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PubMed1999

High polymorphism at the human melanocortin 1 receptor locus.

Variation in human skin/hair pigmentation is due to varied amounts of eumelanin (brown/black melanins) and phaeomelanin (red/yellow melanins) produced by the melanocytes. The melanocortin 1 receptor (MC1R) is a regulator of eu- and phaeomelanin production in the melanocytes, and MC1R mutations causing coat color changes are known in many mammals. We have sequenced the MC1R gene in 121 individuals sampled from world populations with an emphasis on Asian populations. We found variation at five nonsynonymous sites (resulting in the variants Arg67Gln, Asp84Glu, Val92Met, Arg151Cys, and Arg163Gln), but at only one synonymous site (A942G). Interestingly, the human consensus protein sequence is observed in all 25 African individuals studied, but at lower frequencies in the other populations examined, especially in East and Southeast Asians. The Arg163Gln variant is absent in the Africans studied, almost absent in Europeans, and at a low frequency (7%) in Indians, but is at an exceptionally high frequency (70%) in East and Southeast Asians. The MC1R gene in common and pygmy chimpanzees, gorilla, orangutan, and baboon was sequenced to study the evolution of MC1R. The ancestral human MC1R sequence is identical to the human consensus protein sequence, while MC1R varies considerably among higher primates. A comparison of the rates of substitution in genes in the melanocortin receptor family indicates that MC1R has evolved the fastest. In addition, the nucleotide diversity at the MC1R locus is shown to be several times higher than the average nucleotide diversity in human populations, possibly due to diversifying selection.

Alleles↗
PubMed1993

The embryonic lethality of homozygous lethal yellow mice (Ay/Ay) is associated with the disruption of a novel RNA-binding protein.

Lethal yellow (Ay) is a mutation at the mouse agouti (a) locus that is associated with an all-yellow coat color, obesity, diabetes, tumors in heterozygotes, and preimplantation embryonic lethality in homozygotes. Previously, we cloned and characterized the wild-type agouti gene and demonstrated that it expresses a 0.8-kb mRNA in neonatal skin. In contrast, Ay expresses a 1.1-kb transcript that is ectopically overexpressed in all tissues examined. The Ay mRNA is identical to the wild-type a transcript for the entire coding region, but the 5'-untranslated sequence of the a gene has been replaced by novel sequence. Here, we demonstrate that the novel 5' sequence in the Ay mRNA corresponds to the 5'-untranslated sequence of another gene that is normally tightly linked to a in mouse chromosome 2. This other gene (Raly) has the potential to encode a novel RNA-binding protein that is normally expressed in the preimplantation embryo, throughout development, and in all adult tissues examined. Importantly, the Ay mutation disrupts the structure and expression of the Raly gene. The data suggest that the Ay mutation arose from a DNA structural alteration that affects the expression of both agouti and Raly. We propose that the dominant pleiotropic effects associated with Ay may result from the ectopic overexpression of the wild-type a gene product under the control of the Raly promoter and that the recessive embryonic lethality may be the result of the lack of Raly gene expression in the early embryo.

Agouti Signaling Protein↗
PubMed1992

Traits that influence longevity in mice: a second look.

Analysis of genetic interactions in the F2 of an intercross of (C57BL/6 x DBA/2) F1J revealed influences of genetic factors on life span. Females lived longer than males. Dilute brown females died sooner than females of other colors. H-2b/H-2b males died sooner than H-2b/H-2d or H-2d/H-2d males, except that among dilute brown males those of typeH-2b/H-2d died sooner. Cluster analysis suggested that male and female genotypes each fall into two groups, with female dilute brown mice having shorter lives than other females, and male H-2b/H-2b mice except dilute brown and dilute brown H-2b/H-2d mice having shorter lives than other males. The association of heterozygosity with life span was clearer in females than in males, yet the longest-lived female genotype was homozygous H-2d/H-2d, of dominant Black phenotype at the Brown locus of chromosome 4, and homozygous dd at the Dilute locus of chromosome 9. The shortest-lived females were dilute brown H-2b/H-2b. The longest-lived and shortest-lived male genotypes were dilute brown H-2d/H-2d and dilute brown H-2b/H-2d, respectively. Although histological findings at postmortem differed between the sexes, there was no association of particular disorders with other genetic markers. The importance of H-2 in males was confirmed, but the allelic effects were perturbed, possibly by the absence of Sendai infection in this experiment. Overall our studies suggest that genetic influences on life span involve interactions between loci, and allelic interactions may change with viral infections or other environmental factors.

