Assuntos
Biomarcadores , Lentigo , MicroRNAs , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Lentigo/genética , MicroRNAs/genéticaRESUMO
Although the pathogenesis of solar lentigo (SL) involves chronic ultraviolet (UV) exposure, cellular senescence, and upregulated melanogenesis, underlying molecular-level mechanisms associated with SL remain unclear. The aim of this study was to investigate the gene regulatory mechanisms intimately linked to inflammation in SL. Skin samples from patients with SL with or without histological inflammatory features were obtained. RNA-seq data from the samples were analyzed via multiple analysis approaches, including exploration of core inflammatory gene alterations, identifying functional pathways at both transcription and protein levels, comparison of inflammatory module (gene clusters) activation levels, and analyzing correlations between modules. These analyses disclosed specific core genes implicated in oxidative stress, especially the upregulation of nuclear factor kappa B in the inflammatory SLs, while genes associated with protective mechanisms, such as SLC6A9, were highly expressed in the non-inflammatory SLs. For inflammatory modules, Extracellular Immunity and Mitochondrial Innate Immunity were exclusively upregulated in the inflammatory SL. Analysis of protein-protein interactions revealed the significance of CXCR3 upregulation in the pathogenesis of inflammatory SL. In conclusion, the upregulation of stress response-associated genes and inflammatory pathways in response to UV-induced oxidative stress implies their involvement in the pathogenesis of inflammatory SL.
Assuntos
Lentigo , Família Multigênica , Humanos , Inflamação/genética , Senescência Celular , Imunidade Inata , Lentigo/genéticaAssuntos
Antineoplásicos , Hiperpigmentação , Mesilato de Imatinib , Lentigo , Proteínas Proto-Oncogênicas c-kit , Humanos , Mesilato de Imatinib/uso terapêutico , Hiperpigmentação/genética , Hiperpigmentação/induzido quimicamente , Hiperpigmentação/patologia , Hiperpigmentação/tratamento farmacológico , Lentigo/genética , Lentigo/patologia , Proteínas Proto-Oncogênicas c-kit/genética , Feminino , Masculino , Inibidores de Proteínas Quinases/efeitos adversos , Pirimidinas/uso terapêutico , Adulto , Pessoa de Meia-IdadeAssuntos
População do Leste Asiático , Lentigo , Humanos , Lentigo/genética , Mutação , Fenótipo , Proteínas Supressoras de Tumor , Masculino , Pré-Escolar , CriançaRESUMO
Lentigines are well-defined, small, brown macules resulting from the accumulation of melanin content in the basement membrane zone with an increase in the number of melanocytes. Hereditary multiple lentigines (ML) can be associated with multiple genes and are not commonly encountered in clinical practice. Patients can solely have skin involvement or present with multisystemic deformative phenotypes. This study aimed to describe four unrelated Chinese families presenting with ML as their first visit symptom. We performed whole-exome sequencing (WES) and Sanger sequencing on all patients and immediate family members for precise molecular diagnosis. Two novel variants c.1548 T > A (p.Ser516Arg) and c.1811C > A (p.Thr604Lys) in SASH1, and two recurrent variants c.1403C > T (p.Thr468Met) and c.1493G > T (p.Arg498Leu) in PTPN11, were identified in these four families. We also summarized the genes associated with ML and differential diagnosis of pigment abnormality. We suggested that the molecular diagnosis of ML should be emphasized because it can help in the clinical differential diagnosis and further genetic counseling and prognosis.
