Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.10.3.1 (tyrosinase)
 9,065 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Single nucleotide polymorphisms (SNPs) within the SLC45A2/MATP, SLC24A5/NCKX5, and OCA2/P genes have been associated with natural variation of pigmentation traits in human populations. Here, we describe the characterization of human primary melanocytic cells genotyped for polymorphisms within the MATP, NCKX5, or OCA2 loci. On the basis of genotype, these cultured cells reflect the phenotypes observed by others in terms of both melanin content and tyrosinase (TYR) activity when comparing skin designated as either "White" or "Black". We found a statistically significant association of MATP-374L (darker skin) with higher TYR protein abundance that was not observed for any NCKX5-111 or OCA2 rs12913832 allele. MATP-374L/L homozygous strains displayed significantly lower MATP transcript levels compared to MATP-374F/F homozygous cells, but this did not reach statistical significance based on NCKX5 or OCA2 genotype. Similarly, we observed significantly increased levels of OCA2 mRNA in rs12913832-T (brown eye) homozygotes compared to rs12913832-C (blue eye) homozygous strains, which was not observed for MATP or NCKX5 gene transcripts. In genotype-phenotype associations performed on a collection of 226 southern European individuals using these same SNPs, we were able to show strong correlations in MATP-L374F, OCA2, and melanocortin-1 receptor with skin, eye, and hair color variation, respectively.
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PMID:Analysis of cultured human melanocytes based on polymorphisms within the SLC45A2/MATP, SLC24A5/NCKX5, and OCA2/P loci. 1865 Aug 49

The genetic basis underlying normal variation in the pigmentary traits of skin, hair and eye colour has been the subject of intense research directed at understanding the diversity seen both between and within human populations. A combination of approaches have been used including comparative genomics of candidate genes and the identification of regions of the human genome under positive selection, together with genome-wide and specific allele association studies. Independent selection for different pigmentation gene sets has been found between Asian, European and African populations. Several genome-wide association studies for pigmentation have now been conducted and identified single nucleotide polymorphism (SNP) markers in known, TYR, TYRP1, OCA2, SLC45A2, SLC24A5, MC1R, ASIP, KITLG and previously unknown SLC24A4, IRF4, TPCN2, candidate genes. The contribution of SNP polymorphisms present in populations from South Asia have been tested and alleles found at TYR, SLC45A2 and SLC24A5 can largely account for differences between those of darkest and lightest skin reflectance using a simple additive model. Skin and hair colour associations in Europeans are found within a range of pigmentation gene alleles, whereas blue-brown eye colour can be explained by a single SNP proposed to regulate OCA2 expression. Functional testing of variant alleles has begun to connect phenotype correlations with biological differences. Variant MC1R alleles show direct correlations between the biochemical signalling properties of the encoded receptor and the red-hair fair skin pigmentation phenotype. Direct testing of a range of clonal melanocyte cultures derived from donor skin tissue characterized for three causal SNPs within SLC45A2, SLC24A5 and OCA2 has assessed their impact on melanin content and tyrosinase enzyme activity. From a culmination of genetic and functional studies, it is apparent that a number of genes impacting melanosome biogenesis or the melanin biosynthetic pathway are candidates to explain the diversity seen in human pigmentation.
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PMID:Molecular genetics of human pigmentation diversity. 1929 6

Melanins are synthesized in melanocytes within specialized organelles called melanosomes. Numerous studies have shown that the pH of melanosome plays a key role in the regulation of melanin synthesis. However, until now, acute regulation of melanosome pH by a physiological stimulus has never been demonstrated. In the present study, we show that the activation of the cAMP pathway by alphaMSH or forskolin leads to an alkalinization of melanosomes and a concomitant regulation of vacuolar ATPases and ion transporters of the solute carrier family. The solute carrier family members include SLC45A2, which is mutated in oculocutaneous albinism type IV, SLC24A4 and SLC24A5, proteins implicated in the control of eye, hair, and skin pigmentation, and the P protein, encoded by the oculocutaneous albinism type II locus. Interestingly, H89, a pharmacological inhibitor of protein kinase A (PKA), prevents the cAMP-induced pigmentation and induces acidification of melanosomes. The drastic depigmenting effect of H89 is not due to an inhibition of tyrosinase expression. Indeed, H89 blocks the induction of melanogenesis induced by LY294002, a potent inhibitor of the PI 3-kinase pathway, without any effect on tyrosinase expression. Furthermore, PKA is not involved in the inhibition of pigmentation promoted by H89 because LY294002 induces pigmentation independently of PKA. Also, other PKA inhibitors do not affect pigmentation. Taken together, our results strengthen the support for a key role of melanosome pH in the regulation of melanin synthesis and, for the first time, demonstrate that melanosome pH is regulated by cAMP and alphaMSH. Notably, these are both mediators of the response to solar UV radiation, the main physiological stimulus of skin pigmentation.
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PMID:{alpha}MSH and Cyclic AMP elevating agents control melanosome pH through a protein kinase A-independent mechanism. 1938 8