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SLC45A2 (solute carrier family 45 member 2)

Written2019-01Mainak Sengupta, Tithi Dutta, Kunal Ray
University of Calcutta, Department of Genetics, 35, Ballygunge Circular Road, Kolkata - 700 019, India. sengupta.mainak@gmail.com; tithi613@gmail.com (MS, TD) ATGC Diagnostics Private Limited, Kolkata, India, kunalray@gmail.com (KR)

Abstract SLC45A2 gene, having a chromosomal location 5p13.2, encodes a membrane associated transporter protein (MATP). MATP is a transmembrane protein. It is present in the melanosomal membrane in the melanocytes. It maintains the osmotic potential by regulating the pH of the melanosomal lumen. Defects in the SLC45A2 gene causes oculocutaneous albinism type IV; OCA IV

Keywords SLC45A2, MATP, albinism, OCA IV

(Note : for Links provided by Atlas : click)

Identity

Alias_namesMATP
membrane associated transporter
solute carrier family 45, member 2
Alias_symbol (synonym)AIM-1
OCA4
Other aliasMembrane Associated Transporter Protein
Melanoma Antigen AIM1
AIM1 (absent in melanoma 1)
Underwhite
SHEP5
HGNC (Hugo) SLC45A2
LocusID (NCBI) 51151
Atlas_Id 41306
Location 5p13.2  [Link to chromosome band 5p13]
Location_base_pair Starts at 33944616 and ends at 33984675 bp from pter ( according to hg19-Feb_2009)  [Mapping SLC45A2.png]
 
  SLC45A2 Gene in genomic location: Cytogenetic band: 5p13.2 by Entrez Gene, 5p13.2 by HGNC, 5p13.2. The figure represents the cytogenetic banding of SLC45A2 locus (Ref https://www.genecards.org/cgi-bin/carddisp.pl?gene=SLC45A2)
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)

DNA/RNA

Description In Chromosome 5, the 40,529 bases of DNA starts from 33,944,616 and ends at 33,985,144(GRCh38/hg38). Orientation: Minus strand. It contains 7 exons.
Transcription The gene after transcription produces 7 different mRNAs, 6 alternatively spliced variants and 1 unspliced form. There are 4 non overlapping alternative last exons (https://www.ncbi.nlm.nih.gov/IEB/Research/Acembly/av.cgi?db=human&term=slc45a2&submit=Go).

Protein

Description The human SLC45A2 protein is a 530-amino acid polypeptide that contains 12 putative trans-membrane domains, and is only expressed in the melanosomes in the melanocytes (Newton et al., 2001). The SLC45A2 gene initially identified as AIM1 (absent in melanoma 1) by Newton et al, 2001 encodes a Membrane-Associated Transporter Protein (MATP). It acts as a transporter and regulates the melanosomal pH using a proton gradient.
Expression The MATP protein (58 kDa) is expressed in most melanoma cell lines and melanocytes and sorted into the melanosomal membrane. The highest expression level has been observed in the pigmented layer of retina (https://www.uniprot.org/uniprot/Q9UMX9).
Localisation It is a transmembrane protein present in the melanosomal membrane in melanin producing melanocytes.
Function SLC45A2 (MATP) allows the transport of sugar molecule across the membrane into the cytoplasm and maintains osmotic potential of the melanosomes (Rabea Bartolke, 2014, Reinders et al 2015). It maintains the pH of the melanosome which facilitates the binding of Copper to Tyrosinase resulting in the conversion of Apo-Tyrosinase to Tyrosinase. (Newton et al, 2011).
 
  The SLC45A2 (MATP) acts as a transporter present on the melanosomal membrane. Under normal condition it controls the pH by using a proton gradient. Thus helps in Copper to bind to Apo-Tyrosinase and convert it to active Tyrosinase. In oculocutaneous albinism type IV (OCA4), any deleterious mutation in melanosomal MATP transporter protein makes the melanosomal lumen acidic. Under this condition, the Cu fails to bind to the Apo-Tyr and Tyrosinase activity is reduced. (Bin et al, 2015).
Homology The human MATP shows syntenic homology with the proximal region of mouse chromosome 15. The human orthologue for the mouse underwhite gene locus (uw gene) is encoded by SLC45A2 gene. The predicted mouse MATP protein is 82% identical and 87% similar to the human MATP protein.
The highest degree of homology was found between MATP and sucrose/proton symporters found in plants. The homologous region of MATP includes the sucrose-transporter signature sequence: R-X-G-R-[K/R], found in between the transmembrane domains 2 and 3 (Meyer H et al, 2011, Newton et al, 2011).
The sucrose transporter Slc45-1 in Drosophila shows significant similarity to mammalian SLC45A2 and plays a role in melanin synthesis.

