Molecular analysis of common polymorphisms within the human <i>Tyrosinase</i> locus and genetic association with pigmentation traits

Jagirdar, Kasturee; Smit, Darren J.; Ainger, Stephen A.; Lee, Katie J.; Brown, Darren L.; Chapman, Brett; Zhao, Zhen; Montgomery, Grant W.; Martin, Nicholas G.; Stow, Jennifer L.; Duffy, David L.; Sturm, Richard A.

doi:10.1111/pcmr.12253

Cited by 51 publications

(74 citation statements)

References 60 publications

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“…The 192Y allele is associated with light skin, eye colour, absence of freckles and an increased SCC risk, whereas the 402Q change was reported to increase the risk of BCC [43] , was frequently associated with albinism patients [44] and significantly increased SK, multiple melanoma risk [42] and familial CM risk in a French population [41] . Protein expression studies have shown that the 402Q variant encodes a thermolabile enzyme [40] , and in primary melanocyte cultures we have shown that it is retained in the endoplasmic reticulum, hypoglycosylated and preferentially degraded [45] . Interestingly, thermolabile TYR alleles are the basis of the Siamese/Burmese cat coat colours, where pigment appears darkest at the extremities of the body [46] ; this condition is also present in some human albino patients as subtype OCA1B [39] .…”

Section: Tyr (Oca1)mentioning

confidence: 99%

“…Interestingly, thermolabile TYR alleles are the basis of the Siamese/Burmese cat coat colours, where pigment appears darkest at the extremities of the body [46] ; this condition is also present in some human albino patients as subtype OCA1B [39] . Recent studies have shown that the TYR genotype is likely to be a significant modifier of other pigmentation gene polymorphisms in human skin, hair and eye colour, and associated with naevus count, though not apparent by body site there is potential for thermal changes in pigmentation of the skin and hair [45] . The 2 polymorphisms were present on 4 TYR haplotypes, designated as WT being 192S-402R, single variants 192Y-402R and 192S-402Q, with a double-variant 192Y-402Q of low frequency at 1.9%.…”

Section: Tyr (Oca1)mentioning

confidence: 99%

“…We have used an additive model to assess the penetrance of the 10 possible TYR genotypes derived from the combination of these haplotypes. The double-variant 192Y-402Q haplotype is likely to be deleterious, and may explain the association of the 402Q SNP with albinism and hypopigmentation in the general population [45] .…”

Section: Tyr (Oca1)mentioning

confidence: 99%

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Skin Pigmentation Genetics for the Clinic

Ainger

Jagirdar²,

Lee³

et al. 2017

Dermatology

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Human pigmentation characteristics play an important role in the effects of sun exposure, skin cancer induction and disease outcomes. Several of the genes most important for this diversity are involved in the regulation and distribution of melanin pigmentation or enzymes involved in melanogenesis itself within the melanocyte cell present in the skin, hair and eyes. The single nucleotide polymorphisms and extended haplotypes within or surrounding these genes have been identified as risk factors for skin cancer, in particular, melanoma. These same polymorphisms have been under selective pressure leading towards lighter pigmentation in Europeans in the last 5,000-20,000 years that have driven the increase in frequency in modern populations. Although pigmentation is a polygenic trait, due to interactive and quantitative gene effects, strong phenotypic associations are readily apparent for these major genes. However, predictive value and utility are increased when considering gene polymorphism interactions. In melanoma, an increased penetrance is found in cases when pigmentation gene risk alleles such as MC1R variants are coincident with mutation of higher-risk melanoma genes including CDKN2A, CDK4 and MITF E318K, demonstrating an interface between the pathways for pigmentation, naevogenesis and melanoma. The clinical phenotypes associated with germline changes in pigmentation and naevogenic genes must be understood by clinicians, and will be of increasing relevance to dermatologists, as genomics is incorporated into the delivery of personalised medicine.

