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Carrascosa-Romero M.C.,Complejo Hospitalario Universitario Of Albacete | Suela J.,NIMGenetics New Integrated Medical Genetics | Pardal-Fernandez J.M.,Complejo Hospitalario Universitario Of Albacete | Bermejo-Sanchez E.,Instituto Of Investigacion Of Enfermedades Raras Iier | And 10 more authors.
American Journal of Medical Genetics, Part A | Year: 2013

We present a girl with the characteristic clinical picture associated with Marden-Walker syndrome (MWS; OMIM 248700), including mask-like face with blepharophimosis, joint contractures, intellectual disability, a multicystic dysplastic kidney and cerebral dysgenesis. The long-term follow-up allowed us to monitor the evolution of the phenotype in this patient, and among the main findings we highlight the following: demyelination of the pyramidal tract demonstrated by transcranial magnetic stimulation and the involvement of the levator muscles of angle of mouth in fixed facial expression with relative integrity of the rest of the facial expression muscles. A 244k array comparative genomic hybridization (aCGH) was carried out and showed a de novo interstitial deletion of approximately 2.84Mb affecting only the cytoband 21q22.11 (genome coordinates chr21:31,874,016-34,711,763). We selected 10 of the most recent published cases with either total or partial deletions of cytoband 21q22.11 that provided good characterization of the genomic size or the genes in the deleted regions. We observed that in nine of the 10 cases the deleted regions included the RUNX1 gene in 21q22.12, which is not affected in the current patient's deletion or in that of Patient 3 from Roberson et al. [2011]. After a comparison of shared deleted genes between cases, and correlation of their potential phenotypes, we concluded that the pattern of defects considered for a diagnosis of MWS may represent part of the phenotypic expression of a partial or total deletion of 21q22.11. © 2013 Wiley Periodicals, Inc.


Mota A.,Instituto Of Investigacion Of Enfermedades Raras Iier | Mota A.,Institute Investigaciones Biomedicas Alberto Sols | Jimenez-Garcia L.,Instituto Of Investigacion Of Enfermedades Raras Iier | Herranz S.,Instituto Of Investigacion Of Enfermedades Raras Iier | And 2 more authors.
Toxicology and Applied Pharmacology | Year: 2015

Hispanolone derivatives have been previously described as anti-inflammatory and antitumoral agents. However, their effects on overcoming Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) resistance remain to be elucidated. In this study, we analyzed the cytotoxic effects of the synthetic hispanolone derivative α-hispanolol (α-H) in several tumor cell lines, and we evaluated the induction of apoptosis, as well as the TRAIL-sensitizing potential of α-H in the hepatocellular carcinoma cell line HepG2. Our data show that α-H decreased cell viability in a dose-dependent manner in HeLa, MDA-MB231, U87 and HepG2 cell lines, with a more prominent effect in HepG2 cells. Interestingly, α-H had no effect on non-tumoral cells. α-H induced activation of caspase-8 and caspase-9 and also increased levels of the proapoptotic protein Bax, decreasing antiapoptotic proteins (Bcl-2, X-IAP and IAP-1) in HepG2 cells. Specific inhibition of caspase-8 abrogated the cascade of caspase activation, suggesting that the extrinsic pathway has a critical role in the apoptotic events induced by α-H. Furthermore, combined treatment of α-H with TRAIL enhanced apoptosis in HepG2 cells, activating caspase-8 and caspase-9. This correlated with up-regulation of both the TRAIL death receptor DR4 and DR5. DR4 or DR5 neutralizing antibodies abolished the effect of α-H on TRAIL-induced apoptosis, suggesting that sensitization was mediated through the death receptor pathway. Our results demonstrate that α-H induced apoptosis in the human hepatocellular carcinoma cell line HepG2 through activation of caspases and induction of the death receptor pathway. In addition, we describe a novel function of α-H as a sensitizer on TRAIL-induced apoptotic cell death in HepG2 cells. © 2015 Elsevier Inc.


Cuadrado-Berrocal I.,Complutense University of Madrid | Guedes G.,University of La Laguna | Estevez-Braun A.,University of La Laguna | Hortelano S.,Instituto Of Investigacion Of Enfermedades Raras Iier | de las Heras B.,Complutense University of Madrid
Bioorganic and Medicinal Chemistry Letters | Year: 2015

A series of naphthoimidazoles derivatives (3a-3f) were tested for potential anti-inflammatory activity on lipopolysaccharide (LPS)-treated macrophages. Naphthoimidazole 3e exhibited significant inhibitory effects on nitric oxide (NO) production (IC50 <10μM) and decreased the expression of nitric oxide synthase-2 (NOS-2) and cycloxygenase-2 (COX-2) enzymes. It also inhibited the activation of transcription factor NF-κB. Naphthoimidazole 3e might represent a starting point for the synthesis of new anti-inflammatory naphthoimidazoles derivatives. © 2015 Elsevier Ltd.


