Alternative titles; symbols
HGNC Approved Gene Symbol: SLC45A2
SNOMEDCT: 715632003;
Cytogenetic location: 5p13.2 Genomic coordinates (GRCh38) : 5:33,944,623-33,984,693 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5p13.2 | [Skin/hair/eye pigmentation 5, black/nonblack hair] | 227240 | Autosomal recessive | 3 |
| [Skin/hair/eye pigmentation 5, dark/fair skin] | 227240 | Autosomal recessive | 3 | |
| [Skin/hair/eye pigmentation 5, dark/light eyes] | 227240 | Autosomal recessive | 3 | |
| Albinism, oculocutaneous, type IV | 606574 | Autosomal recessive | 3 |
The AIM1 gene encodes a melanocyte differentiation antigen that is expressed in a high percentage of melanoma cell lines. Its homolog in medaka fish, 'B,' encodes a transporter that mediates melanin synthesis (Fukamachi et al., 2001).
SLC45A2 is an H(+)-dependent sugar transporter (Bartolke et al., 2014).
Harada et al. (2001) identified an antigen in human melanoma that they called AIM1 protein. The AIM1 gene was expressed in 3 melanoma cell lines, but not in a fibroblast cell line, and not at significant levels in any of 15 normal tissues. The human AIM1 gene encodes a protein of 530 amino acids. Northern blot analysis detected 2 transcripts, one of 1.7 kb and the other of 2.8 kb. Harada et al. (2001) concluded that the AIM1 gene encodes a melanocyte differentiation antigen that is expressed in a high percentage of melanoma cell lines.
Fukamachi et al. (2001) used a positional cloning effort to isolate a medaka pigment gene highly homologous to human AIM1. This gene encodes a transporter that mediates melanin synthesis. The medaka AIM1 protein consists of 12 transmembrane domains and is 55% identical to human AIM1. Fukamachi et al. (2001) also isolated a highly homologous gene from the mouse, indicating a conserved function of vertebrate melanogenesis.
Newton et al. (2001) identified the human AIM1 gene, which they designated MATP, by study of human chromosome 5p, a region showing syntenic homology with the proximal region of mouse chromosome 15 where the underwhite (uw) locus maps. They cloned the human MATP and mouse uw cDNAs and determined that the deduced human and mouse proteins share 82% sequence identity. Both proteins are approximately 58 kD and are predicted to span a lipid bilayer 12 times.
Using real-time PCR, Bartolke et al. (2014) detected Slc45a2 expression predominantly in mouse eye and skin, with little to no expression in other tissues.
Du and Fisher (2002) determined that MATP is transcriptionally modulated by MITF (156845), a melanocyte-specific transcription factor. Chromatin immunoprecipitation did not detect direct binding of MITF to a 5-prime flanking region of MATP, suggesting that MITF may act indirectly or may bind to a remote regulatory sequence.
By expressing the full-length protein in S. cerevisiae, Bartolke et al. (2014) found that mouse Slc45a2 functioned as an H(+)-sucrose symporter. Inhibition studies suggested that Slc45a2 also transports glucose and fructose.
Newton et al. (2001) determined that the SLC45A2 gene contains 7 exons spanning a region of approximately 40 kb.
By sequence analysis, Newton et al. (2001) mapped the SLC45A2 gene to chromosome 5p.
Gross (2021) mapped the SLC45A2 gene to chromosome 5p13.2 based on an alignment of the SLC45A2 sequence (GenBank AF172849) with the genomic sequence (GRCh38).
Sabeti et al. (2007) reported an analysis of over 3 million polymorphisms from the International HapMap Project Phase 2. The analysis revealed more than 300 strong candidate regions that appeared to have undergone recent natural selection. Examination of 22 of the strongest regions highlighted 3 cases in which 2 genes in a common biologic process had apparently undergone positive selection in the same population: LARGE (603590) and DMD (300377), both related to infection by the Lassa virus, in West Africa; SLC24A5 (609802) and SLC45A2, both involved in skin pigmentation, in Europe; and EDAR (604095) and EDA2R (300276), both involved in the development of hair follicles, in Asia.