Mutations

Epigenetics In an attempt to identify genetic and epigenetic marks involved in population structure, a coding SNP: rs16891982 (p.L374F) of SLC45A2, known to play a role in normal pigmentation variation, was found to positively correlate with the methylation level of PM20D1 gene. The minor allele A was been found to be associated with lower methylation of the target gene. (https://www.ncbi.nlm.nih.gov/pubmed/20949057).
Germinal Homozygous mutation or Compound Heterozygote mutations in SLC45A2 gene has been found responsible for causing Oculocutaneous Albinism Type 4 (OCA4). To date around 80 mutations have been reported in SLC45A2 responsible for OCA4. (Kamaraj et al. 2014, Toth et al. 2017). OCA4 was first observed in Turkish population, it is rare among Caucasians and Africans and in Japan it is diagnosed in one of four persons affected with OCA.

There are several non-pathogenic polymorphisms which result into mild pigmentation.

The haplotypes at SLC45A2 is significantly associated in determination of dark or light pigmentation features in human population. (Fracasso et al.2017)

Implicated in

  
Entity Oculocutaneous albinism type IV (OCA IV)
Disease OCA IV is an autosomal recessive disorder of melanin biosynthesis that results in congenital hypopigmentation of ocular and cutaneous tissues. Common developmental abnormalities of the eye like decreased visual acuity, macular hypoplasia, optic dysplasia, atypical choroidal vessels, and nystagmus are observed in patient suffering from OCA type IV. The severity of hypopigmentation is correlated with melanosome size, shape, melanin content and maturity of the melanosomal structures demonstrating that the encoded protein is a major determinant of mammalian pigmentation.
  
  
Entity Melanoma
Note n 2017, Park et al reported that a few variants present in SLC45A2 gene can be a promising immune therapeutic target for melanoma with high tumor selectivity and reduced potential for autoimmune toxicity. It is associated with an increased risk for melanoma in light-skinned populations, and the encoded protein can elicit immune recognition. The Cancer Genome Atlas Research Network (TCGA) database reported that it is expressed by approximately 80% of cutaneous melanomas. In the same year Hafner et al showed that SLC45A2 (also called AIM1, absent in melanoma 1) function as a key suppressor of invasive phenotypes by working in association with the actin cytoskeleton. SLC45A2 becomes dysregulated and suppresses cytoskeletal remodelling in primary and metastatic prostate cancer and in non-malignant prostate epithelial cells. In 2012, Fernandez et al reported in a family that adult siblings presented with congenital neutropenia which later developed into Crohn's Disease. Molecular characterisation revealed homozygous mutations both in G6PC3 and SLC45A2 in the sister and mutation in single allele for both genes in the brother.
  

Bibliography

Proton-associated sucrose transport of mammalian solute carrier family 45: an analysis in Saccharomyces cerevisiae
Bartölke R, Heinisch JJ, Wieczorek H, Vitavska O
Biochem J 2014 Dec 1;464(2):193-201
PMID 25164149
 
Membrane-Associated Transporter Protein (MATP) Regulates Melanosomal pH and Influences Tyrosinase Activity
Bin BH, Bhin J, Yang SH, Shin M, Nam YJ, Choi DH, Shin DW, Lee AY, Hwang D, Cho EG, Lee TR
PLoS One 2015 Jun 9;10(6):e0129273
PMID 26057890
 
Mutational analysis of oculocutaneous albinism: a compact review
Kamaraj B, Purohit R
Biomed Res Int 2014;2014:905472
PMID 25093188
 
SLC24A5, a putative cation exchanger, affects pigmentation in zebrafish and humans
Lamason RL, Mohideen MA, Mest JR, Wong AC, Norton HL, Aros MC, Jurynec MJ, Mao X, Humphreville VR, Humbert JE, Sinha S, Moore JL, Jagadeeswaran P, Zhao W, Ning G, Makalowska I, McKeigue PM, O'donnell D, Kittles R, Parra EJ, Mangini NJ, Grunwald DJ, Shriver MD, Canfield VA, Cheng KC
Science 2005 Dec 16;310(5755):1782-6
PMID 16357253
 