Martinez-Fernandez M.L.,CIBER ISCIII | Martinez-Fernandez M.L.,Institute Salud Carlos III | Bermejo-Sanchez E.,CIBER ISCIII | Bermejo-Sanchez E.,Institute Salud Carlos III | And 7 more authors.
American Journal of Medical Genetics, Part A | Year: 2014

In 2005, we reported on a family as having Frías syndrome (OMIM: 609640), with four affected members displaying a pattern of congenital defects nearly identical to those observed in a mother and son described by Frias [Frías et al. (1975). Birth Defects Orig Artic Ser 11:30-33]. These defects included growth deficiency, facial anomalies, and hand and foot alterations. We had the opportunity to study this family again due to the birth of another affected girl, who presented with similar facial characteristics to those of her elder half-sister and the rest of affected relatives, which consisted of mild exophthalmia, bilateral palpebral ptosis, downslanting palpebral fissures, and hypertelorism. We performed array-CGH, which identified an identical interstitial deletion of chromosome 14q22.1-q22.3 in the mother and two daughters. The deletion is 4.06Mb in length and includes the BMP4 gene, a member of the bone morphogenetic protein (BMP) family of secreted proteins. A review of the literature showed that deletions or mutations of this gene underlie congenital defects affecting brain, eye, teeth, and digit development. Although the clinical manifestations of the current family correlate with the defects observed in patients having either 14q22-q23 deletions or mutations of BMP4, they show a milder phenotype. In order to understand the clinical variability, we evaluated the already known functional characteristics of the BMP gene members. This gene family plays an important role during early embryogenesis, and the complex synergistic functions and redundancies of the BMPs led us to conclude that haploinsufficiency of BMP4 is likely to be responsible for the clinical expression of Frías syndrome. © 2013 Wiley Periodicals, Inc.


PubMed | Complutense University of Madrid, Instituto Of Investigacion Of Enfermedades Raras Iier and University of La Laguna
Type: Journal Article | Journal: Bioorganic & medicinal chemistry letters | Year: 2015

A series of naphthoimidazoles derivatives (3a-3f) were tested for potential anti-inflammatory activity on lipopolysaccharide (LPS)-treated macrophages. Naphthoimidazole 3e exhibited significant inhibitory effects on nitric oxide (NO) production (IC50 <10M) and decreased the expression of nitric oxide synthase-2 (NOS-2) and cycloxygenase-2 (COX-2) enzymes. It also inhibited the activation of transcription factor NF-B. Naphthoimidazole 3e might represent a starting point for the synthesis of new anti-inflammatory naphthoimidazoles derivatives.


PubMed | La Jolla Salk Institute, Instituto Of Investigacion Of Enfermedades Raras Iier, European University at Madrid and Complutense University of Madrid
Type: Journal Article | Journal: The Biochemical journal | Year: 2016

Endothelial activation contributes to lung inflammatory disorders by inducing leucocyte recruitment to pulmonary parenchyma. Consequently, vascular-targeted therapies constitute promising strategies for the treatment of inflammatory pathologies. In the present study, we evaluated the effect of 8,9-dehydrohispanolone-15,16-lactol diterpene (DT) on lung endothelium during inflammation. Lung endothelial cells pre-treated with DT and activated with lipopolysaccharide (LPS) or tumour necrosis factor- (TNF-) exhibited reduced expression of the pro-inflammatory cytokines Cxcl10, Ccl5 and Cxcl1, whereas the anti-inflammatory molecules IL1r2 and IL-10 were induced. Consistent with this result, DT pre-treatment inhibited nuclear factor B (NF-B) nuclear translocation, by interfering with IB phosphorylation, and consequently NF-B transcriptional activity in endothelium activated by LPS or TNF-. Furthermore, DT, probably through p38 signalling, induced transcriptional activation of genes containing activator protein 1 (AP-1)-binding elements. Inhibition of p38 prevented IL1r2 mRNA expression in endothelium incubated with DT alone or in combination with LPS or TNF-. Accordingly, conditioned medium (CM) from these cells failed to stimulate leucocytes as measured by a reduction in adhesive ability of the leucocyte cell line J774 to fibronectin (FN). Additionally, DT reduced the expression of the endothelial adhesion molecules E-selectin, vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1) after activation. Similarly, expression of VCAM-1 and ICAM-1 molecules on the lung endothelial layer of C57/BL6 mice pre-treated with DT and challenged with LPS were unchanged. Finally, inhibition of vascular adhesion molecule expression by DT decreased the interaction of J774 cells with lung endothelial cells in an inflammatory environment. Our findings establish DT as a novel endothelial inhibitor for the treatment of inflammatory-related diseases triggered by Gram-negative bacteria or by the associated cytokine TNF-.


