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      Inactivation of Pmel Alters Melanosome Shape But Has Only a Subtle Effect on Visible Pigmentation

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          Abstract

          PMEL is an amyloidogenic protein that appears to be exclusively expressed in pigment cells and forms intralumenal fibrils within early stage melanosomes upon which eumelanins deposit in later stages. PMEL is well conserved among vertebrates, and allelic variants in several species are associated with reduced levels of eumelanin in epidermal tissues. However, in most of these cases it is not clear whether the allelic variants reflect gain-of-function or loss-of-function, and no complete PMEL loss-of-function has been reported in a mammal. Here, we have created a mouse line in which the Pmel gene has been inactivated ( Pmel −/−). These mice are fully viable, fertile, and display no obvious developmental defects. Melanosomes within Pmel −/− melanocytes are spherical in contrast to the oblong shape present in wild-type animals. This feature was documented in primary cultures of skin-derived melanocytes as well as in retinal pigment epithelium cells and in uveal melanocytes. Inactivation of Pmel has only a mild effect on the coat color phenotype in four different genetic backgrounds, with the clearest effect in mice also carrying the brown/Tyrp1 mutation. This phenotype, which is similar to that observed with the spontaneous silver mutation in mice, strongly suggests that other previously described alleles in vertebrates with more striking effects on pigmentation are dominant-negative mutations. Despite a mild effect on visible pigmentation, inactivation of Pmel led to a substantial reduction in eumelanin content in hair, which demonstrates that PMEL has a critical role for maintaining efficient epidermal pigmentation.

          Author Summary

          Pigmentation has since long constituted a prime model to study how genes act and interact. The PMEL gene encodes a protein exclusively found in the melanosomes of pigment-producing cells. Mutations in PMEL underlie some spectacular color phenotypes in animals including Dominant white color in chickens, Silver in horses, and Merle in dogs, but no spontaneous mutation causing a complete inactivation of this gene has yet been found in mammals. We have now developed a PMEL knockout mouse to further study the function of this protein. We show that mice lacking PMEL have almost normal visible pigmentation. However, loss of PMEL has a dramatic effect on the morphology of the melanosomes in skin, hair, and eye, such that the normally rod-shaped melanosomes in wild-type animals are spherical in the knockout mice. The knockout animals also have a substantial reduction in the content of black pigment in hair. The study establishes that PMEL has a critical role for maintaining normal pigment production.

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          Most cited references43

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          Derivation of completely cell culture-derived mice from early-passage embryonic stem cells.

          Several newly generated mouse embryonic stem (ES) cell lines were tested for their ability to produce completely ES cell-derived mice at early passage numbers by ES cell tetraploid embryo aggregation. One line, designated R1, produced live offspring which were completely ES cell-derived as judged by isoenzyme analysis and coat color. These cell culture-derived animals were normal, viable, and fertile. However, prolonged in vitro culture negatively affected this initial totipotency of R1, and after passage 14, ES cell-derived newborns died at birth. However, one of the five subclones (R1-S3) derived from single cells at passage 12 retained the original totipotency and gave rise to viable, completely ES cell-derived animals. The total in vitro culture time of the sublines at the time of testing was equivalent to passage 24 of the original line. Fully potent early passage R1 cells and the R1-S3 subclone should be very useful not only for ES cell-based genetic manipulations but also in defining optimal in vitro culture conditions for retaining the initial totipotency of ES cells.
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            The Mouse Genome Database (MGD): mouse biology and model systems

            The Mouse Genome Database, (MGD, http://www.informatics.jax.org/), integrates genetic, genomic and phenotypic information about the laboratory mouse, a primary animal model for studying human biology and disease. MGD data content includes comprehensive characterization of genes and their functions, standardized descriptions of mouse phenotypes, extensive integration of DNA and protein sequence data, normalized representation of genome and genome variant information including comparative data on mammalian genes. Data within MGD are obtained from diverse sources including manual curation of the biomedical literature, direct contributions from individual investigator's laboratories and major informatics resource centers such as Ensembl, UniProt and NCBI. MGD collaborates with the bioinformatics community on the development of data and semantic standards such as the Gene Ontology (GO) and the Mammalian Phenotype (MP) Ontology. MGD provides a data-mining platform that enables the development of translational research hypotheses based on comparative genotype, phenotype and functional analyses. Both web-based querying and computational access to data are provided. Recent improvements in MGD described here include the association of gene trap data with mouse genes and a new batch query capability for customized data access and retrieval.
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              Genome-wide association study identifies three loci associated with melanoma risk.