Oculocutaneous Albinism Type IV
In a Turkish patient with oculocutaneous albinism type IV (OCA4; 606574), Newton et al. (2001) identified a homozygous mutation in the MATP gene (606202.0001).
Rundshagen et al. (2004) screened 176 German patients with albinism for mutations in the MATP gene; in 5, they identified homozygous or compound heterozygous mutations (see 606202.0002-606202.0005).
In 18 of 75 (24%) Japanese patients with OCA, Inagaki et al. (2004) identified 7 mutations in the MATP gene (see, e.g., 606202.0006).
Normal Pigment Variation
Studying Caucasians, Asians, African Americans, and Australian Aborigines, Graf et al. (2005) found association particularly with 2 polymorphisms, G272K (606202.0007) and F374L (606202.0008), with normal variation in human pigmentation (SHEP5; 227240).
Graf et al. (2007) examined the association between normal skin color variation in several populations and 3 different promoter polymorphisms in the MATP gene: -1721C-G (rs13289), -1169G-A (rs6867641), and a 3-bp duplication, -1174dupAAT. In Caucasian samples, -1721C-G and -1174dupAAT were in complete linkage disequilibrium. In Caucasians only, the -1721G, -1169A, and +dup alleles were significantly associated with olive skin color. Functional analysis in melanoma skin cells showed that this promoter haplotype decreased MATP transcription, suggesting a functional significance.
Stokowski et al. (2007) demonstrated an association between the SNP rs16891982 (F374L; 606202.0008) and skin pigmentation variation in individuals of South Asian descent.
Newton et al. (2001) and Du and Fisher (2002) determined that mutations in the mouse Matp gene underlie the underwhite (uw) pigmentation phenotype. Underwhite alleles manifest altered pigmentation of both eye and fur, sometimes in an age-dependent fashion.
Xu et al. (2013) found that white tigers, characterized by white fur and dark stripes, are homozygous for a C-to-T transition in exon 7 of the Slc45a2 gene, resulting in an ala477-to-val (A477V) substitution in transmembrane domain 11. Homology modeling suggested that A477 faces the inner surface of the transporter cavity and that its mutation may hinder substrate transport. Xu et al. (2013) hypothesized that Slc45a2 may be a sucrose/proton symporter that regulates organellar pH and/or osmotic balance for synthesis of red/yellow pheomelanin, with little or no effect on the synthesis of black eumelanin.
In a Turkish patient with oculocutaneous albinism type IV (OCA4; 606574), whose generalized hypopigmentation and ocular abnormalities were relatively mild, Newton et al. (2001) identified a homozygous G-to-A transition in the splice acceptor sequence of exon 2 of the SLC45A2 gene. The patient's parents were heterozygous for this mutation. The authors noted that the mutation likely results in the in-frame deletion of exon 2, which codes for transmembrane domain-4, and would result in a change in the orientation of transmembrane domains 5-12 relative to the membrane.
In a German patient with oculocutaneous albinism type IV (OCA4; 606574), Rundshagen et al. (2004) identified a homozygous 1082T-C transition in exon 5 of the MATP gene, resulting in a leu361-to-pro (L361P) change. Each parent was heterozygous for the mutation.
In 2 German patients with oculocutaneous albinism type IV (OCA4; 606574), Rundshagen et al. (2004) identified a 1-bp deletion in exon 4 of the MATP gene, 986delC, resulting in a frameshift at codon 329 and a translation stop in exon 6. In each patient the frameshift mutation was present in compound heterozygous state: in one patient with a 3-bp deletion (nucleotides 661-663), resulting in deletion of phe221 (606202.0004), and in the other with an A486V mutation (606202.0005).
For discussion of the 3-bp deletion (361_363del) in the MATP gene that was found in compound heterozygous state in a patient with oculocutaneous albinism type IV (OCA4; 606574) by Rundshagen et al. (2004), see 606202.0003.
For discussion of the ala486-to-val (A486V) mutation in the MATP gene that was found in compound heterozygous state in a patient with oculocutaneous albinism type IV (OCA4; 606574) by Rundshagen et al. (2004), see 606202.0003.
