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Groesser L.,University of Regensburg | Herschberger E.,University of Regensburg | Sagrera A.,CSIC - National Center for Metallurgical Research | Shwayder T.,Ford Motor Company | And 17 more authors.
Journal of Investigative Dermatology | Year: 2013

Phacomatosis pigmentokeratotica (PPK) is a rare epidermal nevus syndrome characterized by the co-occurrence of a sebaceous nevus and a speckled lentiginous nevus. The coexistence of an epidermal and a melanocytic nevus has been explained by two homozygous recessive mutations, according to the twin spot hypothesis, of which PPK has become a putative paradigm in humans. However, the underlying gene mutations remained unknown. Multiple tissues of six patients with PPK were analyzed for the presence of RAS, FGFR3, PIK3CA, and BRAF mutations using SNaPshot assays and Sanger sequencing. We identified a heterozygous HRAS c.37G>C (p.Gly13Arg) mutation in four patients and a heterozygous HRAS c.182A>G (p.Gln61Arg) mutation in two patients. In each case, the mutations were present in both the sebaceous and the melanocytic nevus. In the latter lesion, melanocytes were identified to carry the HRAS mutation. Analysis of various nonlesional tissues showed a wild-type sequence of HRAS, consistent with mosaicism. Our data provide no genetic evidence for the previously proposed twin spot hypothesis. In contrast, PPK is best explained by a postzygotic-activating HRAS mutation in a multipotent progenitor cell that gives rise to both a sebaceous and a melanocytic nevus. Therefore, PPK is a mosaic RASopathy. © 2013 The Society for Investigative Dermatology.


Sandoval J.,Bellvitge Biomedical Research Institute IDIBELL | Diaz-Lagares A.,Bellvitge Biomedical Research Institute IDIBELL | Salgado R.,Laboratori Of Citogenetica Molecular | Servitje O.,Hospital Universitari Of Bellvitge | And 15 more authors.
Journal of Investigative Dermatology | Year: 2015

MicroRNAs usually regulate gene expression negatively, and aberrant expression has been involved in the development of several types of cancers. Microarray profiling of microRNA expression was performed to define a microRNA signature in a series of mycosis fungoides tumor stage (MFt, n=21) and CD30+ primary cutaneous anaplastic large cell lymphoma (CD30+ cALCL, n=11) samples in comparison with inflammatory dermatoses (ID, n=5). Supervised clustering confirmed a distinctive microRNA profile for cutaneous T-cell lymphoma (CTCL) with respect to ID. A 40 microRNA signature was found in MFt including upregulated onco-microRNAs (miR-146a, miR-142-3p5p, miR-21, miR-181ab, and miR-155) and downregulated tumor-suppressor microRNAs (miR-200ab429 cluster, miR-10b, miR-193b, miR-141200c, and miR-23b27b). Regarding CD30+ cALCL, 39 differentially expressed microRNAs were identified. Particularly, overexpression of miR-155, miR-21, or miR-142-3p5p and downregulation of the miR-141200c clusters were observed. DNA methylation in microRNA gene promoters, as expression regulatory mechanism for deregulated microRNAs, was analyzed using Infinium 450K array and approximately one-third of the differentially expressed microRNAs showed significant DNA methylation differences. Two different microRNA methylation signatures for MFt and CD30+ cALCL were found. Correlation analysis showed an inverse relationship for microRNA promoter methylation and microRNA expression. These results reveal a subgroup-specific epigenetically regulated microRNA signatures for MFt and CD30+ cALCL patients. © 2015 The Society for Investigative Dermatology.


Pros E.,Institute Catala Doncologia Institute Dinvestigacio Biomedica Of Bellvitge | Fernandez-Rodriguez J.,Institute Catala Doncologia Institute Dinvestigacio Biomedica Of Bellvitge | Benito L.,Institute Catala Doncologia Institute Dinvestigacio Biomedica Of Bellvitge | Ravella A.,Servei de Dermatologia | And 4 more authors.
European Journal of Human Genetics | Year: 2010

Neurofibromatosis type 1 is one of the most common neurocutaneous autosomal dominant disorders. It is caused by mutations in the neurofibromatosis type 1 (NF1) gene and approximately 30-40% of them affect the correct splicing of NF1 pre-mRNA. In this report, we evaluate the effect of five different drugs, previously found to modify splicing in several genetic disorders, on the splicing of mutated NF1 alleles. For this purpose, cell lines derived from patients bearing 19 different NF1-splicing defects were used. Our results showed that kinetin partially corrects the splicing defect in four of the studied mutations (c.910C > T, c.3113G > A, c.6724C > T and c.6791dupA). Our study is a valuable contribution to the field because it identifies new exon-skipping events that can be reversed by kinetin treatment and provides new information about kinetin splicing modulation. However, owing to the nature of mutations in our patients, kinetin treatment could not be used as a therapeutic agent in these cases. © 2010 Macmillan Publishers Limited All rights reserved.


Garcia-Linares C.,Institute Of Medicina Predictiva I Personalitzada Del Cancer Imppc | Garcia-Linares C.,Institute Dinvestigacio Biomedica Of Bellvitge Idibell | Fernandez-Rodriguez J.,Institute Catala Doncologia Ico Idibell | Terribas E.,Institute Of Medicina Predictiva I Personalitzada Del Cancer Imppc | And 12 more authors.
Human Mutation | Year: 2011

Dermal neurofibromas (dNFs) are benign tumors of the peripheral nervous system typically associated with Neurofibromatosis type 1 (NF1) patients. Genes controlling the integrity of the DNA are likely to influence the number of neurofibromas developed because dNFs are caused by somatic mutational inactivation of the NF1 gene, frequently evidenced by loss of heterozygosity (LOH). We performed a comprehensive analysis of the prevalence and mechanisms of LOH in dNFs. Our study included 518 dNFs from 113 patients. LOH was detected in 25% of the dNFs (N = 129). The most frequent mechanism causing LOH was mitotic recombination, which was observed in 62% of LOH-tumors (N = 80), and which does not reduce the number of NF1 gene copies. All events were generated by a single crossover located between the centromere and the NF1 gene, resulting in isodisomy of 17q. LOH due to the loss of the NF1 gene accounted for a 38% of dNFs with LOH (N = 49), with deletions ranging in size from ~80 kb to ~8 Mb within 17q. In one tumor we identified the first example of a neurofibroma-associated second-hit type-2 NF1 deletion. Analysis of the prevalence of mechanisms causing LOH in dNFs in individual patients (possibly under genetic control) will elucidate whether there exist interindividual variation. © 2010 Wiley-Liss, Inc.


Sanchez-Manubens J.,Unitat de Reumatologia Pediatrica | Clemente E.I.,Diagnostic per la Imatge | Jou C.,Servei dAnatomia Patologica | Ensenat M.A.G.,Servei de Dermatologia | Iglesias E.,Unitat de Reumatologia Pediatrica
Pediatria Catalana | Year: 2015

Juvenile dermatomyositis, the most common inflammatory myopathy in children, is a systemic vasculopathy that usually affects skin and musculoskeletal tissue, but can also affect the gastrointestinal tract and other organs. Diagnosis is based on the criteria of Bohan and Peter and the treatment goal includes controlling symptoms and preventing complications. Escalting early treatment reduces disease activity and improves long-term prognosis.

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