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MITF (microphthalmia-associated transcription factor)

Written2013-04Nicole D Riddle, Paul Zhang
Department of Pathology, University of Texas Health Science Center, San Antonio, TX, USA (NDR); Department of Pathology, University of Pennsylvania Health System, Philadelphia, PA, USA (PZ)

(Note : for Links provided by Atlas : click)

Identity

Alias_namesWS2A
WS2
Waardenburg syndrome, type 2A
microphthalmia-associated transcription factor
Alias_symbol (synonym)MI
bHLHe32
HGNC (Hugo) MITF
LocusID (NCBI) 4286
Atlas_Id 44193
Location 3p14.1  [Link to chromosome band 3p14]
Location_base_pair Starts at 69985751 and ends at 70017488 bp from pter ( according to hg19-Feb_2009)  [Mapping MITF.png]
Local_order The MITF gene is located between the genes PDHB (telomeric) and PROK2 (centromeric).
 
Fusion genes
(updated 2016)
ACTG1 (17q25.3) / MITF (3p13)CGGBP1 (3p11.1) / MITF (3p13)MITF (3p13) / MTERF3 (8q22.1)
Note Total size: 228903 bps.
MITF has 18 transcripts and encodes a transcription factor that contains both a helix-loop-helix structure as well as a leucine zipper.
Target genes: MITF has been shown to recognize the E-box (CAYRTG) and M-box (TCAYRTG or CAYRTGA) sequences in the promoter regions of multiple target genes, including ACP5, BCL2, BEST1, BIRC7, CDK2, CLCN7, DCT, EDNRB, GPNMB, GPR143, MC1R, MLANA, OSTM1, RAB27A, SILV, SLC45A2, TBX2, TRPM1, TYR and TYRP1 (Hoek et al., 2008b).

DNA/RNA

Description The gene encompasses 229 kb, and has 9 exons.
Transcription Nine different isoforms have been described for MITF, each with different 5' specificity (MITF -A, -J, -C, -MC, -E, -H, -D, -B, -M). All isoforms have exons 2-9 in common, encoding the functional domains of the transcription factors. Exon 1 is variable and the domains within it are the transactivation domain (TAD) and the beta-helix-loop-helix-zipper (B-HLH-Zip). Some isoforms are specific for certain cells types, i.e. M: melanocytes, MC: mast cells (Levy et al., 2006).

Protein

Description 526 aa, 58795 Da.
Regulates the differentiation and development of melanocytes, neural crest-derived cells, retinal epithelium (optic cup-derived retinal pigment epithelium), mast cells, and osteoclasts (Lin and Fisher, 2007; Adijanto et al., 2012).

Post translational modifications:
- Phosphorylation at Ser-405 significantly enhances the ability to bind the tyrosinase promoter.
- Phosphorylation at Ser-180 and Ser-516 by MAPK and RPS6KA1 activate the transcription factor activity and promote ubiquitiniation and subsequent degradation.
- Can be deubiquitinated by USP13, preventing its degradation.

