3P14.1. View the map and BAC clones (data from UCSC genome browser).
isoform 1 (NM_198159): 10 exons, 228,854 bp, chr3:69871323-70100176.
isoform 2 (NM_198177): 10 exons, 102,045 bp, chr3:69998132-70100176.
isoform 3 (NM_006722): 10 exons, 204,525 bp, chr3:69895652-70100176.
isoform 4 (NM_000248): 9 exons, 31,734 bp, chr3:70068443-70100176.
isoform 5 (NM_198158): 9 exons, 31,734 bp, chr3:70068443-70100176.
isoform 6 (NM_198178): 9 exons, 89,231 bp, chr3:70010946-70100176.
The exon 1 of six isoforms are aligned as 1A-1J-1C-1MC-1E-1H-1D-1B-1M, except 1J, 1E and 1D, each exon is associated with a distinct mRNA isoform (also denoted as isoform A(1), C(2), MC(3), H(4), B(5), M(6)), and the common exons are 2-9. All of the isoforms also produce alternative splice forms modifying exon 6 (6A/6B) that lead to inclusion or exclusion of the sequence ACIFPT upstream of the basic domain. The bHLH-Zip domain is contributed by part of exon 6B, all of exon 7 and 8, and part of exon 9.
The figure below shows the structure of the MITF gene (data from UCSC genome browser).
Search the 5'UTR and 1kb upstream regions (seq1=mouse Mitf, seq2=human MITF) by CONREAL with 80% Position Weight Matrices (PWMs) threshold (view results here).
a) isoform 1( NM_198159), 4,788 bp, view ORF and the alignment to genomic.
b) isoform 2 ( NM_198177), 4,624 bp, view ORF and the alignment to genomic.
c) isoform 3 ( NM_006722), 4,700 bp, view ORF and the alignment to genomic.
d) isoform 4 (NM_000248), 4,490 bp, view ORF and the alignment to genomic.
e) isoform 5 (NM_198158), 4,472 bp, view ORF and the alignment to genomic.
f) isoform 6 (NM_198178), 4,597 bp, view ORF and the alignment to genomic.
MITF is expressed in developing NC-derived melanocyte precursors before the initial expression of Dopachrome tautomerase (DCT). M-MITF is a major isoform in NC stem cell-derived melanocytes. Isoform M is exclusively expressed in melanocytes and melanoma cells. Isoform A and isoform H are widely expressed in many cell types including melanocytes and retinal pigment epithelium (RPE). Isoform C is expressed in many cell types including RPE but not in melanocyte-lineage cells. Mitf regulation in the developing eye is isoform-selective, both temporally and spatially (Bharti, et al). Expression of mature miR-137 in melanoma cell lines down-regulates MITF expression (Bemis, et al).
Affymetrix microarray expression pattern in SymAtlas from GNF is shown below.
a) microphthalmia-associated transcription factor isoform 1 (NP_937802): 520 aa, UniProtKB/Swiss-Prot entry O75030.
b) microphthalmia-associated transcription factor isoform 2 (NP_937820): 504 aa, UniProtKB/Swiss-Prot entry O75030-8.
c) microphthalmia-associated transcription factor isoform 3 (NP_006713): 519 aa, UniProtKB/Swiss-Prot entry Q8WYR3.
d) microphthalmia-associated transcription factor isoform 4 (NP_000239): 419 aa, UniProtKB/Swiss-Prot entry Q96EB5.
e) microphthalmia-associated transcription factor isoform 5 (NP_937801): 413 aa, UniProtKB/Swiss-Prot entry Q96EB5.
f) microphthalmia-associated transcription factor isoform 6 (NP_937821): 495 aa, UniProtKB/Swiss-Prot entry O75030-4.
|Protein||XP_001138876 (520 aa)||XP_855594 (419 aa)||NP_032627 (419 aa)||XP_001065702 (520 aa)||NP_990360 (468 aa)|
|Identities||518/520 (99%)||392/409 (95%)||378/409 (92%)||489/520 (94%)||394/431 (91%)|
(1) Domains predicted by SMART:
a) low complexity: 41-55
b) coiled coil: 60-90
c) HLH: 311-364
d) low complexity: 435-450
e) low complexity: 504-517
(2) Transmembrane domains predicted by SOSUI:
This amino acid sequence is of a SOLUBLE PROTEIN.
(3) Graphic view of InterPro domain structure.
(1) Predicted results by ScanProsite:
Site : 99 to 102 NVSV.
