Analysis of genetic variant in a case of sporadic neurofibromatosis type I with alopecia areata and vitiligo / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a patient with clinically suspected neurofibromatosis type I, alopecia areata and vitiligo.@*METHODS@#Variant of the NF1 gene was detected by chip capture and high-throughput sequencing. Candidate variant was verified by Sanger sequencing of the family trio.@*RESULTS@#The patient was found to harbor a novel missense c.1885G>A (p.Gly629Arg) variant of the NF1 gene, for which neither parent was carrier. The variant was not recorded in the public database. Based on the guidelines for genetic variation of the American College of Medical Genetics and Genomics, the c.1885G>A missense variant was predicted to be pathogenic (PS1+PS2+PM2+PP3+PP4).@*CONCLUSION@#The c.1885G>A missense variant probably underlay the disease in this child. Above finding has enriched the spectrum of the NF1 gene variants.

Critical role of metabotropic glutamate receptor 4 in bone marrow-derived dendritic cells in the Th17 cell differentiation and the melanogenesis of B16 cells

Vitiligo is an acquired pigmentary disorder resulting from selective destruction of melanocytes. Emerging studies have suggested that T helper cell 17 (Th17) is potentially implicated in vitiligo development and progression. It was recently discovered that metabotropic glutamate receptor 4 (mGluR4) can modulate Th17-mediated adaptive immunity. However, the influence of mGluR4 on melanogenesis of melanocytes has yet to be elucidated. In the present study, we primarily cultured mouse bone marrow-derived dendritic cells (BMDC) and then knocked down and over-expressed mGluR4 using transfection. Transduced BMDC were co-cultured with CD4+ T cells and the expression of Th17-related cytokines were measured. The morphology and melanogenesis of B16 cells were observed after being treated with co-culture medium of CD4+ T cells and transduced BMDC. We found that mGluR4 knockdown did not affect the co-stimulatory CD80 and CD86 upregulation after lipopolysaccharide stimulation but did increase the expression of Th17-related cytokines, and further down-regulated the expression of microphthalmia-associated transcription factor (MITF) and the downstream genes, decreased melanin production, and destroyed the morphology of B16 cells. Conversely, over-expression of mGluR4 reduced the expression of CD80 and CD86, suppressed the production of Th17-related cytokines, increased the expression of MITF, and did not destroy the morphology of B16 cells. Our study confirmed that mGluR4 modulated the Th17 cell polarization and resulted in the alteration of melanogenesis and morphology of B16 cells. Collectively, these findings suggest mGluR4 might be a potent target involved in the immune pathogenesis of vitiligo.

Evaluation of skin expression profiles of patients with vitiligo treated with narrow-band UVB therapy by targeted RNA-seq

Abstract: Background: Vitiligo is characterized by a lack of pigmentation in the skin. To date, there are no studies that analyze the changes in gene expression in the skin of vitiligo patients in response to narrow-band ultraviolet B (nb-UVB) phototherapy treatment. Objective: Explore the usefulness of new generation RNA sequencing in the identification of gene expression changes in the skin of vitiligo patients treated with nb-UVB phototherapy. Methods: Four skin biopsies (4mm in diameter) were collected from 45 Mexican vitiligo vulgaris patients, 2 specimens before and 2 after treatment with nb-UVB phototherapy, obtained from pigmented and non-pigmented tissue. RNA extracted from the biopsies was analyzed using the Illumina TruSeq Targeted RNA Expression protocol to study the expression of genes that participate in pathways of skin homeostasis. The 2 groups were compared using Student's t-test and the Mann-Whitney U-test. Results: The expression analysis identified differences in 12 genes included in this study after comparing the samples obtained before and after treatment: 5 genes involved in skin pigmentation, 2 genes involved in apoptosis, 2 genes involved in cell survival, 2 genes involved in oxidative stress responses and 1 gene involved in signal transduction mechanisms (p<0.05). Study limitations: The small size of skin biopsies limits the amount of RNA obtained, the number of genes to be analyzed and the use of conventional techniques such as RT-qPCR. Conclusion: We demonstrated usefulness of new generation RNA sequencing in the identification of gene expression changes, in addition to identifying new targets in the study of vitiligo.