In 2 Japanese patients with oculocutaneous albinism type IV (OCA4; 606574), Inagaki et al. (2004) identified homozygosity for a G-to-A transition in exon 2 of the MATP gene, resulting in an asp157-to-asn (D157N) substitution. The mutation occurs at the first residue in the second cytoplasmic loop of the protein. Ten other patients had 1 D157N mutant allele; the allele frequency of D157N in all patients with OCA4 was 0.39, indicating that it is the most common mutant allele in Japanese patients with OCA4.
Inagaki et al. (2005) investigated the haplotypes of 20 alleles carrying the D157N mutation from 1 Korean and 21 Japanese OCA4 patients and found 1 Korean and 12 Japanese alleles to be associated with so-called 'haplotype 15' (G-A-G-A-G), consistent with a founder effect for the D157N mutation in East Asia.
In Caucasians, Graf et al. (2005) found a significant association between 2 polymorphisms of the MATP gene, an 814G-A transition resulting in a glu272-to-lys substitution (G272K) and a 1122C-G transversion resulting in a phe374-to-leu substitution (F374L; 606202.0008). The 2 alleles, leu374 and lys272, were significantly associated with dark hair, skin, and eye color in Caucasians (SHEP5; 227240). The odds ratios of the leu/leu genotype for black hair and olive skin were 25.63 and 28.65, respectively, and for the lys/lys genotype were 43.23 and 8.27, respectively. The odds ratio for eye color was lower at 3.48 for the leu/leu and 6.57 for the lys/lys genotypes.
For discussion of the phe374-to-leu (F374L) mutation in the MATP gene that was found in compound heterozygous state in Caucasian individuals with dark hair, skin, and eye color (SHEP5; 227240) by Graf et al. (2005), see 606202.0007.
Yuasa et al. (2006), who referred to this polymorphism as L374F, studied the distribution of the F374 allele in 1,649 unrelated subjects from 13 Eurasian populations and 1 African population. The highest allele frequency was observed in Germans (0.965); French and Italians showed somewhat lower frequencies; and Turks had an intermediate value (0.615). Indians and Bangladeshis from South Asia were characterized by low frequencies (0.147 and 0.059, respectively). They also found the F374 allele in some East and Southeast Asian populations, and explained this by admixture. Haplotype analysis revealed that the haplotype diversity was much lower in Germans than in Japanese, suggesting that the L374F mutation occurred only once in the ancestry of Caucasians. The large differences in distribution of the F374 allele and its haplotype suggested that this allele may be an important factor in hypopigmentation in Caucasian populations.
In a genomewide association study of skin pigmentation variation (SHEP5; 227240) using 1,620,742 SNPs in a population of 737 individuals of South Asian ancestry living in the United Kingdom, Stokowski et al. (2007) found association of the SLC45A2 SNP rs16891982 (L374F) with skin pigmentation. The association was replicated in a second independent cohort of 235 individuals.
Stacey et al. (2009) confirmed the association of the rs16891982 variant with fair pigmentation and found association of this SNP with susceptibility to basal cell carcinoma in 3,326 basal cell carcinoma cases and 5,493 controls of European ancestry (odds ratio = 1.97, P = 1.6 x 10(-12)).
Guedj et al. (2008) analyzed the F374L variant in 1,019 Caucasian melanoma patients (see 155600) and 1,466 Caucasian controls and found an association for protection from melanoma (p = 2.12 x 10(-15); odds ratio = 0.35 and 0.32 for the F/L and F/F genotypes, respectively). The association remained significant in a logistic model integrating pigmentation characteristics (p = 4.16 x 10(-3)).
In a Spanish case-control study involving 131 consecutive melanoma patients and 245 controls, Fernandez et al. (2008) found the F374L variant of the SLC45A2 gene to be associated with protection from malignant melanoma (odds ratio = 0.41; p = 0.008 after adjustment for multiple testing). Adjustment for 6 potential confounders (age, blond/red hair color, fair/pale skin color, solar lentigines, number of nevi, and the presence of childhood sunburn) reduced the estimated degree of protection (odds ratio = 0.56; p = 0.08), reflecting their likely participation in the causal pathway. Only blond/red hair color and childhood sunburns were independently associated with risk of malignant melanoma; adjustment for those 2 covariates gave an estimated per allele odds ratio of 0.55 (p = 0.05) for the F374L variant.
