Richard Spritz

..Generalized vitiligo is an autoimmune disease characterized by melanocyte loss, which results in patchy depigmentation of skin and hair, and is associated with an elevated risk of other autoimmune diseases...

..In contrast to unstructured gene lists, these networks often represent coherent functional groupings...

..Recent discoveries show that several of these mutations directly affect components in the pathway of organelle-specific protein trafficking, and provide new insights into the relationships of these pathways in mammals, flies and yeast...

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..It is anticipated that the discovery of biological pathways of vitiligo pathogenesis will provide novel targets for future approaches to the treatment and prevention of vitiligo and its associated autoimmune diseases...

..To investigate the pattern and distribution of nonsyndromic orofacial clefts among patients in the Rift Valley region of northwestern Kenya...

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..Our understanding of disorders of pigmentation indicates that these diseases may be most usefully considered as abnormalities of melanocyte development, function, or survival...

..These results suggest that genomic analysis of families with generalized vitiligo and this specific constellation of associated autoimmune disorders will be important to identify the mechanisms of genetic susceptibility to autoimmunity...

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..To characterize the epidemiology and genetics of vitiligo and associated autoimmune diseases in a population isolate in Romania in which there is a high frequency of these diseases...

..Our results indicate that the association of CTLA4 with vitiligo is weak, and indeed may be secondary, driven by primary genetic association of CTLA4 with other autoimmune diseases that are epidemiologically associated with vitiligo...

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..These findings have important implications for autoimmune disease surveillance in families in which multiple members are affected with vitiligo...

..These support the validity of the chromosomes 7 and 9 linkage/association signals and underscore the utility of gene-gene interaction analysis in characterizing the genetic effects of candidate association signals...

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..04x10(-8)) and with variants at 6q27 encompassing CCR6 (rs6902119, combined P=3.94x10(-7))...

..An additional seven signals, on chromosomes 1, 7, 8, 11, 19, and 22, met genomewide criteria for "suggestive linkage," and will thus be of particular importance for follow-up studies...

..The group includes various combinations of generalized vitiligo, autoimmune thyroid disease, latent autoimmune diabetes in adults, rheumatoid arthritis, psoriasis, pernicious anemia, systemic lupus erythematosus, and Addison's disease...

..Overall, our results indicate that specific MHC-linked genetic variation contributes to risk of familial vitiligo, although HLA does not completely explain familial clustering of vitiligo-associated autoimmune/autoinflammatory diseases...

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..This study demonstrates that, contrary to long-held clinical lore, OCA1, not OCA2, is by far the most frequent cause of OCA among Caucasian patients...

..00. SMOC2 encodes a modular extracellular calcium-binding glycoprotein of unknown function. Our findings indicate that SMOC2 is a risk locus for generalized vitiligo and perhaps other autoimmune diseases...

..These results implicate PTPN22 in mediating susceptibility to generalized vitiligo and associated autoimmune diseases, but do not support a role for CTLA4...

..20 compared with individuals carrying a high-risk allele from only one signal. These findings support the involvement of NALP1 in predisposition to generalized vitiligo...

..The purpose of this study was to characterize the relative prevalence of different genetic forms of AROA, and to characterize a sample repertoire of gene mutations in a large series of Caucasian patients with AROA...

..In the cytosol, HPS1 (but not HPS4) is part of yet another complex, termed BLOC-5. We propose that the BLOC-3 and BLOC-4 HPS1.HPS4 complexes play a central role in trafficking cargo proteins to newly formed cytoplasmic organelles...

..These findings indicate that some cases of human piebaldism result from mutation of the SLUG gene on chromosome 8, and provide further strong evidence for the role of SLUG in the development of human melanocytes...

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..Thus, we have found that the Slc7a11 gene controls the production of pheomelanin pigment directly. Cells from sut mice provide a model for oxidative stress-related diseases and their therapies...

..In addition, the HPS1 protein is absent in tissues of le mutant mice. These results suggest that the HPS4 and HPS1 proteins may function in the same pathway of organelle biogenesis...

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..VPS33A thus is a good candidate gene for a previously uncharacterized form of human HPS...

..Both genes are previously unknown and are found only in higher eukaryotes, and together represent a new class of genes that have evolved in higher organisms to govern the synthesis of highly specialized lysosome-related organelles...

..Unlike HPS or CHS genes, it has no apparent effect on other lysosome-related organelles such as melanosomes or lysosomes. The ash-Roswell mouse mutant is an appropriate model for human congenital-isolated delta-storage pool deficiency...

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..We will apply state-of-art bioinformatics tools to analyze and interpret the data, all of which we will deposit in appropriate public data repositories. ..

..Together, these studies should provide a greatly improved understanding of the molecular pathogenesis of oculocutaneous and ocular albinism. ..

..The long-term significance of this work may be to develop specific approaches to disease therapy and prevention and to apply those modalities to patients at high genetic risk. ..

..We will apply state-of-art bioinformatics tools to analyze and interpret the data, ali of which we will deposit in appropriate public data repositories. ..

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..The long-term goal of these studies is improve understanding of disease pathogenesis to facilitate developing novel treatments for vitiligo and perhaps other autoimmune diseases. ..

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..The third specific aim is to map and positionally clone a novel major human OCA locus, and to carry out eventual mutational and functional analyses of this gene and its polypeptide. ..

..The last aim is to initiate studies to determine the function of the ED4 gene. ..

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