Vitiligo patients show significant up-regulation of aryl hydrocarbon receptor transcription factor

Abstract: IL-22 has been implicated in the pathogenesis of vitiligo. However, the role of aryl hydrocarbon receptor transcription factor that acts as a master regulator of IL-22-producing Th22 cells is not fully understood. The goal of this study was to investigate the expression pattern of aryl hydrocarbon receptor in peripheral blood mononuclear cells of patients with vitiligo and in normal controls. Transcript levels were determined by a reverse transcription quantitative real-time polymerase chain reaction. Aryl hydrocarbon receptor mRNA expression was drastically increased in patients with vitiligo compared to healthy controls (P = 0.000). Th22 cells may contribute to abnormal immune responses underlying vitiligo.

A study of the association of glutathione S-transferase M1/T1 polymorphisms with susceptibility to vitiligo in Egyptian patients

Abstract: Background: The association of glutathione S-transferases M1/T1 (GSTM1/T1) null polymorphisms with vitiligo was proposed in several studies including two Egyptian studies with contradictory results. Objective: The aim here was to assess the association between GSTM1/T1 null polymorphisms and the susceptibility to vitiligo in a larger sample of Egyptian patients with generalized vitiligo. Methods: This study included 122 vitiligo patients and 200 healthy controls that were age, and gender matched. Assessment of GSTM1/T1 gene polymorphisms was done using a multiplex polymerase chain reaction (PCR). Results: Increased odds of generalized vitiligo was observed with the null genotypes of GSTM1 and GSTT1 polymorphisms (P<0.05). Controls with GSTM1 null/GSTT1+ heterozygosis presented with a 2.97 odds protection from having generalized vitiligo (OR=2.97, 95%CI=1.1-7.7) (P=0.02) compared with patients. Study Limitations: Small sample size of patients. Conclusions: This study showed a significant trend towards an association with the combination of the GSTM1/GSTT1 double null polymorphism and generalized vitiligo. Individuals with GSTM1 null/GSTT1+ heterozygosis have a 2.97 odds protection from having generalized vitiligo compared with patients. It was is the first time, to our knowledge, that such an association has been reported.

Vitiligo - Part 1

Vitiligo is a chronic stigmatizing disease, already known for millennia, which mainly affects melanocytes from epidermis basal layer, leading to the development of hypochromic and achromic patches. Its estimated prevalence is 0.5% worldwide. The involvement of genetic factors controlling susceptibility to vitiligo has been studied over the last decades, and results of previous studies present vitiligo as a complex, multifactorial and polygenic disease. In this context, a few genes, including DDR1, XBP1 and NLRP1 have been consistently and functionally associated with the disease. Notwithstanding, environmental factors that precipitate or maintain the disease are yet to be described. The pathogenesis of vitiligo has not been totally clarified until now and many theories have been proposed. Of these, the autoimmune hypothesis is now the most cited and studied among experts. Dysfunction in metabolic pathways, which could lead to production of toxic metabolites causing damage to melanocytes, has also been investigated. Melanocytes adhesion deficit in patients with vitiligo is mainly speculated by the appearance of Köebner phenomenon, recently, new genes and proteins involved in this deficit have been found.

Three New Single Nucleotide Polymorphisms Identified by a Genome-Wide Association Study in Korean Patients with Vitiligo

Genetic susceptibility is involved in the pathogenesis of vitiligo. Association studies with a whole genome-based approach instead of a single or a few candidate genes may be useful for discovering new susceptible genes. Although the etiology of non-segmental and segmental types is different, the association between gene polymorphisms and vitiligo has been reported, without defining types or in non-segmental type. Whole genome-based single nucleotide polymorphisms (SNPs) were examined in patients with non-segmental and segmental types of vitiligo using the Affymetrix GeneChip 500K mapping array, and 10 functional classes of significant SNPs were selected. Genotyping and data analysis of selected 10 SNPs was performed using real-time PCR. Genotype and allele frequencies were significantly different between both types of vitiligo and three of the target SNPs, DNAH5 (rs2277046), STRN3 (rs2273171), and KIAA1005 (rs3213758). A stronger association was suggested between the mutation in KIAA1005 (rs3213758) and the segmental type compared to the non-segmental type of vitiligo. DNAH5 (rs2277046), STRN3 (rs2273171), and KIAA1005 (rs3213758) may be new vitiligo-related SNPs in Korean patients, either non-segmental or segmental type.