Assuntos
População do Leste Asiático , Lentigo , Humanos , Lentigo/diagnóstico , Lentigo/genética , Melanócitos , Mutação , Fenótipo , SíndromeRESUMO
Solar lentigines (SLs) are a hallmark of human skin aging. They result from chronic exposure to sunlight and other environmental stressors. Recent studies also imply genetic factors, but findings are partially conflicting and lack of replication. Through a multi-trait based analysis strategy, we discovered that genetic variants in telomerase reverse transcriptase were significantly associated with non-facial SL in two East Asian (Taizhou longitudinal cohort, n = 2,964 and National Survey of Physical Traits, n = 2,954) and one Caucasian population (SALIA, n = 462), top SNP rs2853672 (P-value for Taizhou longitudinal cohort = 1.32 × 10â28 and P-value for National Survey of Physical Traits = 3.66 × 10â17 and P-value for SALIA = 0.0007 and Pmeta = 4.93 × 10â44). The same variants were nominally associated with facial SL but not with other skin aging or skin pigmentation traits. The SL-enhanced allele/haplotype upregulated the transcription of the telomerase reverse transcriptase gene. Of note, well-known telomerase reverse transcriptaseârelated aging markers such as leukocyte telomere length and intrinsic epigenetic age acceleration were not associated with SL. Our results indicate a previously unrecognized role of telomerase reverse transcriptase in skin agingârelated lentigines formation.
Assuntos
Lentigo , Transtornos de Fotossensibilidade , Telomerase , Humanos , Telomerase/genética , Telomerase/metabolismo , Lentigo/genética , Lentigo/epidemiologia , Envelhecimento , Pele/metabolismo , Telômero/metabolismoRESUMO
SASH1 has been reported as a causal gene of lentiginous phenotypes with and without heredity, including an autosomal dominant type characterized by lentigines predominantly on sun-exposed areas such as the face and limbs. Recently, cases of dyschromatosis with SASH1 mutations have been reported worldwide; however, only one case has been reported from Japan. Here, we analyzed six Japanese patients who characteristically showed many lentigines on sun-exposed areas, using next-generation sequencing. We identified five novel heterozygous mutations in SASH1 (p.I586M, p.S531Y, p.R644W, p.T525R, and p.S516I) in our patients and their families. The p.R644W substitution identified in two unrelated families was the first mutation located in the sterile alpha motif 1 (SAM1) domain. The degree and location of the lentigines were variable across individuals, even if they shared the same SASH1 mutation. All mutations were predicted to be deleterious by six different algorithms used to evaluate the functional impact of a variation. In addition, immunohistopathological findings and RNA sequencing results suggested that SASH1 mutations were associated with an increase in the number of melanocytes, acceleration of melanogenesis, and upregulated hair keratin expression.
Assuntos
Lentigo/patologia , Mutação de Sentido Incorreto , Fenótipo , Proteínas Supressoras de Tumor/genética , Adolescente , Adulto , Pré-Escolar , Feminino , Humanos , Lentigo/genética , Masculino , Linhagem , PrognósticoRESUMO
Autophagy is a membrane traffic system that provides sustainable degradation of cellular components for homeostasis, and is thus considered to promote health and longevity, though its activity declines with aging. The present findings show deterioration of autophagy in association with premature skin aging. Autophagy flux was successfully determined in skin tissues, which demonstrated significantly decreased autophagy in hyperpigmented skin such as that seen in senile lentigo. Furthermore, an exacerbated decline in autophagy was confirmed in xerotic hyperpigmentation areas, accompanied by severe dehydration and a barrier defect, which showed correlations with skin physiological conditions. The enhancement of autophagy in skin ex vivo ameliorated skin integrity, including pigmentation and epidermal differentiation. The present results indicate that the restoration of autophagy can contribute to improving premature skin aging by various intrinsic and extrinsic factors via the normalization of protein homeostasis.