Animals↗
PubMed1994

Enhanced synthesis of metallothionein as a possible cause of abnormal copper accumulation in LEC rats.

Long-Evans rats with a cinnamon-like coat color (LEC) is an inbred strain accumulating copper (Cu) in the liver abnormally and showing spontaneous hepatitis and hepatoma. The present study was intended to clarify how Cu accumulates in the LEC rat liver. For this purpose, the distribution profiles of Cu and zinc (Zn) and the inducibility of metallothionein (MT) synthesis were examined in the liver between Cu-loaded Long Evans agouti (LEA, the original strain of LEC) rats and were compared with those in control LEC rats. LEA rats (female, five weeks old) were injected subcutaneously with CuCl2 daily at a dose of 3 mg Cu/kg body weight for 2, 4, 6, and 9 days. The concentration of Cu (124 micrograms/g) accumulated in the LEA rat liver after four injections was comparable to that in control LEC rats. Only 20% of Cu in the liver of LEA rats was recovered in the supernatant fraction in the form of MT, while Cu in the LEC rat liver (113 micrograms/g) was recovered mostly in the supernatant fraction, and was bound to MT. Although the increased concentration of Cu in the LEA rat liver was further elevated after additional injections of Cu, the amount of MT did not increase further. The MT mRNA content in the LEA rat liver remained lower than that of LEC rats even after further injections of Cu. Therefore, the present results suggest that LEC rats can accumulate Cu at a high concentration in the liver because of their extremely high inducibility of MT.

Animals↗
PubMed2005

Tyrosinase and tyrosinase related protein 1 alleles specify domestic cat coat color phenotypes of the albino and brown loci.

The genes encoding enzymes of the tyrosinase family are strong candidates for coat color variation in mammals. To investigate their influence in domestic cat coat color, we determined the complete nucleotide coding sequence of the domestic cat genes tyrosinase (TYR)--a plausible candidate gene for the albino (C) locus, and tyrosinase related protein 1 (TYRP1)--a candidate gene for the brown (B) locus. Sequence variants between individuals exhibiting variation in pigmentation were submitted to association studies. In TYR, two nonsynonymous substitutions encoding TYR-G301R and TYR-G227W were associated with the siamese and burmese phenotypes of the albino locus, respectively. TYRP1 was mapped on chromosome D4 within 5 cM of a highly polymorphic microsatellite, previously found to be fixed in a cat breed selected for the chocolate (b) allele of the B locus, which reinforced TYRP1 as a candidate gene for the B locus in the domestic cat. Two DNA polymorphisms, one leading to a TYRP1-A3G substitution in the signal peptide and another to an in-frame insertion TYRP1-421ins17/18 caused by a donor splice site mutation in intron 6, were associated with the chocolate (b) allele. A premature UAG stop codon at position 100 of TYRP1 was associated with a second allele of the B locus, cinnamon (b(l)). The results provide very strong evidence that the specific nucleotide variants of feline TYR (chromosome D1) are causative of the siamese (c(s)) and burmese (c(b)) alleles of the albino locus, as well as nucleotide variants of TYRP1 (chromosome D4) as specifying the chocolate (b) and cinnamon (b(l)) alleles of the B locus.

Albinism↗
PubMed1993

The mouse brown (b) locus protein has dopachrome tautomerase activity and is located in lysosomes in transfected fibroblasts.

