Made available in DSpace on 2014-06-11T19:32:14Z (GMT). No. of bitstreams: 0 Previous issue date: 2013-10-31Bitstream added on 2014-06-13T20:23:14Z : No. of bitstreams: 1 souza_dh_dr_botib.pdf: 1267745 bytes, checksum: ce5cbf1a14320a4be0ba78bff6fc479e (MD5) / A síndrome de Williams-Beuren (SWB) é uma afecção genética rara, com frequência estimada em 1:7500 nascidos vivos, caracterizada por alterações do desenvolvimento associados a deficiência mental moderada, anomalias cardíacas e fácies peculiar, além de um comportamento amigável, alegre e desinibido. O diagnóstico clínico é bastante acurado, porém as diferenças fenotípicas conforme a idade pode dificultar o diagnóstico. O diagnóstico clínico pode ser confirmado pelo diagnóstico molecular, sendo a técnica de FISH, o padrão ouro deste diagnóstico. A SWB tem por etiologia a deleção em 7q11.23, sendo esta ocorrência esporádica. A deleção típica envolve uma região cromossômica de 1.5 Mb ou 1.8 Mb contendo 28 genes denominada de região crítica da SWB. O mecanismo de deleção está ligado as duplicações segmentarias (DSs) ou repetições com baixo números de cópias LCRs. A origem da deleção tem sido atribuída ao rearranjo desigual na meiose devido as recombinações homologas não alélicas (Nonallelic homologous recombination-NAHRs), que pode ocorrer entre regiões repetidas de baixo número de cópias (LCRs). Para termos a indicação ou não da realização do exame de FISH, existem na literatura 3 sistemas de pontuações (escores), publicados por Lowery et al,1997, AAP, 2001 e Sugayama et al, 2007. O presente estudo teve como um dos seus objetivos a verificação da especificidade e da sensibilidade dentre os 3 sistemas publicados, para termos a indicação de qual seria o melhor a ser aplicado. Para tanto foram utilizados um banco de características clínicas com 250 pacientes que já haviam realizados exames da FISH e onde foram aplicados os 3 sistemas de escores. Todos os três sistemas de escores apresentaram alta sensibilidade e baixa especificidade, porém o escore descrito por Lowery et al., 1995 foi... / The Williams - Beuren syndrome (WBS ) is a rare genetic disorder , often estimated at 1:7500 live births , characterized by developmental disorders associated with moderate mental retardation , cardiac anomalies and peculiar facies , and a friendly demeanor , cheerful and uninhibited . The clinical diagnosis is fairly accurate, but the phenotypic differences according to age can make diagnosis difficult. The clinical diagnosis can be confirmed by molecular diagnosis, and the technique of FISH, the gold standard for this diagnosis . The SWB is etiology deletion in 7q11.23, which is sporadic. The typical deletion involves a chromosomal region of 1.5 Mb or 1.8 Mb containing 28 genes designated critical region of SWB. The mechanism of deletion is linked to segmental duplications (SDs) or repetitions with low copy numbers of LCRs. The origin of the deletion has been attributed to unequal rearrangement in meiosis because nonallelic homologous recombination (NAHRs), which can occur from repeated regions of low copy number (LCRs). To get an indication whether or not the examination of FISH, in literature there are 3 systems scores (scores), published by Lowery et al, 1997, AAP, 2001 and Sugayama et al, 2007. The present study had as one of its objectives to verify the specificity and sensitivity among 3 systems publish, to terms to indicate what would best be applied. Therefore, we used a database of clinical characteristics of 250 patients who had already performed the FISH tests were applied and where the three scoring systems. All the three scoring systems showed high sensitivity and low specificity, but the score described powder Lowery et al., 1995 was considered the easiest application. The second objective of this study was to evaluate the sizes of the fragments deleted in order to infer the local break points. Thus were studied for the first time in the literature,...(Complete abstract click electronic access below)