Piebaldism and vitiligo in two brothers

Piebaldism is an autosomal dominant uncommon [<1 in 20,000] congenital pigmentary disorder. Depigmented patches are present since birth. They usually remain unchanged throughout life. Vitiligo is its closest differential diagnosis. We report a unique family in which these two dissimilar depigmentations, i.e. piebaldism and vitiligo [with nevus depigmentosus], were noted in two brothers. To the best of our knowledge, this is the first report of this presentation in the literature

Vitiligo: pathomechanisms and genetic polymorphism of susceptible genes.

Vitiligo is a depigmenting disorder resulting from the loss of melanocytes in the skin and affects 1-4% of the world population. Incidence of vitiligo is found to be 0.5-2.5% in India with a high prevalence of 8.8% in Gujarat and Rajasthan states. The cellular and molecular mechanisms that lead to melanocyte destruction in this disorder are not yet been fully elucidated. Genetic factors, neural factors, toxic ROS metabolites, autoantibodies and autoreactive T lymphocytes may be the causative agents for the selective destruction of melanocytes. Three major hypotheses of pathogenesis of vitiligo are neural, autoimmune and oxidative stress hypotheses, however none of them explains the pathogenesis of vitiligo in toto. Genetics of vitiligo is characterized by incomplete penetrance, multiple susceptibility loci and genetic heterogeneity. Recent advances in this field are linkage and association of candidate gene studies. The linkage and association studies provide a strong evidence for the presence of multiple vitiligo susceptibility genes on different chromosomes. Several candidate genes for vitiligo are identified from different populations. In this review, we have provide an overview of different hypotheses of vitiligo pathogenesis, and discuss the recent advances in this field with special reference to linkage, association and candidate gene approach.

Estudo clínico dos pacientes portadores de vitiligo no Serviço de Dermatologia do HU-UFJF / Clinical study of patients with vitiligo in the dermatology department of HU-UFJF

Os autores apresentam um estudo clínico dos pacientes portadores de vitiligo no Serviço de Dermatologia do Hospital Universitário da UFJF. Foram cadastrados 40 pacientes, no período compreendido entre março de 2000 a março de 2001. Foram avaliados dados referentes à idade do início da enfermidade, característica inicial, doenças associadas, fatores precipitantes, peliose, fenômeno de Koebner, história familiar, classificação e terapêutica.

Avaliaçäo da funçäo tireóidea e presença de anticorpos antitireóideos em crianças com vitiligo / Evaluation of thyroid function and the presence of thyroid antibodies in children with vitiligo

Uma amostra de 32 crianças e adolescentes portadoras de vitiligo localizado ou generalizado, foi avaliada para a presença de história familiar de doenças auto-imunes, disfunçäo tireóidea e presença de anticorpos antitireóideos. História familiar para tireoidopatia foi encontrada em 15,6 por cento do total da amostra e para vitiligo em 18,7 por cento. A funçäo tireóidea, avaliada através das dosagens de T3, T4 e TSH medidos por quimioluminescência, foi normal em todos os casos. Os anticorpos antitireoglobulina e antiperoxidase foram positivos em, respectivamente, 2 pacientes (6,25 por cento) e 8 pacientes (25 por cento). Concluiu-se pela alta frequência de anticorpos antitireóideos em crianças com vitiligo, o que sugere a necessidade de avaliaçäo tireóidea inicial destas crianças e posterior acompanhamento, com a finalidade de detecçäo precoce de disfunçäo tireóidea clínica ou subclínica

review: Pathogenesis of vitiligo

Vitiligo is a disease of unknown etiology characterized by depigmentation of the skin secondary to the local destruction of melanocytes. In this review of the pathogenesis of vitiligo, information has been assimilated from clinical studies, histologic features, genetic studies, tissue culture experiments, animal models and therapeutic studies in an attempt to enhance our understanding of its pathogenesis. It is clear that there is no single hypothesis to unify all the observations. Postulated mechanisms of the neuro-chemical theory, self-destructive and immune theories seem to act cooperatively. The extent of the role played by each may vary from one patient to the other. It appears that most patients produce an anti-melanocyte antibody. However, a significant number of patients produce other autoantibodies and have ocular problems. There are very important lacunae in the present understanding of the pathogenesis of vitiligo. We anticipate that the new techniques of molecular biology will significantly enhance the understanding of this ancient disease