Fundacion Publica Galega de Medicina Xenomica SERGAS

Santiago de Compostela, Spain

Fundacion Publica Galega de Medicina Xenomica SERGAS

Santiago de Compostela, Spain
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Boone P.M.,Baylor College of Medicine | Yuan B.,Baylor College of Medicine | Campbell I.M.,Baylor College of Medicine | Scull J.C.,Baylor College of Medicine | And 23 more authors.
American Journal of Human Genetics | Year: 2014

Intragenic copy-number variants (CNVs) contribute to the allelic spectrum of both Mendelian and complex disorders. Although pathogenic deletions and duplications in SPAST (mutations in which cause autosomal-dominant spastic paraplegia 4 [SPG4]) have been described, their origins and molecular consequences remain obscure. We mapped breakpoint junctions of 54 SPAST CNVs at nucleotide resolution. Diverse combinations of exons are deleted or duplicated, highlighting the importance of particular exons for spastin function. Of the 54 CNVs, 38 (70%) appear to be mediated by an Alu-based mechanism, suggesting that the Alu-rich genomic architecture of SPAST renders this locus susceptible to various genome rearrangements. Analysis of breakpoint Alus further informs a model of Alu-mediated CNV formation characterized by small CNV size and potential involvement of mechanisms other than homologous recombination. Twelve deletions (22%) overlap part of SPAST and a portion of a nearby, directly oriented gene, predicting novel chimeric genes in these subjects' genomes. cDNA from a subject with a SPAST final exon deletion contained multiple SPAST:SLC30A6 fusion transcripts, indicating that SPAST CNVs can have transcriptional effects beyond the gene itself. SLC30A6 has been implicated in Alzheimer disease, so these fusion gene data could explain a report of spastic paraplegia and dementia cosegregating in a family with deletion of the final exon of SPAST. Our findings provide evidence that the Alu genomic architecture of SPAST predisposes to diverse CNV alleles with distinct transcriptional - and possibly phenotypic - consequences. Moreover, we provide further mechanistic insights into Alu-mediated copy-number change that are extendable to other loci. © 2014 The American Society of Human Genetics.


Sobrido M.-J.,Fundacion Publica Galega de Medicina Xenomica SERGAS | Sobrido M.-J.,Institute of Health Carlos III | Cacheiro P.,University of Santiago de Compostela | Carracedo A.,Fundacion Publica Galega de Medicina Xenomica SERGAS | And 3 more authors.
Human Mutation | Year: 2012

The importance for research and clinical utility of mutation databases, as well as the issues and difficulties entailed in their construction, is discussed within the Human Variome Project. While general principles and standards can apply to most human diseases, some specific questions arise when dealing with the nature of genetic neurological disorders. So far, publically accessible mutation databases exist for only about half of the genes causing neurogenetic disorders; and a considerable work is clearly still needed to optimize their content. The current landscape, main challenges, some potential solutions, and future perspectives on genetic databases for disorders of the nervous system are reviewed in this special issue of Human Mutation on neurogenetics. © 2012 Wiley Periodicals, Inc.


Pazos E.,University of Santiago de Compostela | Perez M.,Fundacion Publica Galega de Medicina Xenomica SERGAS | Gutierrez-De-Teran H.,Fundacion Publica Galega de Medicina Xenomica SERGAS | Orzaez M.,Research Center Principe Felipe | And 3 more authors.
Organic and Biomolecular Chemistry | Year: 2011

We report the design and development of a fluorescent sensor specifically designed to target cyclin A, a protein that plays a key role in the regulation of the cell cycle. Computational studies provide a molecular picture that explains the observed emission increase, suggesting that the 4-DMAP fluorophore in the peptide is protected from the bulk solvent when inserted into the hydrophobic binding groove of cyclin A. © 2011 The Royal Society of Chemistry.


Fachal L.,Fundacion Publica Galega de Medicina Xenomica SERGAS | Mosquera-Miguel A.,University of Santiago de Compostela | Gomez-Caamano A.,Complexo Hospitalario | Sanchez-Garcia M.,Complexo Hospitalario | And 4 more authors.
Radiotherapy and Oncology | Year: 2014

Background and purpose Mitochondrial DNA common variants have been reported to be associated with the development of radiation-induced toxicity. Using a large cohort of patients, we aimed to validate these findings by investigating the potential role of common European mitochondrial DNA SNPs (mtSNPs) to the development of radio-toxicity. Material and methods Overall acute and late toxicity data were assessed in a cohort of 606 prostate cancer patients by means of Standardized Total Average Toxicity (STAT) score. We carried out association tests between radiation toxicity and a selection of 15 mtSNPs (and the haplogroups defined by them). Results Statistically significant association between mtSNPs and haplogroups with toxicity could not be validated in our Spanish cohort. Conclusions The present study suggests that the mtDNA common variants analyzed are not associated with clinically relevant increases in risk of overall radiation-induced toxicity in prostate cancer patients. © 2014 Elsevier Ireland Ltd. All rights reserved.