Assuntos
Autofagia/fisiologia , Diferenciação Celular/fisiologia , Epiderme/fisiologia , Envelhecimento da Pele/fisiologia , Pigmentação da Pele/fisiologia , Pele/fisiopatologia , Adulto , Senilidade Prematura/metabolismo , Senilidade Prematura/fisiopatologia , Autofagia/genética , Diferenciação Celular/genética , Linhagem Celular , Epiderme/metabolismo , Feminino , Regulação da Expressão Gênica , Humanos , Queratinócitos/citologia , Queratinócitos/fisiologia , Lentigo/genética , Lentigo/metabolismo , Lentigo/fisiopatologia , Masculino , Pessoa de Meia-Idade , Proteínas Ribossômicas/genética , Proteínas Ribossômicas/metabolismo , Proteínas Quinases Associadas a Fase S/genética , Proteínas Quinases Associadas a Fase S/metabolismo , Pele/metabolismo , Envelhecimento da Pele/genética , Pigmentação da Pele/genéticaAssuntos
Neoplasias Gastrointestinais/diagnóstico , Tumores do Estroma Gastrointestinal/diagnóstico , Lentigo/genética , Síndromes Neoplásicas Hereditárias/diagnóstico , Quimioterapia Adjuvante , Análise Mutacional de DNA , Dermoscopia , Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico , Feminino , Gastrectomia , Neoplasias Gastrointestinais/complicações , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/terapia , Tumores do Estroma Gastrointestinal/complicações , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/terapia , Gastroscopia , Humanos , Mesilato de Imatinib/uso terapêutico , Lentigo/terapia , Pessoa de Meia-Idade , Síndromes Neoplásicas Hereditárias/complicações , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/terapia , Mutação Puntual , Proteínas Proto-Oncogênicas c-kit/genética , Pele/diagnóstico por imagem , Estômago/diagnóstico por imagem , Estômago/patologia , Resultado do TratamentoRESUMO
Although lentigines are usually benign, they can be associated with a number of genetic syndromes in which neoplasms and other multi-system pathological processes occur. Here, we report the case of a 6-year-old girl who presented with atypical lentiginosis and hyperpigmentation caused by a de novo genetic variant in the KIT gene.
Assuntos
Lentigo/genética , Mutação de Sentido Incorreto , Proteínas Proto-Oncogênicas c-kit/genética , Criança , Feminino , Humanos , Sequenciamento do ExomaRESUMO
Solitary congenital or early apparent pigmented macules are usually without relevance; however, when multiple, extensive or in a patterned arrangement, they are not uncommonly the first sign of an underlying genetic syndrome. The present article gives an overview on the clinical significance of multiple café-au-lait macules, multiple lentigines and pigmentary mosaicism and discusses the differential diagnosis of associated syndromes. Early diagnosis with the essential contribution of the dermatologist is not only important for genetic counseling but can also contribute to avoidance of sometimes life-threatening complications.
Assuntos
Manchas Café com Leite , Hiperpigmentação , Lentigo , Anormalidades da Pele/genética , Manchas Café com Leite/diagnóstico , Manchas Café com Leite/genética , Diagnóstico Diferencial , Aconselhamento Genético , Doenças Genéticas Inatas , Humanos , Hiperpigmentação/diagnóstico , Hiperpigmentação/genética , Lentigo/genética , Lentigo/patologia , Mosaicismo , SíndromeRESUMO
Wnt/ß-catenin signalling promotes melanogenesis in melanocytes and also induces melanocytogenesis from melanocyte stem cells (McSCs). Previous study reported that WNT1, a ligand which activates Wnt/ß-catenin signalling pathway, was more highly expressed in the epidermis at SLs than in normal skin areas, suggesting that WNT1 causes hyperpigmentation. To elucidate the mechanism by which WNT1 expression is increased in SLs, we examined the methylation of 5-carbon of cytosine (5mC), that is 5-methylcytosine (5mC) level, in a region within the WNT1 promoter; the methylation of the region was known to negatively regulate WNT1 gene expression. We used an immortalized cell line of human interfollicular epidermal stem cells to analyse the effect of UVB irradiation on DNA methylation level of WNT1 promoter and found that UVB irradiation caused demethylation of WNT1 promoter and promoted WNT1 mRNA expression. It was also found that UVB irradiation reduced the expression of DNA methyltransferase 1 (DNMT1), an enzyme responsible for maintaining methylation patterns during cell division. Pathological analysis of SLs and non-SL regions in the human skin revealed that both DNMT1 expression and 5mC level were decreased at SLs compared to non-SL skins. Furthermore, bisulphite sequencing showed that the methylated CpG level in WNT1 promoter was also lower at SLs than in non-SL skins. Thus, in the skin exposed to a high amount of UV rays, excessive expression of WNT1 is thought to be caused by the demethylation of WNT1 promoter, and the upregulated WNT1 promotes melanocytogenesis and melanogenesis, then resulting in SL formation.