Expression Found in most human tissues. Particularly high quantities in retina, uterus, pineal gland, and adipocytes (biogps.org).
Localisation Nucleus.
Function A transcription factor that activates the transcription of tyrosinase and tyrosinase-related protein 1 (TYRP1), and dopachrome tautomerase (DCT). These are enzymes that are specifically expressed in melanocytes (Yasumoto et al., 1995). For tyrosinase, MITF binds to a symmetrical DNA sequence found in the promoter region: a restricted subset of E-box motives containing canonical CATGTG sequence flanked by a 5' thymidine (Aksan and Goding, 1998). The regulation of the DCT promoter is even more complex and involves other proteins like CREB and SOX10; and PAX3 has an inhibitory effect on DCT activation by MITF (Bertolotto et al., 1998; Ludwig et al., 2004; Lang et al., 2005).
Not only does MITF activate genes involved in melanin synthesis, it also activates the transcription of genes involved in melanosome structure (PMEL17, MART-1), biogenesis (ocular albinism type 1 gene), and transport (RAB27A) (Du et al., 2003; Vetrini et al., 2004; Chiaverini et al., 2008). Also, MITF activates the transcription of the melanocortin 1 receptor gene which encodes a melanocyte-stimulating hormone receptor normally present on the plasma membrane of melanocytes: this binding is the first step in the hormonal regulation of pigmentation (Vachtenheim and Borovansky, 2010).
In addition, MITF plays a role in apoptosis through several target genes, showing importance of MITF in melanocyte development and survival. MITF controls the transcription of BCL-2, and known inhibitor of apoptosis (McGill et al., 2002). Therefore, MITF mutation may explain the reduced number of melanocytes in certain disorders (Samija et al., 2010). MITF also induces transcription of melanoma-inhibitor-of-apoptosis (BIRC7, ML-IAP) (Dynek et al., 2008). Furthermore, it regulates a receptor for hepatocyte growth factor (MET), whose activation inhibits melanocyte apoptosis (Beuret et al., 2007).
MITF also plays a role in melanocyte proliferation by regulating several genes involved in the cell-cycle: cyclin-dependant kinase 2 (CDK2), transcription factor TBX2, and Dia1 protein (Diaph1). These promote cell-cycle progression, prevent senescence and cell-cycle arrest, and increase cellular proliferation, respectively (Du et al., 2004; Carreira et al., 2005; Carreira et al., 2006). However, MITF also has anti-proliferative properties by way of inducing cell-cycle arrest by activating cyclin-dependent kinase inhibitor 1A and 2A (CDKN1A/p21, CDKN2A/p16) (Carreira et al., 2005; Loercher et al., 2005). It has believed that both depletion and over-expression inhibit proliferation whereas normal levels promote proliferation (Kido et al., 2009).
MITF also has important roles in osteoclast and mast cell development and function. In osteoclasts it activates transcription of functional proteins tartrate-resistant alkaline phosphatase (TRAP), cathepsin K, OSCAR, e-cadherin, OSTM1 and CLCN7 (Meadows et al., 2007). In mast cells MITF activates the transcription of mast cell proteases 2,4,5,6, and 9, granzyme B, tryptophan hydroxylase, and kit, all important for differentiation and function (Kitamura et al., 2006).
Up-stream regulation: LysRS-Ap4A-MITF signaling pathway (Lee et al., 2004); Wnt signaling pathway (Takeda et al., 2000); alpha melanocyte-stimulating hormone signaling pathway (Bertolotto et al., 1998).
Homology High homology to TFE genes (TFE3, TFEB, TFEC, etc.) and the myc family of bHLH transcription factors (Dickson et al., 2011).

Mutations

Note The MITF promoter is partially regulated by certain transcription factors such as PAX3, SOX10, LEF-1/TCF and CREB during development. Mutations affecting the MITF and the MITF pathway lead to pigmentary and auditory defects (Cimadamore et al., 2012; Pierrat et al., 2012).
Germinal Mutations in the MITF at germline will lead to syndromes with pigmentary and/or auditory defects. Mutations in MITF are also known to give a predisposition to certain cancers, including melanoma and renal cell carcinoma (Bertolotto et al., 2011). Heterozygous mutations lead to auditory/pigmentary syndromes such as Waardenburg type 2 and Tietz syndrome (Lin and Fisher, 2007).