              We report a genome-wide association study of melanoma conducted by the GenoMEL consortium based on 317K tagging SNPs for 1,650 selected cases and 4,336 controls, with replication in an additional two cohorts (1,149 selected cases and 964 controls from GenoMEL, and a population-based case-control study in Leeds of 1,163 cases and 903 controls). The genome-wide screen identified five loci with genotyped or imputed SNPs reaching P < 5 x 10(-7). Three of these loci were replicated: 16q24 encompassing MC1R (combined P = 2.54 x 10(-27) for rs258322), 11q14-q21 encompassing TYR (P = 2.41 x 10(-14) for rs1393350) and 9p21 adjacent to MTAP and flanking CDKN2A (P = 4.03 x 10(-7) for rs7023329). MC1R and TYR are associated with pigmentation, freckling and cutaneous sun sensitivity, well-recognized melanoma risk factors. Common variants within the 9p21 locus have not previously been associated with melanoma. Despite wide variation in allele frequency, these genetic variants show notable homogeneity of effect across populations of European ancestry living at different latitudes and show independent association to disease risk.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Genet
                plos
                plosgen
                PLoS Genetics
                Public Library of Science (San Francisco, USA )
                1553-7390
                1553-7404
                September 2011
                September 2011
                15 September 2011
                : 7
                : 9
                : e1002285
                Affiliations
                [1 ]Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden
                [2 ]Department of Pathology and Laboratory Medicine, Department of Physiology, and Cell and Molecular Biology Graduate Group, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
                [3 ]Department of Neuroscience, Uppsala University, Uppsala, Sweden
                [4 ]Institut Curie, Centre de Recherche, CNRS, UMR144, Structure and Membrane Compartments, PICT IBiSA, Paris, France
                [5 ]Center for Hearing and Communication Research and Department of Clinical Neuroscience, Intervention, and Technology, Karolinska Institutet, Stockholm, Sweden
                [6 ]Department of Veterinary Medicine and Surgery, College of Veterinary Medicine, University of Missouri–Columbia, Columbia, Missouri, United States of America
                [7 ]Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden
                [8 ]Department of Chemistry, Fujita Health University School of Health Sciences, Toyoake, Japan
                [9 ]Department of Immunology, Genetics, and Pathology, Uppsala University, Uppsala, Sweden
                [10 ]Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, Uppsala, Sweden
                Medical Research Council Human Genetics Unit, United Kingdom
                Author notes

                Conceived and designed the experiments: ARH BW SSF DT PM KN BE SI KW JL MU KK GR SK FH MSM LA. Performed the experiments: ARH BW SSF DT PM KN BE SI KW JL. Analyzed the data: ARH BW SSF DT PM KN BE SI KW JL MU KK GR SK FH MSM LA. Wrote the paper: ARH MSM LA. Contributed to the manuscript: BW SSF DT PM KN BE SI KW JL MU KK GR SK FH.

                Article
                PGENETICS-D-11-00275
                10.1371/journal.pgen.1002285
                3174228
                21949658
                320d5391-3851-4fdb-9a88-6c95d26aba30
                Hellström et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 8 February 2011
                : 18 June 2011
                Page count
                Pages: 16
                Categories
                Research Article
                Biology
                Genetics
                Genetic Mutation
                Mutagenesis
                Animal Genetics
                Gene Function
                Model Organisms
                Animal Models
                Mouse

                Genetics
                Genetics

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