PubMed | Hospitales Universitarios Virgen Macarena y Virgen del Rocio, Instituto Of Investigacion Of Enfermedades Raras Iier and Institute Salud Carlos III
Type: Journal Article | Journal: Journal of human genetics | Year: 2016

Retinoblastoma (RB, MIM 180200) is the paradigm of hereditary cancer. Individuals harboring a constitutional mutation in one allele of the RB1 gene have a high predisposition to develop RB. Here, we present the first case of familial RB caused by a de novo insertion of a full-length long interspersed element-1 (LINE-1) into intron 14 of the RB1 gene that caused a highly heterogeneous splicing pattern of RB1 mRNA. LINE-1 insertion was inferred by mRNA studies and full-length sequenced by massive parallel sequencing. Some of the aberrant mRNAs were produced by noncanonical acceptor splice sites, a new finding that up to date has not been described to occur upon LINE-1 retrotransposition. Our results clearly show that RNA-based strategies have the potential to detect disease-causing transposon insertions. It also confirms that the incorporation of new genetic approaches, such as massive parallel sequencing, contributes to characterize at the sequence level these unique and exceptional genetic alterations.


Bermejo Sanchez E.,Instituto Of Investigacion Of Enfermedades Raras Iier | Bermejo Sanchez E.,Research Center sobre Anomalias Congenitas | Bermejo Sanchez E.,Research Center Biomedica En Red Of Enfermedades Raras Ciberer
Semergen | Year: 2010

A review is presented of the main aspects arising from the study of the frequency of congenital defects, explaining the importance and use of this knowledge, and illustrating it with different examples based on the analysis of data from the ECEMC (Estudio Colaborativo Español de Malformaciones Congénitas) (Spanish Collaborative Study of Congenital Malformations). From this analysis it was observed that the overall frequency of newborns with congenital defects in Spain has been decreasing gradually for many defects. This drop is mainly a result of voluntary termination of pregnancy (TOP) after the detection of foetal abnormalities. However, other factors, such as the improved care of pregnant women and pregnancy planning, plus the increase in the health culture of the population, could also be having some effect, although a lot less obvious than that due to TOP. This decrease in frequency has not been uniform in all the Autonomous Communities. On the other hand, there are certain defects that have shown a secular increase, arising from the improvement and general use of both prenatal and post-natal diagnostic techniques. Furthermore, it has been observed that the ethnical diversification in our country, resulting from immigration, is also having a certain impact on the frequency of newborns with congenital abnormalities in Spain. These minority population groups, in general, along with the differences in the frequency of certain recessive gene mutations, have socio-health conditions that lead to a higher risk of congenital defects. All these aspects are important and have to be taken into account when designing prevention plans for these diseases. © 2010 Elsevier España, S.L. y SEMERGEN.


Jimenez-Garcia L.,Instituto Of Investigacion Of Enfermedades Raras Iier | Herranz S.,Instituto Of Investigacion Of Enfermedades Raras Iier | Luque A.,Instituto Of Investigacion Of Enfermedades Raras Iier | Hortelano S.,Instituto Of Investigacion Of Enfermedades Raras Iier
European Journal of Immunology | Year: 2015

Alternative activation of macrophages plays an important role in a range of physiological and pathological processes. This alternative phenotype, also known as M2 macrophages, is induced by type 2 cytokines such as IL-4. The binding of IL-4 to its receptor leads to activation of two major signaling pathways: STAT-6 and PI3K. However, recent studies have described that p38 MAPK might play a role in IL-4-dependent signaling in some cells, although its role in macrophages is still controversial. In this study, we investigated whether p38 MAPK plays a role in the polarization of macrophages in mice. Our results reveal that IL-4 induces phosphorylation of p38 MAPK in thioglycollate-elicited murine peritoneal macrophages, in addition to STAT-6 and PI3K activation. Furthermore, p38 MAPK inactivation, by gene silencing or pharmacological inhibition, suppressed IL-4-induced typical M2 markers, indicating the involvement of p38 MAPK in the signaling of IL-4 leading to M2-macrophage polarization. Moreover, p38 MAPK inhibition blocked phosphorylation of STAT-6 and Akt, suggesting that p38 MAPK is upstream of these signaling pathways. Finally, we show that in an in vivo model of chitin-induced M2 polarization, p38 MAPK inhibition also diminished activation of M2 markers. Taken together, our data establish a new role for p38 MAPK during IL-4-induced alternative activation of macrophages. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


PubMed | Hospital General Universitario Gregorio Maranon and Instituto Of Investigacion Of Enfermedades Raras Iier
Type: | Journal: Familial cancer | Year: 2016

The familial tumor predisposition syndrome known as DICER1-pleuropulmonary blastoma (PPB) or DICER1 tumor predisposition syndrome was first described in 2009, and it involves an increased risk in the occurrence of various tumors, like cystic nephroma and PPB. Here is presented a girl with a cystic nephroma and two cystic lung lesions who was diagnosed years later with the DICER1 gene mutation. This mutation was also found in one of her parents. Thus, the screening for the DICER1 gene mutation may be important in children with certain/multiple tumors and their families.

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