Implicated in

Note
Entity Melanoma
Note A malignant neoplasm of melanocytes, arising either from pre-existing benign nevi or de novo and occurring most commonly on the skin, but may occur in other locations.
There have been linkage and genome wide association studies (GWAS) studies that have shown no evidence to implicate MITF in melanoma (Gillanders et al., 2003; Bishop et al., 2009). However, MITF has been shown to be mutated in a subset of melanomas and overexpressed in others (Garraway et al., 2005; Cronin et al., 2009). This raises the possibility of MITF's involved despite the lack of prior evidence for germline risk. Indeed, individuals with a specific MITF mutation (E318K) have a 5-fold increase risk of developing melanoma (Yokoyama et al., 2011).
MITF amplification has also been associated with decreased survival and chemoresistance (Gallaway et al., 2005). It is postulated the MITF may be a lineage specific oncogene in melanoma, particularly in the subset with CDKN2A mutations (Garraway and Sellers, 2006; Bennett, 2008). This hypothesis is supported by research that has shown that all melanoma cell lines that had MITF gene amplifications also had CDKN2A pathway inactivation (Gallaway et al., 2005). MITFs role as a lineage specific oncogene is also supported by its important part in cell growth, survival, growth, and proliferation through BCL2, CDK2, TBX2, ML-IAP etc, as described above.
In addition, BRAF mutations (found in ~60% of melanomas) have a two-fold regulation of MITF transcription and is believed to keep MITF at appropriate levels promoting melanoma cell proliferation and survival. Supporting this theory is the fact that pure up-regulation of MITF inhibits melanoma cell proliferation and re-expression reduces tumorigenecity in vivo (Wellbrock and Marais, 2005). And MITF expression by immunohistochemistry has been shown to decrease with disease progression, and be a predictor of overall and disease-free survival (Salti et al., 2000; Zhuang et al., 2007).
As mentioned above, MITF is not expressed in all melanomas. This indicates that there are different subsets of melanomas which differ in their need of MITF for their progression and survival (Salti et al., 2000; Miettinen et al., 2001; Granter et al., 2002). There is also evidences that the role of MITF may change within a melanoma during progression (Hoek et al., 2008a).
  
Entity Renal cell carcinoma
Note Malignant transformation of the renal parenchyma. Associated with Von Hippel-Lindau syndrome: a rare, autosomal dominant disease predisposing to clear cell renal cell carcinoma, as well as hemangioblastomas, pheochromocytomas, pancreatic cysts and neuroendocrine tumors, endolymphatic sac tumors, and a general increase risk in cancer; results from mutation of the VHL tumor suppressor gene on chromosome 3p.
A subset of renal cell carcinomas, more common in children, are associated with TFE3 mutations, a member of the microphthalmia (MIT) family, closely related to MITF.
Recent studies have shown that the same MITF mutation associated with increased risk of melanoma (E318K) also leads to increased risk of renal cell carcinoma (Bertolotto et al., 2011). However, it is unclear at this time the role that MITF in particular plays in renal tumors. It may be that this mutation leads to disrupted interaction with TFE3. Or it is possible that mechanisms are similar to that of melanoma, however, MITF is not associated with normal kidney function in the same way that it is in normal melanocyte function. Research is ongoing in this area.
  
Entity Waardenburg syndrome
Note A group of autosomal dominant inherited conditions that involve deafness and lack of pigment of the hair, skin, and/or eyes. There are 4 main types of WS, 1 and 2 being most common. MITF is the gene associated with Waardenburg syndrome 2a (WS2a), characterized by sensorineural hearing loss and patches of depigmentation, with or without ocular albinism. These features may show variable expression and penetrance.
Some of the mutations are single or multiple amino acid changes that alter the helix-loop-helix or leucine zipper motif. There are other mutations that create a shortened, non-functional version of MITF. It is believed that all of these mutations disrupt the formation of the dimers necessary for proper function and development; thereby there is an insufficient concentration of the MITF protein within the cytoplasm for normal function (haploinsufficiency). Also, as described above, MITF regulates BCL-2, ML-IAP, and MET. Without adequate amounts of MITF there is over-apoptosis of melanocytes. This leads to a decreased number of melanocytes in certain areas of the skin, hair, eyes, inner ear, etc (Tachibana, 1997; Samija et al., 2010).
Patients with WS1 will have the addition of craniofacial deformities and those with WS3 (Klein-Waardenburg syndrome) have limb deformities, both are due to mutations in PAX3, which is part of the MITF pathway, Those with WS4 (Waardenburg-Shah Syndrome) will also have Hirchsprung's syndrome, associated with mutations in 3 genes: SOX10, endothelin 3, and endothelin receptor B (Tassabehji et al., 1995; Widlund and Fisher, 2003).
  
