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TYR (tyrosinase (oculocutaneous albinism IA))

Written2012-06Erin E Mendoza, Randy Burd
Department of Nutritional Sciences, University of Arizona, Tucson, AZ 85721, USA

(Note : for Links provided by Atlas : click)

Identity

Alias_symbol (synonym)OCAIA
OCA1A
OCA1
Other aliasCMM8
SHEP3
HGNC (Hugo) TYR
LocusID (NCBI) 7299
Atlas_Id 42738
Location 11q14.3  [Link to chromosome band 11q14]
Location_base_pair Starts at 88911040 and ends at 89028927 bp from pter ( according to hg19-Feb_2009)  [Mapping TYR.png]
Fusion genes
(updated 2016)
EFHB (3p24.3) / TYR (11q14.3)ME3 (11q14.2) / TYR (11q14.3)SLC4A7 (3p24.1) / TYR (11q14.3)
TYR (11q14.3) / MMP20 (11q22.2)TYR (11q14.3) / PICALM (11q14.2)TYR (11q14.3) / SLMAP (3p14.3)

DNA/RNA

 
  Diagram of Tyrosinase promoter region adapted from Ray et al. 2007. H5'URS(human 5' upstream regulatory sequence), TDE (Tyrosinase distal element), and TPE (Tyrosinase proximal element).
Description Gene encompasses 80 kb of DNA, 5 exons.
Transcription 2082 bp.
Pseudogene Tyrosinase Like Gene (TRYL 11p11.2) shares 98,55% sequence identity with the 3' region of Tyrosinase. The sequence similarity lies in exons IV and V and lacks exons I, II, and III (Chaki et al., 2005).

Protein

 
  Schematic of Tyrosinase Polypeptide adapted from Mashima 1994. SP (signal peptide), EGF (Epidermal growth factor)-like domain, CuA and CuB (Copper binding domains) and TM (transmembrane domain).
Description 529 amino acids; nascent protein is 60 kDa; Posttranslationally modified by glycosylation giving an 80 kDa protein. Contains an 18 amino acid long signal peptide, six N glycosylation sites, two copper binding sites (CuA and CuB) and a transmembrane domain (Mashima, 1994; Kosmadaki et al., 2010).
Expression Expressed mainly in neural crest derived melanocytes and is sorted into the melanosomes within the melanocyte. Tyrosinase is also found in retinal pigment epithelium cells (Hearing, 2011).
Localisation Transmembrane protein.
Function Tyrosinase catalyzes conversion of tyrosine to DOPA; the rate limiting step of melanin biosynthesis and subsequently DOPA to dopaquinone (Olivares et al., 2009).
 
  Tyrosinase catalyzes the conversion of tyrosine to DOPA in the rate-limiting step of melanin biosynthesis.
Homology The protein tyrosinase related protein 1 (TRP1) is a member of the tyrosinase protein family and utilizes copper as its cofactor. Its function in humans is not well elucidated but is thought to aid in maintaining tyrosinase catalytic activity and stability. It is also involved in maintaining melanosome structure as well as proliferation and cell death of melanocytes (Sarangarajan et al., 2000; Ghanem et al., 2011). Tyrosinase related protein 2 (TRP2), which is also known as DOPAchrome tautomerase catalyzes the conversion of DOPAchrome to 5,6-dihydroxy indole-2-carboxylic acid (DHICA). TRP2 binds 2 zinc ions as cofactors instead of copper (Olivares et al., 2001; Wan et al., 2011).

Mutations

Germinal Partial or complete deletion of Tyrosinase leads to dysregulation of melanin synthesis within the melanosomes leading to oculocutaneous albinism (OCA1). The presence of non-pathologic polymorphisms results in variations in skin pigmentation. There are a total of 189 reported OCA1 mutations including 148 missense or nonsense, 23 small deletions, 8 small insertions, 2 insertion/deletion type 1, 1 complex rearrangement, and 7 splice site alterations (Ray et al., 2007; Ko et al., 2011).

Implicated in

Note
  
Entity Melanoma
Disease Highly aggressive neoplasma arising from melanocytes. Melanoma is responsible for the majority of skin cancer related deaths with a very high probability of metastasis. This neoplasm is greatly resistant to most conventional therapies. Due to the longevity of melanocytes, these cells are considered to have a greater mutagenic burden. This burden is also greater due to the position of melanocytes within the skin and their exposure to UV light. Tyrosinase enzymatic activity has been found to be associated with a better prognosis due to its association with functional activity of the tumor supressor p53. Tyrosinase-mediated melanin production signaled by p53 activation is a key protective response to UV damage (Flaherty, 2012; Gilcrest, 2011).
Oncogenesis Several environmental and genetic factors are involved in the complex process of melanocytic tumorigenesis. Melanin production involving tyrosinase as the rate-limiting step has been shown to protect keratinocytes from DNA damage and oxidative stress from ultra violet radiation; A low incidence of melanoma in darker skinned populations has been observed, indicating a photoprotective role of melanin (Kanavy, 2011).
  