In 2 Brazilian sibs with oculocutaneous albinism type IV (OCA4; 606574), Lezirovitz et al. (2006) identified a homozygous 1-bp deletion (1121delT) in exon 5 of the MATP gene, resulting in a frameshift and premature termination of the protein at codon 397. One of the affected sibs also had sensorineural deafness (DFNB1; 220290) associated with a homozygous mutation in the GJB2 gene (121011.0005). Lezirovitz et al. (2006) concluded that congenital deafness and oculocutaneous albinism due to mutations in 2 different genes as seen in their Brazilian family suggested a similar coincident inheritance of 2 separate recessive disorders in the Sephardic family reported by Ziprkowski and Adam (1964) (see 220900).
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Du, J., Fisher, D. E. Identification of Aim-1 as the underwhite mouse mutant and its transcriptional regulation by MITF. J. Biol. Chem. 277: 402-406, 2002. [PubMed: 11700328] [Full Text: https://doi.org/10.1074/jbc.M110229200]
Fernandez, L. P., Milne, R. L., Pita, G., Aviles, J. A., Lazaro, P., Benitez, J., Ribas, G. SLC45A2: a novel malignant melanoma-associated gene. Hum. Mutat. 29: 1161-1167, 2008. [PubMed: 18563784] [Full Text: https://doi.org/10.1002/humu.20804]
Fukamachi, S., Shimada, A., Shima, A. Mutations in the gene encoding B, a novel transporter protein, reduce melanin content in medaka. Nature Genet. 28: 381-385, 2001. [PubMed: 11479596] [Full Text: https://doi.org/10.1038/ng584]
Graf, J., Hodgson, R., van Daal, A. Single nucleotide polymorphisms in the MATP gene are associated with normal human pigmentation variation. Hum. Mutat. 25: 278-284, 2005. [PubMed: 15714523] [Full Text: https://doi.org/10.1002/humu.20143]
Graf, J., Voisey, J., Hughes, I., van Daal, A. Promoter polymorphisms in the MATP (SLC45A2) gene are associated with normal human skin color variation. Hum. Mutat. 28: 710-717, 2007. [PubMed: 17358008] [Full Text: https://doi.org/10.1002/humu.20504]
Gross, M. B. Personal Communication. Baltimore, Md. 10/21/2021.
Guedj, M., Bourillon, A., Combadieres, C., Rodero, M., Dieude, P., Descamps, V., Dupin, N., Wolkenstein, P., Aegerter, P., Lebbe, C., Basset-Seguin, N., Prum, B., Saiag, P., Grandchamp, B., Soufir, N. Variants of the MATP/SLC45A2 gene are protective for melanoma in the French population. Hum. Mutat. 29: 1154-1160, 2008. [PubMed: 18683857] [Full Text: https://doi.org/10.1002/humu.20823]
Harada, M., Li, Y. F., El-Gamil, M., Rosenberg, S. A., Robbins, P. F. Use of an in vitro immunoselected tumor line to identify shared melanoma antigens recognized by HLA-A*0201-restricted T cells. Cancer Res. 61: 1089-1094, 2001. [PubMed: 11221837]
Inagaki, K., Suzuki, T., Ito, S., Suzuki, N., Fukai, K., Horiuchi, T., Tanaka, T., Manabe, E., Tomita, Y. OCA4: evidence for a founder effect for the p.D157N mutation of the MATP gene in Japanese and Korean. Pigment Cell Res. 18: 385-388, 2005. [PubMed: 16162179] [Full Text: https://doi.org/10.1111/j.1600-0749.2005.00261.x]
