Skin type, melanoma, and melanocortin 1 receptor variants.
Explore the source record for details and available documents.
Hair Color↗
Biomedical subjects
I J Jackson
Publications and source records attributed to I J Jackson.
Molecular cloning and sequence analysis of a chicken cDNA encoding tyrosinase-related protein-2/DOPAchrome tautomerase.
We have cloned and sequenced a chicken cDNA encoding an l-DOPAchrome tautomerase (DCT) from an embryonic melanocyte cDNA library. The chicken DCT gene encodes a deduced protein of 516 amino acids (aas) and shares 69.2% and 69.9% aa sequence identity with the deduced mouse and human DCT proteins, respectively. Northern blot hybridisation analysis reveals a DCT transcript of 3.5kb in RNA from the retinal pigment epithelium (RPE) of chick embryos. Genomic Southern blot hybridisation analysis suggests that the chicken DCT gene consists of several introns and spans between 15 and 30kb of the chicken genome. This study completes the sequencing of all the members of the chicken tyrosinase-related protein gene family and provides evidence that this gene family is conserved between avians and mammals.
Amino Acid Sequence↗
The cloning and sequencing of a cDNA coding for chick tyrosinase-related protein-1.
We have cloned a cDNA encoding an avian homologue of the mammalian brown/TYRP1 locus protein. The chick tyrosinase-related protein-1 (TRP-1) gene encodes a deduced protein of 535 amino acids, shares > 65% amino acid sequence identity with fish and mammalian TRP-1 proteins, and spans 5-11 kb of the chick genome.
Amino Acid Sequence↗
Melanocortin receptors and antagonists regulate pigmentation and body weight.
The action two genetic loci--agouti and the melanocortin receptor-1 (Mc1r)-- have opposing effects in the control of mammalian pigmentation and ultimately determine the color of the pigment produced. In a recent paper, Ollmann et al. confirmed that the agouti protein acts via the Mc1r. They show that high-affinity binding of the agouti protein to Mc1r expressed in mammalian cells can be inhibited by the receptor's natural ligand, alpha-melanocyte-stimulating hormone (alpha-MSH). In addition, genetic studies using mice carrying mutations at the Mc1r and agouti loci on a sensitized background of low tyrosinase expression confirm that a functional Mc1r is required for the maximum pigmentary effect of agouti. Thus, the Mc1r appears to be a unique, bifunctionally controlled receptor, activated by alpha-MSH and antagonized by agouti, both of which contribute to the variability seen in mammalian coat color.
Agouti Signaling Protein↗
White-based brown (Tyrp1B-w) is a dominant mutation causing reduced hair pigmentation owing to a chromosomal inversion.
Explore the source record for details and available documents.
Animals↗
Acute pain services: a 24-h commitment.
Explore the source record for details and available documents.
Acute Disease↗
Melanocortin 1 receptor variants in an Irish population.
The identification of an association between variants in the human melanocortin 1 receptor (MC1R) gene and red hair and fair skin, as well as the relation between variants of this gene and coat color in animals, suggests that the MC1R is an integral control point in the normal pigmentation phenotype. In order to further define the contribution of MC1R variants to pigmentation in a normal population, we have looked for alterations in this gene in series of individuals from a general Irish population, in whom there is a preponderance of individuals with fair skin type. Seventy-five per cent contained a variant in the MC1R gene, with 30% containing two variants. The Arg151Cys, Arg160Trp, and Asp294His variants were significantly associated with red hair (p = 0.0015, p < 0.001, and p < 0.005, respectively). Importantly, no individuals harboring two of these three variants did not have red hair, although some red-haired individuals only showed one alteration. The same three variants were also over-represented in individuals with light skin type as assessed using a modified Fitzpatrick scale. Despite these associations many subjects with dark hair/darker skin type harbored MC1R variants, but there was no evidence of any particular association of variants with the darker phenotype. The Asp294His variant was similarly associated with red hair in a Dutch population, but was infrequent in red-headed subjects from Sweden. The Asp294His variant was also significantly associated with nonmelanoma skin cancer in a U.K. population. The results show that the Arg151Cys, Arg160Trp, and Asp294His variants are of key significance in determining the pigmentary phenotype and response to ultraviolet radiation, and suggest that in many cases the red-haired component and in some cases fair skin type are inherited as a Mendelian recessive.
Adult↗
Activation of the receptor tyrosine kinase Kit is required for the proliferation of melanoblasts in the mouse embryo.
The development of neural crest-derived melanocytes, as well as haematopoietic and germ cells, is affected by mutations of the Kit and Mgf genes, which lead to dominant spotting (W) or steel (Sl) phenotypes. Mgf codes for the ligand of the receptor tyrosine kinase encoded by the Kit locus. KitW-v, a point mutation exerting a dominant negative effect, causes a substantial reduction in tyrosine kinase activity of the Kit receptor and leads to a characteristic pigmentation phenotype, namely dilute coat colour and a white ventral and head spot with reduced pigmentation of the feet and tail in the heterozygous animal, as well as slight anaemia. Homozygous animals lack coat pigmentation and are severely anaemic and infertile. Dct is a marker for cells of the melanoblast lineage. In order to study these cells in detail we have generated transgenic mouse lines carrying the lacZ reporter under the control of the Dct promoter and have used the embryonic expression of the reporter to identify early melanoblasts before they begin to produce pigment. Our transgenic lines have simplified the study of melanoblasts in the mouse embryo, and by crossing our mice with KitW-v mutants we have been able to identify the midgestation stages at which melanoblasts rely critically on Mgf/Kit interactions. We conclude that the survival of immature melanoblasts depends crucially upon Kit signalling up until E11, and later in development Kit plays a vital role in melanoblast proliferation. Our data do not describe a dependence upon Kit for melanoblast migration or differentiation.