Entity Tietz syndrome
Note An autosomal dominant disorder characterized by generalized hypopigmentation (fair skin and light-colored hair) and profound bilateral congenital hearing loss. Penetrance is complete.
The mutation is a change or deletion of a single amino acid in the basic motif region. This resultant altered protein cannot bind to DNA, thereby affecting the development of melanocytes, and therefore, melanin production (Smith et al., 2000). The mechanism is similar to Waardenburg syndrome, but more severe. In a heterozygote the abnormal protein cannot dimerise effectively even with a normal allele product, i.e. even the normal allele does not function. This concept is referred to as a dominant negative. There is effectively no normal MITF available (Smith et al., 2000).
  

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PMID 8749302
 
A novel recurrent mutation in MITF predisposes to familial and sporadic melanoma.
Yokoyama S, Woods SL, Boyle GM, Aoude LG, MacGregor S, Zismann V, Gartside M, Cust AE, Haq R, Harland M, Taylor JC, Duffy DL, Holohan K, Dutton-Regester K, Palmer JM, Bonazzi V, Stark MS, Symmons J, Law MH, Schmidt C, Lanagan C, O'Connor L, Holland EA, Schmid H, Maskiell JA, Jetann J, Ferguson M, Jenkins MA, Kefford RF, Giles GG, Armstrong BK, Aitken JF, Hopper JL, Whiteman DC, Pharoah PD, Easton DF, Dunning AM, Newton-Bishop JA, Montgomery GW, Martin NG, Mann GJ, Bishop DT, Tsao H, Trent JM, Fisher DE, Hayward NK, Brown KM.
Nature. 2011 Nov 13;480(7375):99-103. doi: 10.1038/nature10630.
PMID 22080950
 
Mcl-1, Bcl-XL and Stat3 expression are associated with progression of melanoma whereas Bcl-2, AP-2 and MITF levels decrease during progression of melanoma.
Zhuang L, Lee CS, Scolyer RA, McCarthy SW, Zhang XD, Thompson JF, Hersey P.
Mod Pathol. 2007 Apr;20(4):416-26.
PMID 17384650
 

Citation

This paper should be referenced as such :
Riddle, ND ; Zhang, P
MITF (microphthalmia-associated transcription factor)
Atlas Genet Cytogenet Oncol Haematol. 2013;17(11):735-739.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/MITFID44193ch3p13.html


Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 1 ]
  Kidney: Renal cell carcinoma with inv(X)(p11q12) NONO/TFE3


Other Cancer prone implicated (Data extracted from papers in the Atlas) [ 2 ]
  Familial melanoma Waardenburg syndrome (WS)


