
2422630	NC_000003.11:g.(?69985874)(69990502_?)del	Pathogenic
2922420	NM_001354604.2(MITF):c.367del (p.Leu123fs)	Pathogenic
3062730	GRCh37/hg19 3p13(chr3:69921510-69928465)x1	Pathogenic
3382232	NM_001354604.2(MITF):c.959A>G (p.Glu320Gly)	Pathogenic
3601241	NM_001354604.2(MITF):c.1574del (p.Thr525fs)	Pathogenic
3601242	NM_001354604.2(MITF):c.673del (p.Asp225fs)	Pathogenic
3601243	NM_001354604.2(MITF):c.689del (p.Ile230fs)	Pathogenic
3601244	NM_001354604.2(MITF):c.723del (p.Leu242fs)	Pathogenic

SpliceAI

1054 predictions. Top by Δscore:

Variant	Effect	Δscore
3:69937808:A:AG	acceptor_gain	1.0000
3:69937808:AT:A	acceptor_gain	1.0000
3:69937808:ATG:A	acceptor_gain	1.0000
3:69937809:T:G	acceptor_gain	1.0000
3:69937809:T:TA	acceptor_gain	1.0000
3:69937810:G:A	acceptor_gain	1.0000
3:69941323:GCAAA:G	donor_gain	1.0000
3:69941324:C:T	donor_gain	1.0000
3:69949045:CTCTA:C	acceptor_loss	1.0000
3:69949046:TCTA:T	acceptor_loss	1.0000
3:69949047:CTA:C	acceptor_loss	1.0000
3:69949049:A:AG	acceptor_gain	1.0000
3:69949049:A:G	acceptor_loss	1.0000
3:69949049:AGTT:A	acceptor_gain	1.0000
3:69949050:G:A	acceptor_loss	1.0000
3:69949050:G:GA	acceptor_gain	1.0000
3:69949050:GT:G	acceptor_gain	1.0000
3:69949050:GTT:G	acceptor_gain	1.0000
3:69949050:GTTG:G	acceptor_gain	1.0000
3:69949050:GTTGC:G	acceptor_gain	1.0000
3:69949158:G:GT	donor_gain	1.0000
3:69949966:G:GT	donor_gain	1.0000
3:69951885:GA:G	donor_gain	1.0000
3:69951887:G:GG	donor_gain	1.0000
3:69956450:T:A	acceptor_gain	1.0000
3:69956453:A:AG	acceptor_gain	1.0000
3:69956454:G:GG	acceptor_gain	1.0000
3:69956454:GTT:G	acceptor_gain	1.0000
3:69956526:GATCC:G	donor_gain	1.0000
3:69956531:G:GG	donor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000030648 (3:69744531 A>G), RS1000031722 (3:69932210 T>C), RS1000032955 (3:69888732 G>A), RS1000053228 (3:69792650 C>T), RS1000056102 (3:69876735 A>C,G,T), RS1000068631 (3:69810996 G>A), RS1000069954 (3:69913974 C>G), RS1000091753 (3:69895964 C>T), RS1000103775 (3:69792856 C>T), RS1000106547 (3:69877051 A>G), RS1000113977 (3:69747607 A>C), RS1000123875 (3:69920500 A>G), RS1000128369 (3:69937128 A>C,G), RS1000147160 (3:69760711 C>A,T), RS1000155965 (3:69810997 A>G)

Disease associations

OMIM: gene MIM:156845 | disease phenotypes: MIM:193510, MIM:103500, MIM:614456, MIM:617306, MIM:606574, MIM:193500, MIM:128600, MIM:142500, MIM:124900

GenCC curated gene-disease

Disease	Classification	Inheritance
Waardenburg syndrome type 2A	Definitive	Autosomal dominant
Tietz syndrome	Definitive	Autosomal dominant
Waardenburg syndrome type 2	Definitive	Autosomal dominant
melanoma, cutaneous malignant, susceptibility to, 8	Strong	Autosomal dominant
coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness	Strong	Autosomal recessive
Waardenburg syndrome	Moderate	Autosomal recessive
renal cell carcinoma	Moderate	Autosomal dominant
Waardenburg-Shah syndrome	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Waardenburg syndrome type 2	Definitive	AD