  
Entity Oculocutaneous albinism 1A
Disease Autosomal recessive condition that results in partial or complete loss of tyrosinase activity. Complete loss of activity results in the absence of melanin in the skin and eyes and is classified as OCA1A and the presence of only reduced tyrosinase activity is classified as OCA1B. Complete loss of tyrosinase activity results in the total absence of melanin in the skin and hair. The iris in patients with OCA1A is light blue or gray and the retina lacks pigmentation as well. Tyrosinase null patients have greatly reduced visual acuity accompanied by nystagmus, strabismus, and usually photophobia (Ray et al., 2007). Patients with OCA1B present with varying levels of pigment. The hair in these patients is often yellow. The yellow color is a result of the pheomelanin synthesis. Dopaquinone has a high affinity for sulfhydryl compounds and produces pheomelanin as a result, causing yellow pigmentation. Patients with OCA1B often develop pigmentation in the cooler regions of the body, like the extremities (Chiang et al., 2008).
Prognosis Prognosis in patients is generally good with no system abnormalities other than the loss or reduction in pigmentation. Patients are advised to protect their skin from sun to prevent sunburn (Ray et al., 2007).
Oncogenesis Transcription of tyrosinase has been shown to increase with activation of the tumor suppressor p53, linking both to the tanning response following exposure to UV damage (Khlgatian et al., 2002 and Cui et al., 2007).
  

Bibliography

Determination of variants in the 3'-region of the tyrosinase gene requires locus specific amplification.
Chaki M, Mukhopadhyay A, Ray K.
Hum Mutat. 2005 Jul;26(1):53-8.
PMID 15895460
 
A new hypothesis of OCA1B.
Chiang PW, Drautz JM, Tsai AC, Spector E, Clericuzio CL.
Am J Med Genet A. 2008 Nov 15;146A(22):2968-70.
PMID 18925668
 
Central role of p53 in the suntan response and pathologic hyperpigmentation.
Cui R, Widlund HR, Feige E, Lin JY, Wilensky DL, Igras VE, D'Orazio J, Fung CY, Schanbacher CF, Granter SR, Fisher DE.
Cell. 2007 Mar 9;128(5):853-64.
PMID 17350573
 
Targeting metastatic melanoma.
Flaherty KT.
Annu Rev Med. 2012;63:171-83. Epub 2011 Oct 27. (REVIEW)
PMID 22034865
 
Tyrosinase related protein 1 (TYRP1/gp75) in human cutaneous melanoma.
Ghanem G, Fabrice J.
Mol Oncol. 2011 Apr;5(2):150-5. Epub 2011 Feb 3. (REVIEW)
PMID 21324755
 
Molecular aspects of tanning.
Gilchrest BA.
J Invest Dermatol. 2011 Nov 17;131(E1):E14-7. (REVIEW)
PMID 22094400
 
Determination of melanin synthetic pathways.
Hearing VJ.
J Invest Dermatol. 2011 Nov 17;131(E1):E8-E11. (REVIEW)
PMID 22094404
 
Ultraviolet radiation and melanoma.
Kanavy HE, Gerstenblith MR.
Semin Cutan Med Surg. 2011 Dec;30(4):222-8. (REVIEW)
PMID 22123420
 
Tyrosinase gene expression is regulated by p53.
Khlgatian MK, Hadshiew IM, Asawanonda P, Yaar M, Eller MS, Fujita M, Norris DA, Gilchrest BA.
J Invest Dermatol. 2002 Jan;118(1):126-32.
PMID 11851885
 
Mutation spectrum of the TYR and SLC45A2 genes in patients with oculocutaneous albinism.
Ko JM, Yang JA, Jeong SY, Kim HJ.
Mol Med Report. 2012 Apr;5(4):943-8. doi: 10.3892/mmr.2012.764. Epub 2012 Jan 25.
PMID 22294196
 
Recent progresses in understanding pigmentation.
Kosmadaki MG, Naif A, Hee-Young P.
G Ital Dermatol Venereol. 2010 Feb;145(1):47-55. (REVIEW)
PMID 20197745
 
Molecular and biological control of melanogenesis through tyrosinase genes and intrinsic and extrinsic regulatory factors.
Mishima Y.
Pigment Cell Res. 1994 Dec;7(6):376-87. (REVIEW)
PMID 7761345
 