External links

Nomenclature
HGNC (Hugo)MITF   7105
LRG (Locus Reference Genomic)LRG_776
Cards
AtlasMITFID44193ch3p13
Entrez_Gene (NCBI)MITF  4286  microphthalmia-associated transcription factor
AliasesCMM8; MI; WS2; WS2A; 
bHLHe32
GeneCards (Weizmann)MITF
Ensembl hg19 (Hinxton)ENSG00000187098 [Gene_View]  chr3:69985751-70017488 [Contig_View]  MITF [Vega]
Ensembl hg38 (Hinxton)ENSG00000187098 [Gene_View]  chr3:69985751-70017488 [Contig_View]  MITF [Vega]
ICGC DataPortalENSG00000187098
TCGA cBioPortalMITF
AceView (NCBI)MITF
Genatlas (Paris)MITF
WikiGenes4286
SOURCE (Princeton)MITF
Genetics Home Reference (NIH)MITF
Genomic and cartography
GoldenPath hg19 (UCSC)MITF  -     chr3:69985751-70017488 +  3p13   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)MITF  -     3p13   [Description]    (hg38-Dec_2013)
EnsemblMITF - 3p13 [CytoView hg19]  MITF - 3p13 [CytoView hg38]
Mapping of homologs : NCBIMITF [Mapview hg19]  MITF [Mapview hg38]
OMIM103470   103500   156845   193510   614456   
Gene and transcription
Genbank (Entrez)AB006909 AB006988 AB006989 AB061771 AK291318
RefSeq transcript (Entrez)NM_000248 NM_001184967 NM_001184968 NM_006722 NM_198158 NM_198159 NM_198177 NM_198178
RefSeq genomic (Entrez)NC_000003 NC_018914 NG_011631 NT_022517 NW_004929310
Consensus coding sequences : CCDS (NCBI)MITF
Cluster EST : UnigeneHs.618266 [ NCBI ]
CGAP (NCI)Hs.618266
Alternative Splicing GalleryENSG00000187098
Gene ExpressionMITF [ NCBI-GEO ]   MITF [ EBI - ARRAY_EXPRESS ]   MITF [ SEEK ]   MITF [ MEM ]
Gene Expression Viewer (FireBrowse)MITF [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)4286
GTEX Portal (Tissue expression)MITF
Protein : pattern, domain, 3D structure
UniProt/SwissProtO75030   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtO75030  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProO75030
Splice isoforms : SwissVarO75030
PhosPhoSitePlusO75030
Domaine pattern : Prosite (Expaxy)BHLH (PS50888)   
Domains : Interpro (EBI)bHLH_dom    MiT/TFE_C    MiT/TFE_N    MITF   
Domain families : Pfam (Sanger)DUF3371 (PF11851)    HLH (PF00010)    MITF_TFEB_C_3_N (PF15951)   
Domain families : Pfam (NCBI)pfam11851    pfam00010    pfam15951   
Domain families : Smart (EMBL)HLH (SM00353)  
Conserved Domain (NCBI)MITF
DMDM Disease mutations4286
Blocks (Seattle)MITF
PDB (SRS)4C7N   
PDB (PDBSum)4C7N   
PDB (IMB)4C7N   
PDB (RSDB)4C7N   
Structural Biology KnowledgeBase4C7N   
SCOP (Structural Classification of Proteins)4C7N   
CATH (Classification of proteins structures)4C7N   
SuperfamilyO75030
Human Protein AtlasENSG00000187098
Peptide AtlasO75030
HPRD01138
IPIIPI00023896   IPI00215772   IPI00217203   IPI00217204   IPI00217206   IPI00217209   IPI00217210   IPI00217211   IPI00217212   IPI00293035   IPI00952616   IPI00852788   IPI00944926   IPI01009311   IPI00853423   IPI00985403   
Protein Interaction databases
DIP (DOE-UCLA)O75030
IntAct (EBI)O75030
FunCoupENSG00000187098
BioGRIDMITF
STRING (EMBL)MITF
ZODIACMITF
Ontologies - Pathways
QuickGOO75030
Ontology : AmiGOnegative regulation of transcription from RNA polymerase II promoter  RNA polymerase II core promoter proximal region sequence-specific DNA binding  transcriptional activator activity, RNA polymerase II core promoter proximal region sequence-specific binding  transcriptional activator activity, RNA polymerase II core promoter proximal region sequence-specific binding  transcriptional repressor activity, RNA polymerase II transcription regulatory region sequence-specific binding  protein binding  nucleus  nucleoplasm  regulation of transcription, DNA-templated  transcription from RNA polymerase II promoter  protein complex assembly  multicellular organism development  positive regulation of gene expression  positive regulation of gene expression  protein sumoylation  melanocyte differentiation  melanocyte differentiation  regulation of apoptotic process  protein complex  regulation of osteoclast differentiation  positive regulation of transcription, DNA-templated  positive regulation of transcription, DNA-templated  positive regulation of transcription from RNA polymerase II promoter  positive regulation of transcription from RNA polymerase II promoter  protein dimerization activity  mast cell migration  positive regulation of DNA-templated transcription, initiation  regulation of RNA biosynthetic process  