Inagaki, K., Suzuki, T., Shimizu, H., Ishii, N., Umezawa, Y., Tada, J., Kikuchi, N., Takata, M., Takamori, K., Kishibe, M., Tanaka, M., Miyamura, Y., Ito, S., Tomita, Y. Oculocutaneous albinism type 4 is one of the most common types of albinism in Japan. Am. J. Hum. Genet. 74: 466-471, 2004. [PubMed: 14961451] [Full Text: https://doi.org/10.1086/382195]
Lezirovitz, K., Nicastro, F. S., Pardono, E., Abreu-Silva, R. S., Batissoco, A. C., Neustein, I., Spinelli, M., Mingroni-Netto, R. C. Is autosomal recessive deafness associated with oculocutaneous albinism a 'coincidence syndrome'? J. Hum. Genet. 51: 716-720, 2006. [PubMed: 16868655] [Full Text: https://doi.org/10.1007/s10038-006-0003-7]
Newton, J. M., Cohen-Barak, O., Hagiwara, N., Gardner, J. M., Davisson, M. T., King, R. A., Brilliant, M. H. Mutations in the human orthologue of the mouse underwhite gene (uw) underlie a new form of oculocutaneous albinism, OCA4. Am. J. Hum. Genet. 69: 981-988, 2001. [PubMed: 11574907] [Full Text: https://doi.org/10.1086/324340]
Rundshagen, U., Zuhlke, C., Opitz, S., Schwinger, E., Kasmann-Kellner, B. Mutations in the MATP gene in five German patients affected by oculocutaneous albinism type 4. Hum. Mutat. 23: 106-110, 2004. [PubMed: 14722913] [Full Text: https://doi.org/10.1002/humu.10311]
Sabeti, P. C., Varilly, P., Fry, B., Lohmueller, J., Hostetter, E., Cotsapas, C., Xie, X., Byrne, E. H., McCarroll, S. A., Gaudet, R., Schaffner, S. F., Lander, E. S., International HapMap Consortium. Genome-wide detection and characterization of positive selection in human populations. Nature 449: 913-918, 2007. [PubMed: 17943131] [Full Text: https://doi.org/10.1038/nature06250]
Stacey, S. N., Sulem, P., Masson, G., Gudjonsson, S. A., Thorleifsson, G., Jakobsdottir, M., Sigurdsson, A., Gudjartsson, D. F., Sigurgeirsson, B., Benediktsdottir, K. R., Thorisdottir, K., Ragnarsson, R., and 52 others. New common variants affecting susceptibility to basal cell carcinoma. Nature Genet. 41: 909-914, 2009. [PubMed: 19578363] [Full Text: https://doi.org/10.1038/ng.412]
Stokowski, R. P., Pant, P. V. K., Dadd, T., Fereday, A., Hinds, D. A., Jarman, C., Filsell, W., Ginger, R. S., Green, M. R., van der Ouderaa, F. J., Cox, D. R. A genomewide association study of skin pigmentation in a South Asian population. Am. J. Hum. Genet. 81: 1119-1132, 2007. [PubMed: 17999355] [Full Text: https://doi.org/10.1086/522235]
Xu, X., Dong, G.-X., Hu, X.-S., Miao, L., Zhang, X.-L., Zhang, D.-L., Yang, H.-D., Zhang, T.-Y., Zou, Z.-T., Zhang, T.-T., Zhuang, Y., Bhak, J., Cho, Y. S., Dai, W.-T., Jiang, T.-J., Xie, C., Li, R., Luo, S.-J. The genetic basis of white tigers. Curr. Biol. 23: 1031-1035, 2013. [PubMed: 23707431] [Full Text: https://doi.org/10.1016/j.cub.2013.04.054]
Yuasa, I., Umetsu, K., Harihara, S., Kido, A., Miyoshi, A., Saitou, N., Dashnyam, B., Jin, F., Lucotte, G., Chattopadhyay, P. K., Henke, L., Henke, J. Distribution of the F374 allele of the SLC45A2 (MATP) gene and founder-haplotype analysis. Ann. Hum. Genet. 70: 802-811, 2006. [PubMed: 17044855] [Full Text: https://doi.org/10.1111/j.1469-1809.2006.00261.x]
Ziprkowski, L., Adam, A. Recessive total albinism and congenital deafmutism. Arch. Derm. 89: 151-155, 1964. [PubMed: 14070830] [Full Text: https://doi.org/10.1001/archderm.1964.01590250157028]