131 research outputs found
The genetics of generalized vitiligo: autoimmune pathways and an inverse relationship with malignant melanoma
Generalized vitiligo (GV) is the most common pigmentation disease, in which white spots of skin and overlying hair result from loss of melanocytes from the involved regions. GV is a complex disease involving both genetic predisposition and unknown environmental triggers. Whereas various pathogenetic mechanisms have been suggested, most evidence supports an autoimmune basis for this disease. Recently, three different genome-wide association studies of GV have been reported, identifying a total of 17 confirmed GV susceptibility loci. Almost all of these genes encode immunoregulatory proteins, together highlighting pathways by which melanocytes might be recognized and killed. Moreover, the biological interaction between two of these GV susceptibility genes, HLA-A and TYR (encoding tyrosinase), points to an apparent inverse relationship between susceptibility to GV versus malignant melanoma, suggesting that GV may result, in part, from dysregulation of normal processes of immune surveillance against melanoma
Comprehensive Analysis of Oculocutaneous Albinism among Non-Hispanic Caucasians Shows that OCA1 Is the Most Prevalent OCA Type
Oculocutaneous albinism (OCA) is a genetically heterogeneous group of disorders characterized by absent or reduced pigmentation of the skin, hair, and eyes. In humans, four genes have been associated with âclassicalâ OCA and another 12 genes with syndromic forms of OCA. To assess the prevalence of different forms of OCA and different gene mutations among non-Hispanic Caucasian patients, we performed DNA sequence analysis of the four genes associated with âclassicalâ OCA (TYR, OCA2, TYRP1, SLC45A2), the two principal genes associated with syndromic OCA (HPS1, HPS4), and a candidate OCA gene (SILV), in 121 unrelated, unselected non-Hispanic/Latino Caucasian patients carrying the clinical diagnosis of OCA. We identified apparent pathologic TYR gene mutations in 69% of patients, OCA2 mutations in 18%, SLC45A2 mutations in 6%, and no apparent pathological mutations in 7% of patients. We found no mutations of TYRP1, HPS1, HPS4, or SILV in any patients. Although we observed a diversity of mutations for each gene, a relatively small number of different mutant alleles account for a majority of the total. 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
Mutation and association analysis of the PVR and PVRL2 genes in patients with non-syndromic cleft lip and palate
Orofacial clefts (OFC; MIM 119530) are among the most common major birth defects. Here, we carried out mutation screening of the PVR and PVRL2 genes, which are both located at an OFC linkage region at 19q13 (OFC3) and are closely related to PVRL1, which has been associated with both syndromic and non-syndromic cleft lip and palate (nsCLP). We screened a total of 73 nsCLP patients and 105 non-cleft controls from the USA for variants in PVR and PVRL2, including all exons and encompassing all isoforms. We identified four variants in PVR and five in PVRL2. One non-synonymous PVR variant, A67T, was more frequent among nsCLP patients than among normal controls, but this difference did not achieve statistical significance
Linkage disequilibrium mapping of the gene for Hermansky-Pudlak syndrome to chromosome 10q23. 1-q23.3
Hermansky-Pudlak syndrome (HPS) is an autosomal recessive disorder characterized by the triad of tyrosinase-positive oculocutaneous albinism, bleeding diathesis due to storage-pool deficiency of platelets, and a lysosomal ceroid storage disease. The disorder is particularly frequent in Puerto Rico and in an isolated village in the Swiss Alps. We have used a linkage disequilibrium mapping approach to localize the HPS gene in both of these groups to a 0.6 centiMorgan interval in chromosome segment 10q23.1-q23.3. These results indicate that the Puerto Rican and Swiss forms of HPS are either allelic or that they result from mutations in very closely linked genes in this region. This region of distal chromosome 10q is syntenic to the region of mouse chromosome 19 that includes âpale ear' (ep) and âruby-eye' (ru), which must be considered as potential murine homologues to human HP
Organization and Nucleotide Sequence of the Human Hermansky-Pudlak Syndrome (HPS) Gene
Hermansky-Pudlak syndrome (HPS) is an autosomal recessive disorder characterized by oculocutaneous albinism, bleeding tendency, and lysosomal ceroid storage disease, associated with defects of multiple cytoplasmic organelles-melanosomes, platelet-dense granules, and lysosomes. HPS is frequently fatal and is the most common single-gene disorder in Puerto Rico. We previously characterized the human HPS cDNA and identified pathologic mutations in the gene in patients with HPS. The HPS protein is a novel apparent transmembrane polypeptide that seems to be crucial for normal organellar development. Here we describe the structural organization, nucleotide sequence, and polymorphisms of the human HPS gene. The gene consists of 20 exons spanning about 30.5kb in chromosome segment l0q23.1-q23.3. One of the intervening sequences is a member of the novel, very rare class of so-called âAT-ACâ introns, defined by highly atypical 5' and 3' splice site and branch site consensus sequences that provide novel targets for possible pathologic gene mutations. This information provides the basis for molecular analyses of patients with HPS and will greatly facilitate diagnosis and carrier detection of this severe disorder