Ontology : EGO-EBInegative regulation of transcription from RNA polymerase II promoter  RNA polymerase II core promoter proximal region sequence-specific DNA binding  transcriptional activator activity, RNA polymerase II core promoter proximal region sequence-specific binding  transcriptional activator activity, RNA polymerase II core promoter proximal region sequence-specific binding  transcriptional repressor activity, RNA polymerase II transcription regulatory region sequence-specific binding  protein binding  nucleus  nucleoplasm  regulation of transcription, DNA-templated  transcription from RNA polymerase II promoter  protein complex assembly  multicellular organism development  positive regulation of gene expression  positive regulation of gene expression  protein sumoylation  melanocyte differentiation  melanocyte differentiation  regulation of apoptotic process  protein complex  regulation of osteoclast differentiation  positive regulation of transcription, DNA-templated  positive regulation of transcription, DNA-templated  positive regulation of transcription from RNA polymerase II promoter  positive regulation of transcription from RNA polymerase II promoter  protein dimerization activity  mast cell migration  positive regulation of DNA-templated transcription, initiation  regulation of RNA biosynthetic process  
Pathways : BIOCARTAMelanocyte Development and Pigmentation [Genes]   
Pathways : KEGGOsteoclast differentiation    Melanogenesis    Pathways in cancer    Melanoma   
NDEx NetworkMITF
Atlas of Cancer Signalling NetworkMITF
Wikipedia pathwaysMITF
Orthology - Evolution
OrthoDB4286
GeneTree (enSembl)ENSG00000187098
Phylogenetic Trees/Animal Genes : TreeFamMITF
HOVERGENO75030
HOGENOMO75030
Homologs : HomoloGeneMITF
Homology/Alignments : Family Browser (UCSC)MITF
Gene fusions - Rearrangements
Fusion : MitelmanACTG1/MITF [17q25.3/3p13]  [t(3;17)(p14;q25)]  
Fusion : MitelmanCGGBP1/MITF [3p11.1/3p13]  [t(3;3)(p11;p14)]  
Fusion : MitelmanMITF/MTERF3 [3p13/8q22.1]  [t(3;8)(p14;q22)]  
Fusion: TCGACGGBP1 3p11.1 MITF 3p13 HNSC
Fusion: TCGAMITF 3p13 MTERFD1 BRCA
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerMITF [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)MITF
dbVarMITF
ClinVarMITF
1000_GenomesMITF 
Exome Variant ServerMITF
ExAC (Exome Aggregation Consortium)MITF (select the gene name)
Genetic variants : HAPMAP4286
Genomic Variants (DGV)MITF [DGVbeta]
DECIPHER (Syndromes)3:69985751-70017488  ENSG00000187098
CONAN: Copy Number AnalysisMITF 
Mutations
ICGC Data PortalMITF 
TCGA Data PortalMITF 
Broad Tumor PortalMITF
OASIS PortalMITF [ Somatic mutations - Copy number]
Cancer Gene: CensusMITF 
Somatic Mutations in Cancer : COSMICMITF  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDMITF
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
LOVD (Leiden Open Variation Database)MSeqDR-LSDB Mitochondrial Disease Locus Specific Database
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
BioMutasearch MITF
DgiDB (Drug Gene Interaction Database)MITF
DoCM (Curated mutations)MITF (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)MITF (select a term)
intoGenMITF
NCG5 (London)MITF
Cancer3DMITF(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM103470    103500    156845    193510    614456   
Orphanet220    3560    21641    22112    20874    22933    10575   
MedgenMITF
Genetic Testing Registry MITF
NextProtO75030 [Medical]
TSGene4286
GENETestsMITF
Huge Navigator MITF [HugePedia]
snp3D : Map Gene to Disease4286
BioCentury BCIQMITF
ClinGenMITF (curated)
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD4286
Chemical/Pharm GKB GenePA30823
Clinical trialMITF
Miscellaneous
canSAR (ICR)MITF (select the gene name)
Probes
Litterature
PubMed225 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineMITF
EVEXMITF
GoPubMedMITF
iHOPMITF
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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