Mondo (19): Waardenburg syndrome type 2A (MONDO:0008671), Tietz syndrome (MONDO:0007077), melanoma, cutaneous malignant, susceptibility to, 8 (MONDO:0013759), hereditary neoplastic syndrome (MONDO:0015356), coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness (MONDO:0015014), oculocutaneous albinism type 4 (MONDO:0011683), hearing loss disorder (MONDO:0005365), Waardenburg syndrome (MONDO:0018094), ear malformation (MONDO:0007500), heterochromia iridis (MONDO:0007722), familial melanoma (MONDO:0018961), Waardenburg syndrome type 2 (MONDO:0019517), renal cell carcinoma (MONDO:0005086), melanoma (MONDO:0005105), autosomal dominant nonsyndromic hearing loss (MONDO:0019587)

Orphanet (16): Waardenburg syndrome (Orphanet:3440), Inherited cancer-predisposing syndrome (Orphanet:140162), MITF-related melanoma and renal cell carcinoma predisposition syndrome (Orphanet:293822), Tietz syndrome (Orphanet:42665), Coloboma-osteopetrosis-microphthalmia-macrocephaly-albinism-deafness syndrome (Orphanet:603494), Oculocutaneous albinism type 4 (Orphanet:79435), Microphthalmia-anophthalmia-coloboma (Orphanet:98555), Familial melanoma (Orphanet:618), Waardenburg syndrome type 2 (Orphanet:895), Rare genetic deafness (Orphanet:96210), Renal cell carcinoma (Orphanet:217071), Rare autosomal dominant non-syndromic sensorineural deafness type DFNA (Orphanet:90635), Waardenburg syndrome type 1 (Orphanet:894), Rare non-syndromic genetic deafness (Orphanet:87884), NON RARE IN EUROPE: Melanoma (Orphanet:411533)

HPO phenotypes

74 total (30 of 74 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000077	Abnormality of the kidney
HP:0000256	Macrocephaly
HP:0000347	Micrognathia
HP:0000358	Posteriorly rotated ears
HP:0000365	Hearing impairment
HP:0000366	Abnormality of the nose
HP:0000407	Sensorineural hearing impairment
HP:0000426	Prominent nasal bridge
HP:0000430	Underdeveloped nasal alae
HP:0000431	Wide nasal bridge
HP:0000478	Abnormality of the eye
HP:0000482	Microcornea
HP:0000488	Retinopathy
HP:0000504	Abnormality of vision
HP:0000506	Telecanthus
HP:0000508	Ptosis
HP:0000518	Cataract
HP:0000534	Abnormal eyebrow morphology
HP:0000568	Microphthalmia
HP:0000586	Shallow orbits
HP:0000589	Coloboma
HP:0000593	Abnormal anterior chamber morphology
HP:0000635	Blue irides
HP:0000664	Synophrys
HP:0000958	Dry skin
HP:0001000	Abnormality of skin pigmentation
HP:0001010	Hypopigmentation of the skin
HP:0001022	Albinism

GWAS associations

36 associations (top):

Study	Trait	p-value
GCST003123_10	Severe influenza A (H1N1) infection	2.000000e-11
GCST003872_6	QRS complex (12-leadsum)	9.000000e-09
GCST004601_44	Red blood cell count	1.000000e-12
GCST004604_88	Hematocrit	2.000000e-11
GCST004615_13	Hemoglobin concentration	4.000000e-10
GCST006491_17	Circulating fibroblast growth factor 23 levels	3.000000e-06
GCST006988_127	Blond vs. brown/black hair color	1.000000e-13
GCST007096_179	Pulse pressure	1.000000e-07
GCST007099_44	Systolic blood pressure	5.000000e-09
GCST007576_211	Chronotype	5.000000e-08
GCST010083_193	Hemoglobin levels	3.000000e-09
GCST010083_199	Hemoglobin levels	2.000000e-19
GCST010151_10	Carotid intima media thickness x smoking interaction	7.000000e-06
GCST010204_121	Low density lipoprotein cholesterol levels	3.000000e-12
GCST010243_88	Apolipoprotein B levels	2.000000e-10
GCST010244_362	Triglyceride levels	5.000000e-08
GCST010245_78	LDL cholesterol levels	5.000000e-10
GCST010276_8	Renal underexcretion gout	1.000000e-07
GCST010303_59	Nevus count or cutaneous melanoma	1.000000e-09
GCST010304_5	Cutaneous malignant melanoma	5.000000e-25
GCST010698_32	Subcortical volume (min-P)	3.000000e-08
GCST010699_42	Brain morphology (min-P)	2.000000e-08
GCST010701_112	Cortical surface area (MOSTest)	9.000000e-12
GCST010702_17	Subcortical volume (MOSTest)	5.000000e-08
GCST010703_41	Brain morphology (MOSTest)	9.000000e-09
GCST010866_8	Coronary artery disease	1.000000e-10
GCST011365_123	Myocardial infarction	8.000000e-06
GCST012099_3	Hypertrophic cardiomyopathy (sarcomere negative)	3.000000e-07
GCST90002383_369	Hematocrit	3.000000e-26
GCST90002384_210	Hemoglobin	3.000000e-25