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Section: Tyr (Oca1)mentioning

confidence: 99%

Section: Tyr (Oca1)mentioning

confidence: 99%

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Skin Pigmentation Genetics for the Clinic

Ainger

Jagirdar²,

Lee³

et al. 2017

Dermatology

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“…However, functional studies reported that 192Tyr and 402Gln alleles have reduced TYR enzyme activity. Heterozygous p.Ser192Tyr and p.Arg402Gln variants caused significant reduction in TYR expression, and a consistent decrease in TYR protein levels was observed in homozygous p.Ser192-Tyr cells [9].…”

Section: Discussionmentioning

confidence: 70%

Identification of Two Novel Mutations in the SLC45A2 Gene in a Hungarian Pedigree Affected by Unusual OCA Type 4

Tóth

Fábos

Farkas

et al. 2015

Hereditary Genetics

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Background: Oculocutaneous albinism (OCA) is a clinically and genetically heterogenic group of pigmentation abnormalities. OCA type IV (OCA4, OMIM 606574) develops due to homozygous or compound heterozygous mutations in the solute carrier family 45, member 2 (SLC45A2) gene. This gene encodes a membrane-associated transport protein, which regulates tyrosinase activity and, thus, melanin content by changing melanosomal pH and disrupting the incorporation of copper into tyrosinase. Methods: Here we report two Hungarian siblings affected by an unusual OCA4 phenotype. After genomic DNA was isolated from peripheral blood of the patients, the coding regions of the SLC45A2 gene were sequenced. In silico tools were applied to identify the functional impact of the newly detected mutations. Results: Direct sequencing of the SLC45A2 gene revealed two novel, heterozygous mutations, one missense (c.1226G > A, p.Gly409Asp) and one nonsense (c.1459C > T, p.Gln437*), which were present in both patients, suggesting the mutations were compound heterozygous. In silico tools suggest that these variations are disease causing mutations. Conclusions: The newly identified mutations may affect the transmembrane domains of the protein, and could impair transport function, resulting in decreases in both melanosomal pH and tyrosinase activity. Our study provides expands on the mutation spectrum of the SLC45A2 gene and the genetic background of OCA4.

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“…Differing degrees of skin pigmentation observed among ethnic groups can also be partially attributed to differences in tyrosinase activity, some of which is accounted for by genetic variants at the TYR (Jagirdar et al, 2014) and IRF4 loci (Praetorius et al, 2013). Tyrosinase, the rate-limiting enzyme required for melanin synthesis, is quantitatively more active in melanocytes from darker skin than lighter skin (Pomerantz and Ances, 1975; Iozumi et al, 1993; Iwata et al, 1990; Maeda et al, 1997), despite similar RNA expression levels (Naeyaert et al, 1991).…”

Section: Introductionmentioning

confidence: 99%

Variation in Hsp70-1A Expression Contributes to Skin Color Diversity

Murase

Hachiya

Fullenkamp³

et al. 2016

Journal of Investigative Dermatology

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The wide range in human skin color results from varying levels of the pigment melanin. Genetic mechanisms underlying coloration differences have been explored, but identified genes do not account for all variation seen in the skin color spectrum. Post-transcriptional and post-translational regulation of factors that determine skin color, including melanin synthesis in epidermal melanocytes, melanosome transfer to keratinocytes and melanosome degradation, is also critical for pigmentation. We therefore investigated proteins that are differentially expressed in melanocytes derived from either White or African American (AA) skin. Two dimensional gel electrophoresis (2-DGE) and mass spectrometry demonstrated that Heat Shock Protein 70-1A (Hsp70-1A) protein levels were significantly higher in AA melanocytes compared to White melanocytes. Hsp70-1A expression significantly correlated with levels of tyrosinase, the rate-limiting melanogenic enzyme, consistent with a proposed role for Hsp70-family members in tyrosinase post-translational modification. Additionally, pharmacologic inhibition and siRNA-mediated down-regulation of Hsp70-1A correlated with pigmentation changes in cultured melanocytes, modified human skin substitutes and ex vivo skin. Furthermore, Hsp70-1A inhibition led to increased autophagy-mediated melanosome degradation in keratinocytes. Our data thus reveal that epidermal Hsp70-1A contributes to the diversity of skin color by regulating the amount of melanin synthesized in melanocytes and modulating autophagic melanosome degradation in keratinocytes.

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Molecular analysis of common polymorphisms within the human Tyrosinase locus and genetic association with pigmentation traits

Cited by 51 publications

References 60 publications

Skin Pigmentation Genetics for the Clinic

Skin Pigmentation Genetics for the Clinic

Identification of Two Novel Mutations in the SLC45A2 Gene in a Hungarian Pedigree Affected by Unusual OCA Type 4

Variation in Hsp70-1A Expression Contributes to Skin Color Diversity

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