Site : 424 to 427 NCSQ.
b) cAMP- and cGMP-dependent protein kinase phosphorylation site:
Site : 507 to 510 RRSS.
c) Protein kinase C phosphorylation site:
Site : 54 to 56 TSR.
Site : 505 to 507 SSR.
Site : 506 to 508 SRR.
d) Casein kinase II phosphorylation site:
Site : 23 to 26 TYYE.
Site : 36 to 39 SSAE.
Site : 121 to 124 THLE.
Site : 189 to 192 SNCE.
Site : 236 to 239 SYNE.
Site : 293 to 296 TESE.
Site : 440 to 443 TTLD.
Site : 457 to 460 TGTE.
Site : 473 to 476 SKLE.
Site : 512 to 515 SMEE.
e) N-myristoylation site:
Site : 274 to 279 GLTISN.
Site : 458 to 463 GTEANQ.
Site : 500 to 505 GASKTS.
f) Leucine zipper pattern:
Site : 368 to 389 LENRQKKLEHANRHLLLRIQEL.
(2) Predicted results of subprograms by PSORT II:
a) N-terminal signal peptide: none
b) Tentative number of TMS(s) for the threshold 0.5: 0
c) KDEL ER retention motif in C-terminus: none
d) ER membrane retention signals: none
e) VAC possible vacuolar targeting motif: none
f) Actinin-type actin-binding motif: type 1: none; type 2: none
g) Prenylation motif: none
h) memYQRL transport motif from cell surface to Golgi: none
i) Tyrosines in the tail: none
j) Dileucine motif in the tail: none
(1) ModBase predicted 3D structure from UCSC Genome Sorter:
O75030 ( isoform 1 ):
From left to right: Front, Top, and Side views of predicted protein.
This protein does not exist in the current release of SWISS-2DPAGE.
Computed theoretical MW=58,162.7Da, pI=5.93 (Isoform 1).
(1) Biological process: DNA binding, DNA-dependent regulation of transcription, sensory perception of sound.
(2) Transcription factor activity.
(3) Sequence-specific (E-boxes) (5'-CACGTG-3') DNA binding.
(4) Plays a critical role in the differentiation of various cell types as neural crest-derived melanocytes, mast cells, osteoclasts and optic cup-derived retinal pigment epithelium.
Transcription factor for tyrosinase and tyrosinase-related protein 1. Efficient DNA binding requires dimerization with another bHLH protein. Binds DNA in the form of homodimer or heterodimer with either TFE3, TFEB or TFEC. Phosphorylation at Ser-405 significantly enhances the ability to bind the tyrosinase promoter.
Interactions in HPRD.
View co-occured partners in literature searched by PPI Finder.
MITF is involved in Wnt receptor signaling pathway. MITF regulates tyrosinase and c-KIT gene. Melanogenesis pathway and Melanoma pathway in KEGG. BioCarta from NCI Cancer Genome Anatomy Project - Melanocyte Development and Pigmentation Pathway.
To date, 14 MITF mutations have been reported: 6 missense/nonsense, 3 splicing, 4 small deletions, and 1 gross deletion. Except the mutations deposited in HGMD, novel mutations are listed here.
Schwarzbraun, et al (2007) reported the entire MITF gene deletion in a WS2A patient with 3p deletion.
Chen, et al (2008) reported a novel frameshift mutation in a Chinese WS2 family, c.639delA.
Monma, et al (2008) identified a novel MITF mutation of IVS4 -1G>C in a Japanese family with WS2 in isoform M.
Note that the numbering of the mutations in HGMD is based on MITF isoform 4 cDNA (NM_000248), view ORF here.
Amplification of MITF gene could be detected in melanoma and other malignancies.
Defects in MITF are the cause of Waardenburg syndrome type 2A (WS2A) [OMIM:193510]. It is a dominant inherited disorder characterized by sensorineural hearing loss and patches of depigmentation. The features show variable expression and penetrance.
Defects in MITF are a cause of Waardenburg syndrome type 2 with ocular albinism (WS2-OA) [OMIM:103470]. It is an ocular albinism with sensorineural deafness.
Defects in MITF are the cause of Tietz syndrome [MIM:103500]. It is an autosomal dominant disorder characterized by generalized hypopigmentation and profound, congenital, bilateral deafness. Penetrance is complete.
MITF is amplified in 15% to 20% of metastatic melanomas. MITF gene amplification was shown to be associated with a reduced survival in metastatic melanoma patients, and reduction of MITF activity was shown to sensitize melanoma cell lines to chemotherapeutics (Ugurel, et al).
(Ho, et al).