Animals↗
Sooty foot, a novel mouse mutation that affects the pigmentation of exposed skin, but not hair, maps to chromosome 2.
We have characterized a novel recessive mouse mutation, named sooty foot, that increases the pigmentation of the exposed skin on the foot pads, the genital region, around the snout and muzzle, the ears, and the tail. By contrast, the pigmentation of the hair is unaffected. We have localized the mutation to Chromosome 2 by polymerase chain reaction (PCR) amplification of simple sequence repeats from pooled DNA from backcross progeny. In an extended backcross we have generated a detailed map of the region around sooty foot.
Agouti Signaling Protein↗
Homologous pigmentation mutations in human, mouse and other model organisms.
Mouse coat colour genes have long been studied as a paradigm for genetic interactions in development. A number of these genes have been cloned and most correspond to human genetic disease loci. The proteins encoded by these genes include transcription factors, receptor tyrosine kinases and growth factors, G-protein coupled receptors and their ligands, membrane proteins, structural proteins and enzymes. Many of the mutations have pleiotropic effects, indicating that these proteins play a wider role in developmental or cellular processes. In this review I tabulate the available data on all pigmentation genes cloned from mouse or human, and I focus on three particular systems. One family of genes, including LYST and HPS/ep, shows the relationship between melanosomes and lysosomes. The G-protein coupled receptor, endothelin receptor-B, and its ligand, endothelin-3, are required for the development of both melanocytes and enteric neurons. The melanocortin-1 receptor is expressed only on melanocytes, but mutations that cause overexpression of agouti protein, an antagonist of the receptor, result in obesity, and highlight a role of melanocortins in weight homoeostasis.
Agouti Signaling Protein↗
Mapping in the region of Danforth's short tail and the localization of tail length modifiers.
We have used an interspecific backcross to generate a detailed genetic map around the mouse tail and kidney developmental mutation Danforth's short tail (Sd). The map includes 14 simple sequence repeat (SSR) markers and four genes in a 5-cM region encompassing Sd. In addition we have used a DNA pooling approach to carry out a genome scan to localize quantitative trait loci (QTL) that modify the tail length of Sd progeny of the backcross. This has allowed us to identify a major QTL on chromosome 10 in the region of nodal and three other putative tail length QTL on chromosomes 1, 9, and 18.
Alleles↗
The Asp84Glu variant of the melanocortin 1 receptor (MC1R) is associated with melanoma.
Melanocyte stimulating hormone (MSH) plays an important role in determining the cutaneous response to ultraviolet radiation and may also influence melanoma progression. We have previously shown that variants of the melanocortin receptor present on melanocytes, MC1R, are associated with sun sensitivity and red hair in a UK population and therefore now consider the gene as a candidate for melanoma susceptibility. We have compared the frequency of known MC1R variants in the second and seventh transmembrane domains in 43 melanoma cases and 44 controls. MC1R variants were more common in cases than controls (chi 2 = 6.75, 1 d.f.; P = 0.0094) with a relative risk to carriers of variant alleles compared with normal homozygotes of 3.91 (95% c.l.: 1.48-10.35), and a population risk attributable to carriers of 34.6% (95% c.i. 10.7-52.1%). The Asp84Glu variant was only present in melanoma cases and appears to be of particular significance. The contribution of variant MC1R alleles was largely independent of skin type. Variants of the MC1R gene are likely to be causally associated with the development of melanoma.
Alleles↗
The retinal pigmented epithelium is required for development and maintenance of the mouse neural retina.
BACKGROUND: During development of the vertebrate eye, there is a series of reciprocal cellular interactions that determine the fate of the eye components. Although evidence from organ culture suggests that the retinal pigmented epithelium (RPE) organizes the laminar structure of the differentiated neural retina, no role has been identified for the RPE in early eye development, nor has the later function of RPE been demonstrated in vivo. RESULTS: To investigate the role of RPE cells in eye development, we generated transgenic mice that carry the attenuated diphtheria toxin-A gene; this transgene was driven by the promoter of the gene encoding the tyrosinase-related protein-1, which is specifically expressed in pigment cells. Depending on the expression level of the transgene, the retinal epithelium was ablated before or after its differentiation into a pigmented cell layer. We show that an early ablation (embryonic day E10-11) resulted in disorganization of the retinal layer, immediate arrest of eye growth and subsequent eye resorption. A later ablation (E11.5-12.5) allowed the eye to be maintained during embryogenesis, but the laminar structure of the retina became disrupted by the end of gestation, the vitreous failed to accumulate the adults were anophthalmic or severely microphthalmic. In some microphthalmic eyes, a number of RPE cells escaped ablation and formed patches of pigmented cells; the laminar structure of the retina was maintained immediately adjacent to such pigmented areas but disrupted elsewhere. In both cases--early or late ablation of the RPE--the retina appears to be the primary affected tissue. CONCLUSIONS: We conclude that presence of the RPE is required for the normal development of the eye in vivo. Its presence early in development is necessary for the correct morphogenesis of the neural retina. After the neural retina has started to differentiate, the RPE is still necessary, either directly or indirectly, to maintain the organization of the retinal lamina.