EFO canonical traits (20, from GWAS)

EFO ID	Trait name
EFO:1001488	influenza A (H1N1)
EFO:0005054	QRS complex
EFO:0007742	QRS amplitude
EFO:0004305	erythrocyte count
EFO:0004348	hematocrit
EFO:0004509	hemoglobin measurement
EFO:0003924	hair color
EFO:0005763	pulse pressure measurement
EFO:0006335	systolic blood pressure
EFO:0008328	chronotype measurement
EFO:0006527	smoking status measurement
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004615	apolipoprotein B measurement
EFO:0004530	triglyceride measurement
EFO:0004632	nevus count
EFO:0004346	neuroimaging measurement
EFO:0004833	neutrophil count
EFO:0007985	platelet crit
EFO:0004309	platelet count
EFO:0007788	BMI-adjusted waist-hip ratio

MeSH disease descriptors (12)

Descriptor	Name	Tree numbers
D002292	Carcinoma, Renal Cell	C04.557.470.200.025.390; C04.588.945.947.535.160; C12.050.351.937.820.535.160; C12.050.351.968.419.473.160; C12.200.758.820.750.160; C12.200.777.419.473.160; C12.900.820.535.160; C12.950.419.473.160; C12.950.983.535.160
D034381	Hearing Loss	C09.218.458.341; C10.597.751.418.341; C23.888.592.763.393.341
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D008545	Melanoma	C04.557.465.625.650.510; C04.557.580.625.650.510; C04.557.665.510; C04.588.805.377; C17.800.882.445
D009386	Neoplastic Syndromes, Hereditary	C04.700; C16.320.700
D014849	Waardenburg Syndrome	C16.131.077.938
C538115	Heterochromia iridis (supp.)
C580334	Nonsyndromic Deafness (supp.)
C564696	Oculocutaneous Albinism, Type IV (supp.)
C536919	Tietz syndrome (supp.)
C536463	Waardenburg syndrome type 2 (supp.)
C536464	Waardenburg syndrome type 2A (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1741165 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

3 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 150,331 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1334033	PERHEXILINE MALEATE	4	1,054
CHEMBL244888	NIFUROXAZIDE	3	1,459
CHEMBL284328	HOMIDIUM BROMIDE	2	147,818

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

ChEMBL bioactivities

1851 potent at pChembl≥5 of 3024 total, top 34 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.72	AC50	19	nM	CHEMBL1971760
7.64	AC50	23	nM	CHEMBL1521172
7.62	AC50	24	nM	CHEMBL1470676
7.52	AC50	30	nM	CHEMBL1507250
7.41	AC50	39	nM	CHEMBL1342896
7.25	AC50	56	nM	CHEMBL1573994
7.25	AC50	56	nM	CHEMBL87
6.91	AC50	122	nM	CHEMBL1299637
6.77	AC50	171	nM	CHEMBL1307091
6.76	AC50	175	nM	CHEMBL1701797
6.56	AC50	275	nM	CHEMBL1559811
6.53	AC50	293	nM	CHEMBL1718830
6.48	AC50	333	nM	CHEMBL3199673
6.48	AC50	329	nM	CHEMBL1537098
6.47	AC50	337	nM	CHEMBL1534546
6.44	AC50	365	nM	CHEMBL1312935
6.43	AC50	371	nM	CHEMBL1370991
6.31	AC50	487	nM	CHEMBL1394409
6.30	AC50	495	nM	CHEMBL1352969
6.29	AC50	511	nM	CHEMBL1518647
6.28	AC50	528	nM	CHEMBL1699881
6.24	AC50	577	nM	CHEMBL1400379
6.22	AC50	601	nM	CHEMBL373137
6.22	AC50	599	nM	CHEMBL1386804
6.22	AC50	601	nM	CHEMBL1601979
6.18	AC50	666	nM	CHEMBL1513566
6.17	AC50	681	nM	CHEMBL1698608
6.16	AC50	696	nM	CHEMBL1976507
6.12	AC50	756	nM	CHEMBL1570216
6.06	AC50	875	nM	8-AZAGUANINE
6.06	AC50	866	nM	CHEMBL1468011
6.05	AC50	899	nM	CHEMBL1336277
6.05	AC50	894	nM	CHEMBL1321427
6.04	AC50	921	nM	CHEMBL1305475