PubMed | Fundacion Publica Galega de Medicina Xenomica SERGAS, University Institute of Health Sciences, University of Rochester, University of Santiago de Compostela and 6 more.
Type: Journal Article | Journal: British journal of cancer | Year: 2016

Numerous germline single-nucleotide polymorphisms increase susceptibility to prostate cancer, some lying near genes involved in cellular radiation response. This study investigated whether prostate cancer patients with a high genetic risk have increased toxicity following radiotherapy.The study included 1560 prostate cancer patients from four radiotherapy cohorts: RAPPER (n=533), RADIOGEN (n=597), GenePARE (n=290) and CCI (n=150). Data from genome-wide association studies were imputed with the 1000 Genomes reference panel. Individuals were genetically similar with a European ancestry based on principal component analysis. Genetic risks were quantified using polygenic risk scores. Regression models tested associations between risk scores and 2-year toxicity (overall, urinary frequency, decreased stream, rectal bleeding). Results were combined across studies using standard inverse-variance fixed effects meta-analysis methods.A total of 75 variants were genotyped/imputed successfully. Neither non-weighted nor weighted polygenic risk scores were associated with late radiation toxicity in individual studies (P>0.11) or after meta-analysis (P>0.24). No individual variant was associated with 2-year toxicity.Patients with a high polygenic susceptibility for prostate cancer have no increased risk for developing late radiotherapy toxicity. These findings suggest that patients with a genetic predisposition for prostate cancer, inferred by common variants, can be safely treated using current standard radiotherapy regimens.


Fachal L.,Fundacion Publica Galega de Medicina Xenomica SERGAS | Gomez-Caamano A.,Complexo Hospitalario Universitario Of Santiago | Peleteiro P.,Complexo Hospitalario Universitario Of Santiago | Carballo A.,Complexo Hospitalario Universitario Of Santiago | And 5 more authors.
Radiotherapy and Oncology | Year: 2012

Background and purpose: We have performed a case-control study among prostate cancer patients treated with three-dimensional conformational radiotherapy (3D-CRT) in order to investigate the association between single nucleotide polymorphisms (SNPs), treatment and patient features with gastrointestinal and genitourinary acute toxicity. Material and methods: A total of 698 patients were screened for 14 SNPs located in the ATM, ERCC2, LIG4, MLH1 and XRCC3 genes. Gastrointestinal and genitourinary toxicities were recorded prospectively using the Common Terminology Criteria for Adverse Events v3.0. Results: The XRCC3 SNP rs1799794 (G/G OR = 5.65; 95% CI: 1.95-16.38; G/A OR = 2.75; 95% CI: 1.25-6.05; uncorrected p-value = 2.8 × 10-03; corrected p-value = 0.03; FDR q-value = 0.06) as well as the mean dose received by the rectum (OR = 1.06; 95% CI: 1.02-1.1; uncorrected p-value = 2.49 × 10-03; corrected p-value = 0.03; FDR q-value = 0.06) were significantly associated with gastrointestinal toxicity after correction for multiple testing. Those patients who undergone previous prostatectomy were less prone to develop genitourinary toxicity (OR = 0.38; 95% CI: 0.18-0.71; uncorrected p-value = 4.95 × 10-03; corrected p-value = 0.03; FDR q-value = 0.08). Our study excludes the possibility of a >2-fold risk increase in genitourinary acute toxicity being due to rs1801516 ATM SNP, the rs1805386 and rs1805388 LIG4 markers, as well as all the SNPs evaluated in the ERCC2, MLH1 and XRCC3 genes. Conclusions: The XRCC3 rs1799794 SNP and the mean dose received by the rectum are associated with the development of gastrointestinal toxicity after 3D-CRT. © 2012 Elsevier Ireland Ltd. All rights reserved.


Rodriguez-Pazos L.,Complejo Hospitalario Universitario | Ginarte M.,Complejo Hospitalario Universitario | Vega A.,Fundacion Publica Galega de Medicina Xenomica SERGAS | Toribio J.,Complejo Hospitalario Universitario
Actas Dermo-Sifiliograficas | Year: 2013

The term autosomal recessive congenital ichthyosis (ARCI) refers to a group of rare disorders of keratinization classified as nonsyndromic forms of ichthyosis. This group was traditionally divided into lamellar ichthyosis (LI) and congenital ichthyosiform erythroderma (CIE) but today it also includes harlequin ichthyosis, self-healing collodion baby, acral self-healing collodion baby, and bathing suit ichthyosis. The combined prevalence of LI and CIE has been estimated at 1 case per 138 000 to 300 000 population. In some countries or regions, such as Norway and the coast of Galicia, the prevalence may be higher due to founder effects. ARCI is genetically highly heterogeneous and has been associated with 6 genes to date: TGM1, ALOXE3, ALOX12B, NIPAL4, CYP4F22, and ABCA12. In this article, we review the current knowledge on ARCI, with a focus on clinical, histological, ultrastructural, genetic, molecular, and treatment-related aspects. © 2012 Elsevier Espana, S.L. and AEDV. All rights reserved.