Identification of an animal sucrose transporter
Meyer H, Vitavska O, Wieczorek H
J Cell Sci 2011 Jun 15;124(Pt 12):1984-91
PMID 21586609
 
Mutations in the human orthologue of the mouse underwhite gene (uw) underlie a new form of oculocutaneous albinism, OCA4
Newton JM, Cohen-Barak O, Hagiwara N, Gardner JM, Davisson MT, King RA, Brilliant MH
Am J Hum Genet 2001 Nov;69(5):981-8
PMID 11574907
 
Investigating polymorphisms in membrane-associated transporter protein SLC45A2, using sucrose transporters as a model
Reinders A, Ward JM
Mol Med Rep 2015 Jul;12(1):1393-8
PMID 25760657
 
Identification of two novel mutations in the SLC45A2 gene in a Hungarian pedigree affected by unusual OCA type 4
Tóth L, Fábos B, Farkas K, Sulák A, Tripolszki K, Széll M, Nagy N
BMC Med Genet 2017 Mar 15;18(1):27
PMID 28298193
 

Citation

This paper should be referenced as such :
Sengupta M, Dutta T, Ray K
SLC45A2 (solute carrier family 45 member 2);
Atlas Genet Cytogenet Oncol Haematol. in press
On line version : http://AtlasGeneticsOncology.org/Genes/SLC45A2ID41306ch5p13.html


Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 2 ]
  SLC45A2/AMACR (5p13)
SLC45A2/AMACR (5p13)