Many genes mapping to pigmentation loci are involved in the regulation of melanin synthesis in the mouse. The brown (b) locus controls black/brown coat coloration, and its product has significant homology to the key melanogenic enzyme tyrosinase. This has led to suggestions that the b-protein is itself a melanogenic enzyme. In order to investigate its function, we have established lines of mouse fibroblasts stably expressing the b-protein by co-transfection of a b-protein expression vector and a plasmid conferring resistance to the antibiotic G418. The b-protein synthesised by these cells has the expected molecular mass of 75 kDa and reacts with three different anti-b-protein antibodies. We were unable to confirm previous reports that the b-protein has tyrosinase or catalase activity, but detected stereospecific dopachrome tautomerase activity in b-protein-expressing fibroblasts. This dopachrome tautomerase binds to Concanavalin A-Sepharose, and the major product of its action on L-dopachrome is 5,6-dihydroxyindole-2-carboxylic acid. Since this activity is not present in untransfected cells we conclude that the b-protein has dopachrome tautomerase activity. Fibroblasts do not contain melanosomes, the specialised organelles in which the b-protein is located in melanocytes. Nevertheless, indirect immunofluorescence localisation of the b-protein in transfected fibroblasts produces a distinctive pattern of intense juxtanuclear staining combined with punctate cytoplasmic staining. Double-labelling shows co-localisation of the b-protein with the late endosomal/lysosomal markers beta-glucuronidase and LAMP-1, both in transfected fibroblasts and in mouse melanoma cells. These findings are consistent with the hypothesis that melanosomes are closely related to lysosomes.

3T3 Cells↗
PubMed1981

Use of the mouse spot test in chemical mutagenesis: interpretation of past data and recommendations for future work.

The mouse spot test, developed 23 years ago, is an in vivo assay capable of detecting genetic effects of several kinds, including intragenic mutations, minute deficiencies, deletions (through breakage or nondisjunction) of various amounts of chromosomal material, and somatic crossing-over. The method involves exposing embryos that are heterozygous for a number of coat-color markers to the test agent, and, 3 weeks later, looking for clones of mutant cells, i.e., spots of color expressing the recessive marker in an otherwise black fur. Spots having other causes may also be induced, specifically white midventral spots due to cytotoxic effects, and certain spots resulting from misdifferentiation. Spot-test results have, to date, been reported from 7 laboratories. Because the control results for any one cross and solvent were found to be reasonably consistent between the laboratories, we pooled these to develop a "historical" control with which experimental results for the same cross and solvent were compared. Experimental results were classified as positive, negative, or inconclusive on the basis of a multiple-decision procedure produced by the testing of the following 2 hypotheses: (1) the mutation frequency (induced + spontaneous) in treated mice is not higher than the mutation frequency in the appropriate pooled control, and (2) the induced mutation frequency of the treated mice is no less than 4 times as high as the observed mutation frequency in the appropriate pooled control. Each hypothesis was tested at the 5% significance level. To date, 30 substances have been employed in the spot test, including 3 that are solvents for some of the others. Of the remaining 27 (26 compounds and 1 mixture), 16 were positive, 6 negative, and 5 inconclusive. The 26 compounds fell into 27 chemical classifications (using a system provided for use by the GENE-TOX program). The inadequacies in the design and reporting of some past experiments indicate a need for a carefully specified protocol. When properly done, the spot test will fulfill a useful role in mutagenicity testing programs because (1) it is an in vivo mammalian assay, (2) it detects genetic effects of many kinds, and (3) it is relatively rapid. Since the test appears well suited to the identification of potent mutagens, its main value should be in screening large numbers of substances and singling out the potentially worst offenders to be further studied in germ-line mutagenesis tests.

Animals↗
PubMed1997

Comparative action spectrum for ultraviolet light killing of mouse melanocytes from different genetic coat color backgrounds.

The photobiology of mouse melanocyte lines with different pigment genotypes was studied by measuring colony-forming ability after irradiation. The cell lines were wild-type black (melan-a) and the mutants brown (melan-b) and albino (melan-c). Four lamps emitting various UV wavelengths were used. These were germicidal (UVC, 200-280 nm), 82.3% output at 254 nm, TL01 (UVB, 280-320 nm), 64.2% at 310-311 nm, FS20, broadband with peak output at 312 nm and Alisun-S (UVA, 320-400 nm), broadband with peak output at 350-354 nm. Appropriate filtration reduced the contaminating UVC to nonlethal levels for the longer waverange lamps. Wild-type melan-a was resistant to UVC and UVA compared to the other two cell lines, but the differences were small. The melan-c cell line was more resistant to UVB and markedly more resistant to FS20 than the pigmented lines. With the exception of FS20 responses, melan-b was more sensitive than melan-a to killing by the various UV lamps. There were more pyrimidine dimers (cyclobutane dimers and 6-4 photoproducts) produced in melan-a than in melan-c cells by UVC, UVB and FS20 lamps. Unlike melan-c, melan-a and melan-b showed a strong free radical signal of melanin character with a detectable contribution of pheomelanin-like centers. The contribution of pheomelanin was higher in melan-b than in melan-a, while the total melanin content in these two cell lines was comparable. The abundant melanin granules of wild-type melan-a melanocytes were well melanized and ellipsoidal, whereas those of melan-b melanocytes tended to be spherical. In the albino line (melan-c) the melanocytes contained only early-stage melanosomes, all of which were devoid of melanin. The results indicate that pigment does not protect against direct effect DNA damage in the form of pyrimidine dimers nor does it necessarily protect against cell death. High pigment content is not very protective against killing by UVC and UVA, and it may photosensitize in UVB the very wavelength range that is of greatest concern with respect to the rising incidence in skin cancer, especially melanoma. It is clear from these studies that, in pigment cells, monochromatic results cannot predict polychromatic responses and that cell death from solar irradiations is a complex phenomenon that depends on more than DNA damage.

