RESUMEN
Ultraviolet (UV) light and incompletely understood genetic and epigenetic variations determine skin color. Here we describe an UV- and microphthalmia-associated transcription factor (MITF)-independent mechanism of skin pigmentation. Targeting the mitochondrial redox-regulating enzyme nicotinamide nucleotide transhydrogenase (NNT) resulted in cellular redox changes that affect tyrosinase degradation. These changes regulate melanosome maturation and, consequently, eumelanin levels and pigmentation. Topical application of small-molecule inhibitors yielded skin darkening in human skin, and mice with decreased NNT function displayed increased pigmentation. Additionally, genetic modification of NNT in zebrafish alters melanocytic pigmentation. Analysis of four diverse human cohorts revealed significant associations of skin color, tanning, and sun protection use with various single-nucleotide polymorphisms within NNT. NNT levels were independent of UVB irradiation and redox modulation. Individuals with postinflammatory hyperpigmentation or lentigines displayed decreased skin NNT levels, suggesting an NNT-driven, redox-dependent pigmentation mechanism that can be targeted with NNT-modifying topical drugs for medical and cosmetic purposes.
Asunto(s)
Factor de Transcripción Asociado a Microftalmía/metabolismo , NADP Transhidrogenasas/metabolismo , Pigmentación de la Piel/efectos de la radiación , Rayos Ultravioleta , Animales , Línea Celular , Estudios de Cohortes , AMP Cíclico/metabolismo , Daño del ADN , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Predisposición Genética a la Enfermedad , Humanos , Melanocitos/efectos de los fármacos , Melanocitos/metabolismo , Melanosomas/efectos de los fármacos , Melanosomas/metabolismo , Melanosomas/efectos de la radiación , Ratones , Ratones Endogámicos C57BL , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Monofenol Monooxigenasa/genética , Monofenol Monooxigenasa/metabolismo , NADP Transhidrogenasas/antagonistas & inhibidores , Oxidación-Reducción/efectos de los fármacos , Oxidación-Reducción/efectos de la radiación , Polimorfismo de Nucleótido Simple/genética , Complejo de la Endopetidasa Proteasomal/metabolismo , Proteolisis/efectos de los fármacos , Proteolisis/efectos de la radiación , ARN Mensajero/genética , ARN Mensajero/metabolismo , Pigmentación de la Piel/efectos de los fármacos , Pigmentación de la Piel/genética , Ubiquitina/metabolismo , Pez CebraRESUMEN
Juvenile xanthogranuloma (JXG) is the most common type of non-Langerhans cell histiocytosis. JXG is a rare benign tumor, which may be present at birth or develop later. The classical form of JXG is characterized by a red-yellowish benign papule or nodule with predilection sites on the head, neck, and trunk, although lesions can appear on extremities or extracutaneous sites. In most cases there is only one lesion, whereas numerous papules or nodules may occur. Special forms of JXG such as mixed, giant, subcutaneous, eruptive, clustered, and plaque-like have been reported and associations between JXG and systemic diseases have been made. Diagnosis mainly relies on the clinical appearance, and histology usually can confirm the disease. Here we present a very rare case of symmetrical giant facial plaque-type juvenile xanthogranuloma (SGFP-JXG) and compare it with classical JXG, variations of JXG, and discuss the differential diagnosis. A 4-year-old Caucasian female presented with plaque-like lesions composed of yellowish confluent papules on both the cheeks. The histological evaluation revealed a histiocytic lesion with a formation of Touton giant cells and immunohistochemistry results confirmed the diagnosis of the SGFP-JXG. In comparison to classical JXG, the onset of SGFP-JXG sometimes occurs later and the spontaneous resolution period may be prolonged. No associated diseases and no systemic involvements were observed. Histopathology is required to differentiate this form of JXG from other histiocytosis. To the best of our knowledge, only four cases of SGFP-JXG have been reported in the literature so far.