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, decreases expression	7
trichostatin A	affects cotreatment, increases expression, affects expression	4
sodium arsenite	decreases expression, increases abundance, affects methylation, decreases reaction, increases expression (+1 more)	4
Cyclosporine	decreases expression, increases methylation	3
mercuric bromide	increases expression, affects cotreatment	2
2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one	decreases reaction, increases expression, affects cotreatment, increases degradation	2
Benzo(a)pyrene	decreases expression, increases methylation	2
Estradiol	decreases expression, affects cotreatment, increases expression	2
Colforsin	increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Cadmium Chloride	decreases expression	2
aristolochic acid I	decreases expression	1
4-(4-cyanophenyl)-2-(2-cyclopentylidenehydrazinyl)thiazole	decreases expression	1
FR900359	affects phosphorylation	1
bisphenol F	increases expression	1
TAK-243	decreases sumoylation	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, affects expression, increases abundance	1
pirinixic acid	decreases expression, increases activity, affects binding	1
bisphenol A	decreases methylation, affects methylation, affects cotreatment	1
methylselenic acid	increases expression	1
arsenite	affects binding, decreases reaction	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
benzo(e)pyrene	increases methylation	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
4-hydroxy-2-nonenal	decreases expression	1
nickel sulfate	increases expression	1
coumarin	affects phosphorylation	1
9-cis-retinal	increases expression, decreases reaction	1
methacrylaldehyde	affects cotreatment, affects expression, increases abundance	1

ChEMBL screening assays

10 unique, capped per target: 10 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1737866	Functional	PUBCHEM_BIOASSAY: MITF Measured in Cell-Based System Using Plate Reader - 2084-01_Inhibitor_DoseNoFile_CherryPick_Activity_Set2. (Class of assay: confirmatory) [Related pubchem assays (depositor defined):AID488944]	PubChem BioAssay data set

Cellosaurus cell lines

9 cell lines: 5 cancer cell line, 3 embryonic stem cell, 1 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A1MU	CSUXHi003-A	Induced pluripotent stem cell	Male
CVCL_A4D7	SEES3-1V human MITF, clone1	Embryonic stem cell	Male
CVCL_A4D8	SEES3-1V human MITF, clone2	Embryonic stem cell	Male
CVCL_A4D9	SEES3-1V human MITF, clone3	Embryonic stem cell	Male
CVCL_B8KI	Abcam HCT 116 MITF KO	Cancer cell line	Male
CVCL_B8YV	Abcam MCF-7 MITF KO	Cancer cell line	Female
CVCL_B9MS	Abcam A-549 MITF KO	Cancer cell line	Male
CVCL_SY42	HAP1 MITF (-)	Cancer cell line	Male
CVCL_VJ84	11CM	Cancer cell line	Sex unspecified