Animals↗
PubMed1999

Elejalde syndrome--a melanolysosomal neurocutaneous syndrome: clinical and morphological findings in 7 patients.

BACKGROUND: Silvery hair and severe dysfunction of the central nervous system (neuroectodermal melanolysosomal disease or Elejalde syndrome) characterize this rare autosomal recessive disease. Main clinical features include silver-leaden hair, bronze skin after sun exposure, and neurologic involvement (seizures, severe hypotonia, and mental retardation). Large granules of melanin unevenly distributed in the hair shaft are observed. Abnormal melanocytes and melanosomes and abnormal inclusion bodies in fibroblasts may be present. Differential diagnosis with Chédiak-Higashi syndrome and Griscelli syndrome must be done. OBSERVATIONS: We studied pediatric patients with silvery hair and profound neurologic dysfunction. Immune impairment was absent. Age of onset of neurologic signs ranged from 1 month to 11 years; the signs included severe muscular hypotonia, ocular alterations, and seizures. Mental retardation since the first months of life was noted in 4 cases. Psychomotor development was normal in 3 cases, but suddenly the patients presented with a regressive neurologic process. Four patients died between 6 months and 3 years after the onset of neurologic dysfunction. One patient showed characteristic ultrastructural findings of Elejalde syndrome. CONCLUSIONS: Elejalde syndrome is different from Chédiak-Higashi and Griscelli syndrome and is characterized by silvery hair and frequent occurrence of fatal neurologic alterations. Psychomotor impairment may have 2 forms of presentation: congenital or infantile. Although Elejalde syndrome and Griscelli syndrome are similar, the possibility that they are 2 different diseases, although probably allelic related, is suggested.

Central Nervous System Diseases↗
PubMed2005

The prevalence of common acquired melanocytic nevi and the relationship with skin type characteristics and sun exposure among children in Lithuania.

OBJECTIVE: To evaluate the prevalence of common acquired melanocytic nevi and its relationship with pigmentary characteristics and severe sunburns in children. DESIGN: Cross-sectional study. SETTING: Kaunas city, Lithuania (latitude of 55 degrees 55 minutes). PATIENTS: A random sample of 484 children aged 1 to 2 years, 4 to 5 years, and 9 to 10 years and adolescents aged 14 to 15 years. INTERVENTIONS: A questionnaire that provided information about the history of sunbathing and skin type. MAIN OUTCOME MEASURES: Atypical melanocytic nevi were defined according to the clinical criteria of the ABCDE rule. RESULTS: The median number of all common acquired melanocytic nevi was 12 in boys and 11 in girls; the median number of melanocytic nevi 2 mm or larger in boys and girls was 4. Twenty-seven percent of children experienced severe sunburns more than once. After adjustment for age and sex, it was found that children who had severe sunburns in summer and skin type I had a higher density of all melanocytic nevi and melanocytic nevi 2 mm or larger. The prevalence of atypical melanocytic nevi was 7% in all children and was age dependent (age 4-5 years, 1%; 9-10 years, 4%; 14-15 years, 16%). Three percent of children had congenital melanocytic nevi. CONCLUSIONS: The total number of common acquired melanocytic nevi in children increased with age. There was a positive association between severe sunburns, the tendency of the skin to burn, and the number of all melanocytic nevi and nevi 2 mm or larger.

Adolescent↗