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


External links

Nomenclature
HGNC (Hugo)SLC45A2   16472
Cards
AtlasSLC45A2ID41306ch5p13
Entrez_Gene (NCBI)SLC45A2  51151  solute carrier family 45 member 2
Aliases1A1; AIM1; MATP; OCA4; 
SHEP5
GeneCards (Weizmann)SLC45A2
Ensembl hg19 (Hinxton)ENSG00000164175 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000164175 [Gene_View]  ENSG00000164175 [Sequence]  chr5:33944616-33984675 [Contig_View]  SLC45A2 [Vega]
ICGC DataPortalENSG00000164175
TCGA cBioPortalSLC45A2
AceView (NCBI)SLC45A2
Genatlas (Paris)SLC45A2
WikiGenes51151
SOURCE (Princeton)SLC45A2
Genetics Home Reference (NIH)SLC45A2
Genomic and cartography
GoldenPath hg38 (UCSC)SLC45A2  -     chr5:33944616-33984675 -  5p13.2   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)SLC45A2  -     5p13.2   [Description]    (hg19-Feb_2009)
GoldenPathSLC45A2 - 5p13.2 [CytoView hg19]  SLC45A2 - 5p13.2 [CytoView hg38]
ImmunoBaseENSG00000164175
Mapping of homologs : NCBISLC45A2 [Mapview hg19]  SLC45A2 [Mapview hg38]
OMIM227240   606202   606574   
Gene and transcription
Genbank (Entrez)AF172849 BC003597 BC064405 BQ677785 BU166522
RefSeq transcript (Entrez)NM_001012509 NM_001297417 NM_016180
RefSeq genomic (Entrez)NC_000005 NG_011691 NT_187551
Consensus coding sequences : CCDS (NCBI)SLC45A2
Cluster EST : UnigeneHs.278962 [ NCBI ]
CGAP (NCI)Hs.278962
Alternative Splicing GalleryENSG00000164175
Gene ExpressionSLC45A2 [ NCBI-GEO ]   SLC45A2 [ EBI - ARRAY_EXPRESS ]   SLC45A2 [ SEEK ]   SLC45A2 [ MEM ]
Gene Expression Viewer (FireBrowse)SLC45A2 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevestigatorExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)51151
GTEX Portal (Tissue expression)SLC45A2
Human Protein AtlasENSG00000164175-SLC45A2 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ9UMX9   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ9UMX9  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ9UMX9
Splice isoforms : SwissVarQ9UMX9
PhosPhoSitePlusQ9UMX9
Domains : Interpro (EBI)MFS_trans_sf   
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Conserved Domain (NCBI)SLC45A2
DMDM Disease mutations51151
Blocks (Seattle)SLC45A2
SuperfamilyQ9UMX9
Human Protein Atlas [tissue]ENSG00000164175-SLC45A2 [tissue]
Peptide AtlasQ9UMX9
HPRD05865
IPIIPI00299427   IPI00413233   IPI00219552   IPI00554732   IPI01019035   IPI00966810   
Protein Interaction databases
DIP (DOE-UCLA)Q9UMX9
IntAct (EBI)Q9UMX9
FunCoupENSG00000164175
BioGRIDSLC45A2
STRING (EMBL)SLC45A2
ZODIACSLC45A2
Ontologies - Pathways
QuickGOQ9UMX9
Ontology : AmiGOvisual perception  sucrose:proton symporter activity  sucrose:proton symporter activity  sucrose transport  membrane  integral component of membrane  melanosome membrane  melanin biosynthetic process  developmental pigmentation  response to stimulus  
Ontology : EGO-EBIvisual perception  sucrose:proton symporter activity  sucrose:proton symporter activity  sucrose transport  membrane  integral component of membrane  melanosome membrane  melanin biosynthetic process  developmental pigmentation  response to stimulus  
REACTOMEQ9UMX9 [protein]
REACTOME PathwaysR-HSA-5662702 [pathway]   
NDEx NetworkSLC45A2
Atlas of Cancer Signalling NetworkSLC45A2
Wikipedia pathwaysSLC45A2
Orthology - Evolution
OrthoDB51151
GeneTree (enSembl)ENSG00000164175
Phylogenetic Trees/Animal Genes : TreeFamSLC45A2
HOGENOMQ9UMX9
Homologs : HomoloGeneSLC45A2
Homology/Alignments : Family Browser (UCSC)SLC45A2
Gene fusions - Rearrangements
Fusion : MitelmanSLC45A2/AMACR [5p13.2/5p13.2]  
Fusion PortalSLC45A2 5p13.2 AMACR 5p13.2 BLCA
Fusion : FusionGDB17797    34524    34525    34526   
Fusion : Fusion_HubAMACR--SLC45A2    C1QTNF3-AMACR--SLC45A2    ITFG1--SLC45A2    SLC45A2--AMACR    SLC45A2--C1QTNF3    SLC45A2--C1QTNF3-AMACR    SLC45A2--CCDC125   
Fusion : QuiverSLC45A2
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerSLC45A2 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)SLC45A2
dbVarSLC45A2
ClinVarSLC45A2
1000_GenomesSLC45A2 
Exome Variant ServerSLC45A2
ExAC (Exome Aggregation Consortium)ENSG00000164175
GNOMAD BrowserENSG00000164175
Varsome BrowserSLC45A2
Genetic variants : HAPMAP51151
Genomic Variants (DGV)SLC45A2 [DGVbeta]
DECIPHERSLC45A2 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisSLC45A2 
Mutations
ICGC Data PortalSLC45A2 
TCGA Data PortalSLC45A2 
Broad Tumor PortalSLC45A2
OASIS PortalSLC45A2 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICSLC45A2  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDSLC45A2
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 SLC45A2
DgiDB (Drug Gene Interaction Database)SLC45A2
DoCM (Curated mutations)SLC45A2 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)SLC45A2 (select a term)
intoGenSLC45A2
NCG5 (London)SLC45A2
Cancer3DSLC45A2(select the gene name)
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM227240    606202    606574   
Orphanet11461   
DisGeNETSLC45A2
MedgenSLC45A2
Genetic Testing Registry SLC45A2
NextProtQ9UMX9 [Medical]
TSGene51151
GENETestsSLC45A2
Target ValidationSLC45A2
Huge Navigator SLC45A2 [HugePedia]
snp3D : Map Gene to Disease51151
BioCentury BCIQSLC45A2
ClinGenSLC45A2
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD51151
Chemical/Pharm GKB GenePA134897756
Clinical trialSLC45A2
Miscellaneous
canSAR (ICR)SLC45A2 (select the gene name)
DataMed IndexSLC45A2
Probes
Litterature
PubMed70 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineSLC45A2
EVEXSLC45A2
GoPubMedSLC45A2
iHOPSLC45A2
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Fri Jun 7 18:40:21 CEST 2019

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