The triennial International Pigment Cell Conference (IPCC)
The International Federation of Pigment Cell Societies (IFPCS) held its XXIII
triennial International Pigment Cell Conference (IPCC) in Denver, Colorado in
August 2017. The goal of the summit was to provide a venue promoting a vibrant
interchange among leading basic and clinical researchers working on
leading-edge aspects of melanocyte biology and disease. The philosophy of the
meeting, entitled Breakthroughs in Pigment Cell and Melanoma Research, was to
deliver a comprehensive program in an inclusive environment fostering
scientific exchange and building new academic bridges. This document provides
an outlook on the history, accomplishments, and sustainability of the pigment
cell and melanoma research community. Shared progress in the understanding of
cellular homeostasis of pigment cells but also clinical successes and hurdles
in the treatment of melanoma and dermatological disorders continue to drive
future research activities. A sustainable direction of the societies creates an
international forum identifying key areas of imminent needs in laboratory
research and clinical care and ensures the future of this vibrant, diverse and
unique research community at the same time. Important advances showcase wealth
and breadth of the field in melanocyte and melanoma research and include
emerging frontiers in melanoma immunotherapy, medical and surgical oncology,
dermatology, vitiligo, albinism, genomics and systems biology, precision
bench-to-bedside approaches, epidemiology, pigment biophysics and chemistry,
and evolution. This report recapitulates highlights of the federate meeting
agenda designed to advance clinical and basic research frontiers from melanoma
and dermatological sciences followed by a historical perspective of the
associated societies and conferences
Spatial and Temporal Analysis of Gene Expression during Growth and Fusion of the Mouse Facial Prominences
Orofacial malformations resulting from genetic and/or environmental causes are frequent human birth defects yet their etiology is often unclear because of insufficient information concerning the molecular, cellular and morphogenetic processes responsible for normal facial development. We have, therefore, derived a comprehensive expression dataset for mouse orofacial development, interrogating three distinct regions â the mandibular, maxillary and frontonasal prominences. To capture the dynamic changes in the transcriptome during face formation, we sampled five time points between E10.5âE12.5, spanning the developmental period from establishment of the prominences to their fusion to form the mature facial platform. Seven independent biological replicates were used for each sample ensuring robustness and quality of the dataset. Here, we provide a general overview of the dataset, characterizing aspects of gene expression changes at both the spatial and temporal level. Considerable coordinate regulation occurs across the three prominences during this period of facial growth and morphogenesis, with a switch from expression of genes involved in cell proliferation to those associated with differentiation. An accompanying shift in the expression of polycomb and trithorax genes presumably maintains appropriate patterns of gene expression in precursor or differentiated cells, respectively. Superimposed on the many coordinated changes are prominence-specific differences in the expression of genes encoding transcription factors, extracellular matrix components, and signaling molecules. Thus, the elaboration of each prominence will be driven by particular combinations of transcription factors coupled with specific cell:cell and cell:matrix interactions. The dataset also reveals several prominence-specific genes not previously associated with orofacial development, a subset of which we externally validate. Several of these latter genes are components of bidirectional transcription units that likely share cis-acting sequences with well-characterized genes. Overall, our studies provide a valuable resource for probing orofacial development and a robust dataset for bioinformatic analysis of spatial and temporal gene expression changes during embryogenesis
Frontiers in Pigment Cell and Melanoma Research
We identify emerging frontiers in clinical and basic research of melanocyte
biology and its associated biomedical disciplines. We describe challenges and
opportunities in clinical and basic research of normal and diseased melanocytes
that impact current approaches to research in melanoma and the dermatological
sciences. We focus on four themes: (1) clinical melanoma research, (2) basic
melanoma research, (3) clinical dermatology, and (4) basic pigment cell
research, with the goal of outlining current highlights, challenges, and
frontiers associated with pigmentation and melanocyte biology. Significantly,
this document encapsulates important advances in melanocyte and melanoma
research including emerging frontiers in melanoma immunotherapy, medical and
surgical oncology, dermatology, vitiligo, albinism, genomics and systems
biology, epidemiology, pigment biophysics and chemistry, and evolution
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