New insights into the active site structure and catalytic mechanism of tyrosinase and its related proteins.
Olivares C, Solano F.
Pigment Cell Melanoma Res. 2009 Dec;22(6):750-60. Epub 2009 Sep 7. (REVIEW)
PMID 19735457
 
Tyrosinase and ocular diseases: some novel thoughts on the molecular basis of oculocutaneous albinism type 1.
Ray K, Chaki M, Sengupta M.
Prog Retin Eye Res. 2007 Jul;26(4):323-58. Epub 2007 Jan 17. (REVIEW)
PMID 17355913
 
Mutant alleles at the brown locus encoding tyrosinase-related protein-1 (TRP-1) affect proliferation of mouse melanocytes in culture.
Sarangarajan R, Zhao Y, Babcock G, Cornelius J, Lamoreux ML, Boissy RE.
Pigment Cell Res. 2000 Oct;13(5):337-44.
PMID 11041210
 
A second tyrosinase-related protein, TRP-2, is a melanogenic enzyme termed DOPAchrome tautomerase.
Tsukamoto K, Jackson IJ, Urabe K, Montague PM, Hearing VJ.
EMBO J. 1992 Feb;11(2):519-26.
PMID 1537333
 
Regulation of melanocyte pivotal transcription factor MITF by some other transcription factors.
Wan P, Hu Y, He L.
Mol Cell Biochem. 2011 Aug;354(1-2):241-6. Epub 2011 Apr 26. (REVIEW)
PMID 21519923
 

Citation

This paper should be referenced as such :
Mendoza, EE ; Burd, R
TYR (tyrosinase (oculocutaneous albinism IA))
Atlas Genet Cytogenet Oncol Haematol. 2012;16(12):918-920.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/TYRID42738ch11q14.html


Other Cancer prone implicated (Data extracted from papers in the Atlas) [ 1 ]
  Oculocutaneous Albinism