Animals↗
Structure of the mouse tyrosinase-related protein-2/dopachrome tautomerase (Tyrp2/Dct) gene and sequence of two novel slaty alleles.
We have isolated the eight exons and 5' and 3' flanking regions of the mouse tyrosinase-related protein-2 (dopachrome tautomerase) gene (Tyrp2/Dct), which is mutated in slaty mice. The gene has a structure that is considerably different from those of other tyrosinase family members in both the number and the position of introns, consistent with the suggestion that the divergence of the family represents an ancient gene duplication. We also identify in the 5' flanking DNA an 11-bp element, the M-box, conserved in other tyrosinase family genes. We have characterized point mutations in two slaty alleles recently identified at the Jackson Laboratory: slaty-2J (slt2J) has a similar phenotype to the original slaty (slt) mutation, and slaty light (Sltlt), which has a more severe effect and is semidominant. We suggest that the slaty-light phenotype is a result of the failure of the enzyme to be correctly targeted to its normal location on the inner face of the melanosomal membrane.
Alleles↗
Peroxidase activity in the ink gland of Sepia officinalis and partial nucleotide sequence of a candidate cDNA encoding the enzyme.
A peroxidase was partially purified from the ink gland of the cuttlefish Sepia officinalis. This enzyme acts on guaiacol and I- as substrates and is inhibited by cyanide and azide. By using the PCR technique we have isolated and sequenced a cDNA clone encoding a protein homologous to other animal peroxidases. These results are discussed in relation to the possible involvement of peroxidase in the biosynthesis of melanin.
Amino Acid Sequence↗
A high-resolution map of the brown (b, Tyrp1) deletion complex of mouse chromosome 4.
For over 40 years germ-cell mutagenesis experiments have generated many new mutations at the brown (b or Tyrp1) locus on mouse Chromosome (Chr) 4. These mutations, many of which are deletions, were recovered by the specific-locus mutagenesis technique. Previous analysis of a panel of brown deletions, generated at Oak Ridge, has enabled both a preliminary molecular and a functional map around the locus to be generated. We have used a panel of hybrid DNA from 25 Oak Ridge deletions, where the deleted chromosome was heterozygous with a Mus spretus chromosome, to map polymorphic markers including microclones, microsatellites, and cloned DNA markers. We have generated a fine structure map, based on 25 new markers, of an 8.5-cM region surrounding the brown locus. This map will prove useful in future mapping studies of this region and in the isolation of the genes that lie within it.
Animals↗
Mutations at the W locus affect survival of neural crest-derived melanocytes in the mouse.
The development of melanoblasts in normally pigmented and dominant spotting (W) embryos was followed by in situ hybridisation to TRP-2/DT mRNA, which labels migratory melanoblasts from 10 days post coitum. Numerous melanoblasts migrate to the inner ear around 11 days. In contrast, few migratory melanoblasts are associated with the eye or skin at this stage and melanoblasts distribution within the trunk and tail is patchy. The distribution of melanoblasts in 10.5-11-day-old Wv/Wv, Wsh/Wsh and W41/W41 mutants was similar to that in controls but melanoblasts density was lower and by 12 days was severely reduced. These results suggest that mutations of the c-kit receptor tyrosine kinase encoded at the W locus do not alter early migration or differentiation of melanoblasts but severely affect melanoblasts survival.
Alleles↗
Molecular characterization of a human tyrosinase-related-protein-2 cDNA. Patterns of expression in melanocytic cells.
Pigmentation in mammals is under complex genetic control. Amongst the genes involved in this process, those encoding tyrosinase and the tyrosinase-related-proteins 1 and 2 have been well characterized and share a number of features. Recently, the murine tyrosinase-related-protein-2 gene was shown to encode dopachrome-tautomerase activity and was mapped to the slaty locus. Human tyrosinase and tyrosinase-related-protein-1 genes have been isolated and demonstrate a high degree of similarity with their murine counterparts. However, there has been limited data regarding the existence of a human homologue for tyrosinase-related-protein-2 and its relationship to the other tyrosinase-related proteins. In this study, we report the molecular isolation of a cDNA encoding a human homologue of the murine tyrosinase-related-protein-2/dopachrome tautomerase. We have characterized its expression in human melanocytic cells and have analyzed the relationship between dopachrome tautomerase and tyrosinase activities with the level of visible pigmentation in these cells. TYRP2 has been mapped to the chromosomal region 13q32, thus extending a region of synteny with mouse-chromosome 14.
Animals↗