Fachal L.,Fundacion Publica Galega de Medicina Xenomica SERGAS
PloS one | Year: 2012

Mutations in the TGM1 gene encoding transglutaminase 1 are a major cause of autosomal recessive congenital ichthyosis. In the Galician (NW Spain) population, three mutations, c.2278C>T, c.1223_1227delACAC and c.984+1G>A, were observed at high frequency, representing ~46%, ~21% and ~13% of all TGM1 gene mutations, respectively. Moreover, these mutations were reported only once outside of Galicia, pointing to the existence of historical episodes of local severe genetic drift in this region. In order to determine whether these mutations were inherited from a common ancestor in the Galician population, and to estimate the number of generations since their initial appearance, we carried out a haplotype-based analysis by way of genotyping 21 SNPs within and flanking the TGM1 gene and 10 flanking polymorphic microsatellite markers spanning a region of 12 Mb. Two linkage disequilibrium based methods were used to estimate the time to the most recent common ancestor (TMRCA), while a Bayesian-based procedure was used to estimate the age of the two mutations. Haplotype reconstruction from unphased genotypes of all members of the affected pedigrees indicated that all carriers for each of the two mutations harbored the same haplotypes, indicating common ancestry. In good agreement with the documentation record and the census, both mutations arose between 2,800-2,900 years ago (y.a.), but their TMRCA was in the range 600-1,290 y.a., pointing to the existence of historical bottlenecks in the region followed by population growth. This demographic scenario finds further support on a Bayesian Coalescent Analysis based on TGM1 haplotypes that allowed estimating the occurrence of a dramatic reduction of effective population size around 900-4,500 y.a. (95% highest posterior density) followed by exponential growth.


Rodriguez-Pazos L.,Complejo Hospitalario Universitario | Ginarte M.,Complejo Hospitalario Universitario | Fachal L.,Fundacion Publica Galega de Medicina Xenomica SERGAS | Toribio J.,Complejo Hospitalario Universitario | And 2 more authors.
British Journal of Dermatology | Year: 2011

Background Mutations in six genes have been identified in autosomal recessive congenital ichthyosis (ARCI). To date, few studies have analysed the spectrum of these mutations in specific populations. Objectives We have studied the characteristics of patients with ARCI in Galicia (NW Spain). Methods We recruited patients by contacting all dermatology departments of Galicia and the Spanish patient organization for ichthyosis. TGM1, ALOX12B, ALOXE3, NIPAL4 and CYP4F22 were analysed in the patients and their relatives. Results We identified 23 patients with ARCI and estimated a prevalence of 1: 122 000. Twenty of the patients were studied. Seventeen of them were clinically categorized as having lamellar ichthyosis (LI) and three as having congenital ichthyosiform erythroderma (CIE). TGM1 and ALOXE3 mutations were identified in 12/16 (75%) probands whereas no ALOX12B, NIPAL4 and CYP4F22 mutations were found. TGM1 mutations were found in 11/13 (85%) of LI probands. ALOXE3 mutations were identified in a single patient with CIE. Remarkably, mutations p.Arg760X, p.Asp408ValfsX21 and c.984+1G>A of TGM1 were present in six, four and two families, accounting for 41%, 23% and 14% of all TGM1 mutant alleles, respectively. Conclusions The high percentage of patients with the same TGM1 mutations, together with the high number of homozygous probands (64%), indicates the existence of a strong founder effect in our population. © 2011 British Association of Dermatologists.


Fachal L.,Fundacion Publica Galega de Medicina Xenomica SERGAS | Gomez-Caamano A.,University of Santiago de Compostela | Sanchez-Garcia M.,University of Santiago de Compostela | Carballo A.,University of Santiago de Compostela | And 4 more authors.
Radiotherapy and Oncology | Year: 2012

Background and purpose: We have performed a case-control study in 413 prostate cancer patients to test for association between TGFβ1 and the development of late normal-tissue toxicity among prostate cancer patients treated with three-dimensional conformational radiotherapy (3D-CRT) Materials and methods: Late gastrointestinal and genitourinary toxicities were assessed for at least two years after radiotherapy in 413 patients according to CTCAEvs3 scores. Codominant genotypic tests and haplotypic analyses were undertaken to evaluate the correlation between TGFβ1 SNPs rs1800469, rs1800470 and rs1800472 and radio-induced toxicity. Results: Neither the SNPs nor the haplotypes were found to be associated with the risk of late toxicity. Conclusions: We were able to exclude up to a 2-fold increase in the risk of developing late gastrointestinal and genitourinary radio-induced toxicity due to the TGFβ1 SNPs rs1800469 and rs1800470, as well as the two most frequent TGFβ1 haplotypes. © 2011 Elsevier Ireland Ltd. All rights reserved.

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