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00414765	PHASE4	COMPLETED	Aldesleukin in Participants With Metastatic Renal Cell Carcinoma or Metastatic Melanoma
NCT00777504	PHASE4	UNKNOWN	Study to the Optimal Duration of Therapy With Oral Angiogenesis Inhibitors
NCT00930345	PHASE4	TERMINATED	Biological, Pathological and Imagery Markers in the First-line Treatment of Metastatic Clear-cell Renal Cell Carcinoma
NCT01206764	PHASE4	COMPLETED	A Trial of Everolimis in Patients With Advanced Renal Cell Carcinoma.
NCT01266837	PHASE4	COMPLETED	Open Label, Single Arm Trial to Characterize Patients With Metastatic RCC Treated With Everolimus After Failure of the First VEGF-targeted Therapy (MARC-2)
NCT02056587	PHASE4	COMPLETED	Everolimus in Patients With Metastatic Renal Cell Carcinoma Following Progression on Prior Bevacizumab Treatment
NCT02338570	PHASE4	TERMINATED	Outcome-related Factors in Patients With Metastatic Renal Cell Carcinoma Treated With Everolimus (ORCHIDEE)
NCT02596035	PHASE4	COMPLETED	An Investigational Immuno-therapy Safety Trial of Nivolumab in Patients With Advanced or Metastatic Renal Cell Carcinoma
NCT02982954	PHASE4	COMPLETED	A Study to Evaluate the Safety of Nivolumab and Ipilimumab in Subjects With Previously Untreated Advanced or Metastatic Renal Cell Cancer
NCT05949424	PHASE4	UNKNOWN	OPTI - DOSE: Optimal Dosing of Oral Anticancer Drugs in Older Adults
NCT07028125	PHASE4	RECRUITING	Digital Monitoring of Self-reported Symptoms by Patients Treated With Cabozantinib Plus Nivolumab for Advanced Clear-cell Renal Carcinoma
NCT07405086	PHASE4	RECRUITING	Morning Versus Afternoon Administration of Immunotherapy for the Treatment of Advanced or Metastatic Solid Tumors, The Knight SHIFT Study
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
NCT00033904	PHASE3	COMPLETED	Survival Study Of Oncophage® vs. Observation In Patients With Kidney Cancer
NCT00126178	PHASE3	TERMINATED	Clinical Trial Studying a Personalized Cancer Vaccine in Patients With Non-metastatic Kidney Cancer
NCT00291369	PHASE3	COMPLETED	Cytokines in Patients With Metastatic Renal Cell Carcinoma of Intermediate Prognosis
NCT00410124	PHASE3	COMPLETED	RAD001 Plus Best Supportive Care (BSC) Versus BSC Plus Placebo in Patients With Metastatic Carcinoma of the Kidney Which Has Progressed After Treatment With Sorafenib and/or Sunitinib
NCT00474786	PHASE3	COMPLETED	Temsirolimus Versus Sorafenib As Second-Line Therapy In Patients With Advanced RCC Who Have Failed First-Line Sunitinib
NCT00478114	PHASE3	COMPLETED	Efficacy and Safety of Sorafenib in Advanced Renal Cell Carcinoma (RCC)
NCT00606632	PHASE3	COMPLETED	Pre-surgical Detection of Clear Cell Renal Cell Carcinoma (ccRCC) Using Radiolabeled G250-Antibody
NCT00606866	PHASE3	COMPLETED	MRI Study of BAY 43-9006 in Metastatic Renal Cell Carcinoma
NCT00631371	PHASE3	COMPLETED	Study Comparing Bevacizumab + Temsirolimus vs. Bevacizumab + Interferon-Alfa In Advanced Renal Cell Carcinoma Subjects
NCT00732914	PHASE3	COMPLETED	Sequential Study to Treat Renal Cell Carcinoma
NCT00869011	PHASE3	UNKNOWN	Exercise for Patients With Renal Cell Cancer Receiving Sunitinib
NCT00930033	PHASE3	COMPLETED	Clinical Trial to Assess the Importance of Nephrectomy
NCT01030783	PHASE3	COMPLETED	A Study to Compare Tivozanib (AV-951) to Sorafenib in Subjects With Advanced Renal Cell Carcinoma
NCT01076010	PHASE3	COMPLETED	An Extension Treatment Protocol for Subjects Who Have Participated in a Study of Tivozanib Versus Sorafenib in Kidney Carcinoma (Protocol AV-951-09-301).
NCT01198158	PHASE3	TERMINATED	Everolimus With or Without Bevacizumab in Treating Patients With Advanced Kidney Cancer That Progressed After First-Line Therapy
NCT01223027	PHASE3	COMPLETED	Study of Dovitinib Versus Sorafenib in Patients With Metastatic Renal Cell Carcinoma
NCT01224288	PHASE3	ACTIVE_NOT_RECRUITING	Dynamic Contrast Enhancement Computed Tomography for Evaluating Tumor Perfusion in Patients With Metastatic Renal Cell Carcinoma Receiving Targeted Therapies: Renal Cell Carcinoma (RCC) Scramble
NCT01235962	PHASE3	COMPLETED	A Study to Evaluate Pazopanib as an Adjuvant Treatment for Localized Renal Cell Carcinoma (RCC)
NCT01265810	PHASE3	COMPLETED	Caphosol in Oral Mucositis Due to Targeted Therapy
NCT01265901	PHASE3	COMPLETED	IMA901 in Patients Receiving Sunitinib for Advanced/Metastatic Renal Cell Carcinoma
NCT01481870	PHASE3	UNKNOWN	Comparison of Sequential Therapies With Sunitinib and Sorafenib in Advanced Renal Cell Carcinoma
NCT01582672	PHASE3	TERMINATED	Phase 3 Trial of Autologous Dendritic Cell Immunotherapy Plus Standard Treatment of Advanced Renal Cell Carcinoma
NCT01613846	PHASE3	COMPLETED	Phase III Sequential Open-label Study to Evaluate the Efficacy and Safety of Sorafenib Followed by Pazopanib Versus Pazopanib Followed by Sorafenib in the Treatment of Advanced / Metastatic Renal Cell Carcinoma (SWITCH-II)