Assuntos
Metilação de DNA , Lentigo/etiologia , Lentigo/genética , Raios Ultravioleta/efeitos adversos , Proteína Wnt1/genética , Idoso , Biópsia , Linhagem Celular , Ilhas de CpG , DNA (Citosina-5-)-Metiltransferase 1/genética , Células Epidérmicas , Feminino , Humanos , Hipopigmentação/metabolismo , Queratinócitos/metabolismo , Masculino , Melanócitos/metabolismo , Pessoa de Meia-Idade , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Pele/metabolismoAssuntos
Genes Dominantes/genética , Lentigo/genética , Proteínas Proto-Oncogênicas c-kit/genética , Idoso de 80 Anos ou mais , Biópsia , Análise Mutacional de DNA , Progressão da Doença , Feminino , Humanos , Japão , Lentigo/patologia , Masculino , Mutação de Sentido Incorreto , Linhagem , Pele/patologia , Sequenciamento do ExomaRESUMO
BACKGROUND: Most subungual melanocytic lesions in children are benign, but some are difficult to classify due to prominent lentiginous growth and high-grade cytologic atypia. OBJECTIVE: To characterize the clinicopathologic features of these rare lesions. METHODS: Subungual atypical lentiginous melanocytic proliferations from patients <20 years of age were collected for clinical and histopathologic review. Fluorescence in situ hybridization (FISH) was performed when possible. RESULTS: Eleven patients aged 2-19 years had expanding or darkening longitudinal pigmented streak(s) with or without Hutchinson sign. Microscopically, all revealed predominantly single-cell growth, pagetoid scatter, and poor circumscription. Eight (73%) cases showed focal or poor nesting, and 3 (27%) demonstrated confluence. Nuclear enlargement, hyperchromasia, and angulation were present in 8 (73%) cases, 7 (64%) cases, and 6 (55%) cases, respectively. One of 4 cases tested by FISH was positive. Three lesions recurred locally without other adverse outcome. LIMITATIONS: Small sample size and short clinical follow-up. Two cases were examined in partial biopsies only. CONCLUSION: Some subungual melanocytic lesions in children and adolescents are histologically indistinguishable from adult subungual melanoma in situ. While the biologic potential remains elusive, FISH might aid in risk stratification. Awareness of this rare group of lesions is crucial for facilitating future investigation into its biologic behavior.
Assuntos
Lentigo/patologia , Melanócitos/patologia , Doenças da Unha/patologia , Adolescente , Criança , Pré-Escolar , Diagnóstico Diferencial , Feminino , Humanos , Sarda Melanótica de Hutchinson/diagnóstico , Sarda Melanótica de Hutchinson/genética , Sarda Melanótica de Hutchinson/patologia , Sarda Melanótica de Hutchinson/cirurgia , Hibridização in Situ Fluorescente , Lentigo/diagnóstico , Lentigo/genética , Lentigo/cirurgia , Masculino , Melanoma/diagnóstico , Melanoma/genética , Melanoma/patologia , Melanoma/cirurgia , Doenças da Unha/diagnóstico , Doenças da Unha/genética , Doenças da Unha/cirurgia , Estudos Retrospectivos , Sensibilidade e Especificidade , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/cirurgia , Adulto JovemRESUMO
Carney complex is a multiple neoplasia syndrome having endocrine and non-endocrine manifestations. Diagnostic criteria include myxoma, lentigines, and primary pigmented nodular adrenocortical disease, amongst other signs/symptoms. In most cases it is an autosomal dominant disease, and diagnosis therefore requires study and follow-up of the family members. Inactivating mutations of the PRKAR1A gene were identified as the main cause of the disease, although since 2015 other disease-related genes, including PRKACA and PRKACB activating mutations, have also been related with Carney complex. This review will address the genetic aspects related to Carney complex.