External links

Nomenclature
HGNC (Hugo)TYR   12442
Cards
AtlasTYRID42738ch11q14
Entrez_Gene (NCBI)TYR  7299  tyrosinase
AliasesATN; CMM8; OCA1; OCA1A; 
OCAIA; SHEP3
GeneCards (Weizmann)TYR
Ensembl hg19 (Hinxton)ENSG00000077498 [Gene_View]  chr11:88911040-89028927 [Contig_View]  TYR [Vega]
Ensembl hg38 (Hinxton)ENSG00000077498 [Gene_View]  chr11:88911040-89028927 [Contig_View]  TYR [Vega]
ICGC DataPortalENSG00000077498
TCGA cBioPortalTYR
AceView (NCBI)TYR
Genatlas (Paris)TYR
WikiGenes7299
SOURCE (Princeton)TYR
Genetics Home Reference (NIH)TYR
Genomic and cartography
GoldenPath hg19 (UCSC)TYR  -     chr11:88911040-89028927 +  11q14.3   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)TYR  -     11q14.3   [Description]    (hg38-Dec_2013)
EnsemblTYR - 11q14.3 [CytoView hg19]  TYR - 11q14.3 [CytoView hg38]
Mapping of homologs : NCBITYR [Mapview hg19]  TYR [Mapview hg38]
OMIM103470   203100   601800   606933   606952   
Gene and transcription
Genbank (Entrez)AB775899 AB775900 AB775901 BC027179 BU736025
RefSeq transcript (Entrez)NM_000372
RefSeq genomic (Entrez)NC_000011 NC_018922 NG_008748 NT_033899 NW_004929380
Consensus coding sequences : CCDS (NCBI)TYR
Cluster EST : UnigeneHs.503555 [ NCBI ]
CGAP (NCI)Hs.503555
Alternative Splicing GalleryENSG00000077498
Gene ExpressionTYR [ NCBI-GEO ]   TYR [ EBI - ARRAY_EXPRESS ]   TYR [ SEEK ]   TYR [ MEM ]
Gene Expression Viewer (FireBrowse)TYR [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)7299
GTEX Portal (Tissue expression)TYR
Protein : pattern, domain, 3D structure
UniProt/SwissProtP14679   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtP14679  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP14679
Splice isoforms : SwissVarP14679
Catalytic activity : Enzyme1.14.18.1 [ Enzyme-Expasy ]   1.14.18.11.14.18.1 [ IntEnz-EBI ]   1.14.18.1 [ BRENDA ]   1.14.18.1 [ KEGG ]   
PhosPhoSitePlusP14679
Domaine pattern : Prosite (Expaxy)TYROSINASE_1 (PS00497)    TYROSINASE_2 (PS00498)   
Domains : Interpro (EBI)Tyrosinase_Cu-bd    Unchr_di-copper_centre   
Domain families : Pfam (Sanger)Tyrosinase (PF00264)   
Domain families : Pfam (NCBI)pfam00264   
Conserved Domain (NCBI)TYR
DMDM Disease mutations7299
Blocks (Seattle)TYR
SuperfamilyP14679
Human Protein AtlasENSG00000077498
Peptide AtlasP14679
HPRD06086
IPIIPI00027286   IPI00218270   
Protein Interaction databases
DIP (DOE-UCLA)P14679
IntAct (EBI)P14679
FunCoupENSG00000077498
BioGRIDTYR
STRING (EMBL)TYR
ZODIACTYR
Ontologies - Pathways
QuickGOP14679
Ontology : AmiGOmonooxygenase activity  monophenol monooxygenase activity  copper ion binding  protein binding  nucleus  cytoplasm  lysosome  Golgi-associated vesicle  cytosol  melanin biosynthetic process from tyrosine  eye pigment biosynthetic process  visual perception  cell proliferation  response to UV  integral component of membrane  melanosome membrane  response to vitamin D  melanin biosynthetic process  melanin biosynthetic process  melanosome  melanosome  protein homodimerization activity  protein heterodimerization activity  perinuclear region of cytoplasm  thymus development  response to cAMP  oxidation-reduction process  
Ontology : EGO-EBImonooxygenase activity  monophenol monooxygenase activity  copper ion binding  protein binding  nucleus  cytoplasm  lysosome  Golgi-associated vesicle  cytosol  melanin biosynthetic process from tyrosine  eye pigment biosynthetic process  visual perception  cell proliferation  response to UV  integral component of membrane  melanosome membrane  response to vitamin D  melanin biosynthetic process  melanin biosynthetic process  melanosome  melanosome  protein homodimerization activity  protein heterodimerization activity  perinuclear region of cytoplasm  thymus development  response to cAMP  oxidation-reduction process  
Pathways : KEGGTyrosine metabolism    Riboflavin metabolism    Melanogenesis   
REACTOMEP14679 [protein]
REACTOME Pathways5662702 [pathway]   
NDEx NetworkTYR
Atlas of Cancer Signalling NetworkTYR
Wikipedia pathwaysTYR
Orthology - Evolution
OrthoDB7299
GeneTree (enSembl)ENSG00000077498
Phylogenetic Trees/Animal Genes : TreeFamTYR
HOVERGENP14679
HOGENOMP14679
Homologs : HomoloGeneTYR
Homology/Alignments : Family Browser (UCSC)TYR
Gene fusions - Rearrangements
Fusion : MitelmanSLC4A7/TYR [3p24.1/11q14.3]  [t(3;11)(p24;q14)]  
Fusion : MitelmanTYR/MMP20 [11q14.3/11q22.2]  [t(11;11)(q14;q22)]  
Fusion: TCGASLC4A7 3p24.1 TYR 11q14.3 LGG
Fusion: TCGATYR 11q14.3 MMP20 11q22.2 SKCM
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerTYR [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)TYR
dbVarTYR
ClinVarTYR
1000_GenomesTYR 
Exome Variant ServerTYR
ExAC (Exome Aggregation Consortium)TYR (select the gene name)
Genetic variants : HAPMAP7299
Genomic Variants (DGV)TYR [DGVbeta]
DECIPHER (Syndromes)11:88911040-89028927  ENSG00000077498
CONAN: Copy Number AnalysisTYR 
Mutations
ICGC Data PortalTYR 
TCGA Data PortalTYR 
Broad Tumor PortalTYR
OASIS PortalTYR [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICTYR  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDTYR
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
BioMutasearch TYR
DgiDB (Drug Gene Interaction Database)TYR
DoCM (Curated mutations)TYR (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)TYR (select a term)
intoGenTYR
NCG5 (London)TYR
Cancer3DTYR(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM103470    203100    601800    606933    606952   
Orphanet22110    22111    22112    11460    11457   
MedgenTYR
Genetic Testing Registry TYR
NextProtP14679 [Medical]
TSGene7299
GENETestsTYR
Huge Navigator TYR [HugePedia]
snp3D : Map Gene to Disease7299
BioCentury BCIQTYR
ClinGenTYR
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD7299
Chemical/Pharm GKB GenePA37095
Clinical trialTYR
Miscellaneous
canSAR (ICR)TYR (select the gene name)
Probes
Litterature
PubMed180 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineTYR
EVEXTYR
GoPubMedTYR
iHOPTYR
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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