Made available in DSpace on 2016-03-15T19:39:35Z (GMT). No. of bitstreams: 1 Miriam Segin.pdf: 2813413 bytes, checksum: f192e7858349d5ff3ad275af7e9ccf69 (MD5) Previous issue date: 2010-08-25 / Williams-Beuren Syndrome (WBS) is a genetic affection determined by the microdelation of contiguous genes in 7q11.23. The genetic profile of WBS is characterized by the visualconstructive deficit that contrasts with the good performance in verbal tasks, which sustains the hypothesis of dissociation between these abilities. This grants the syndrome peculiar cognitive and behavioral frames. The objective of this research is to describe the pattern of competences in tasks of linguistic abilities in 22 children and adolescents with WBS, aged between 7and 18 (M=11,6; DP=3,7), students of the 1st to 6th grades of elementary and special schools. We used the following instruments: WISC-III (to evaluate intellectual abilities); Wisconsin (used in neuropsychological assessment of abstract reasoning and cognitive strategies); CBCL/6-18 (behavioral assessment); Token-Comp (TT) used to working memory assessment; Peabody Picture Vocabulary Test (PPVT) used to receptive language assessment; Phonological Awareness by Oral Production Test; Syntactic Awareness Test; Word-Reading Efficiency Test; Test of Naming Images by Choosing Words; Test of Naming Images by Writing. The results of WISC-III, Wisconsin and CBCL/6-18 demonstrate mild to moderate intellectual disability, difficulty in concentration and identification of patterns of change, emotional and relationship problems, lack of attention, behavior disorders, challenge and opposition and somatic complaints. The results of TT and PPVT show that the receptive vocabulary is below expected for the level of schooling and age, and is close to the data found in 4-year-old-children. In the abilities of phonological and syntactic awareness, results indicate great deficiencies, with performances equivalent to those of 3-year-old children at the Phonological Awareness by Oral Production Test and of 4-year-olds at the Syntactic Awareness Test. No progression was found according to the increase of school grade. The tests Word-Reading Efficiency, Naming Images by Choosing Words and Naming Images by Writing were taken by 4 participants that presented deficits in the reading ability with graphophonemic decoding. They make more orthographic and semantic mistakes and show low capacity of naming by writing. Thus, it was possible to verify that the sample presents deficits in receptive language and work memory, difficulties in phonological and syntactic processing tasks, which are important factors to the proper development of the capacity to read and write / A Síndrome de Williams-Beuren (SWB) é uma afecção genética determinada pela microdeleção de genes contíguos em 7q11.23. O perfil cognitivo da SWB é conhecido pelo prejuízo viso-construtivo que contrasta com melhor desempenho em tarefas verbais, o que sustenta a hipótese de dissociação entre essas habilidades, conferindo a esta síndrome um quadro cognitivo e comportamental peculiar. O objetivo deste estudo é descrever o padrão das competências em provas de habilidades lingüísticas de 22 crianças e adolescentes com SWB, com idades entre 7 e 18 anos (M= 11,6; DP=3,7), estudantes do 1º ao 6º ano do ensino fundamental e de Escolas Especiais. Foram utilizados os instrumentos: WISC-III (avaliação do potencial intelectual); Wisconsin (avaliação neuropsicológica de habilidades de raciocínio abstrato e estratégias cognitivas); CBCL/6 18 (perfil comportamental); Token-Comp (TT) (memória de trabalho); Teste de Vocabulário por Imagens Peabody (TVIP) (linguagem receptiva); Prova de Consciência Fonológica por produção Oral (PCFO); Prova de Consciência Sintática (PCS); Teste de Competência de Leitura de Palavras (TCLP); Teste de nomeação de figuras por escolha de palavras (TNF1 escolha) e o Teste de nomeação de figuras por escrita (TNF2 escrita). Os resultados nos testes WISC-III, Wisconsin e CBCL/6 18 apresentaram deficiência intelectual de leve à moderada, maior dificuldade em concentração e identificação de padrões de mudança, problemas afetivos e de relacionamento, desatenção, transtornos de conduta, desafio e oposição e queixas somáticas. Nos testes TT e TVIP foi possível observar que o vocabulário receptivo está abaixo do esperado para a escolaridade e para a idade, próximo ao encontrado em crianças de 4 anos. Nas habilidades de consciência fonológica e consciência sintática, os resultados mostraram grande comprometimento, com desempenho equivalente ao de crianças de 3 anos de idade na PCFO e de 4 anos na PCS, sendo que não foi identificada progressão em relação á série. Os testes TCLP, TNF1 e TNF2 foram realizados por 4 sujeitos que apresentam déficits de habilidade de leitura com decodificação grafofonemica, cometem mais erros semânticos e ortográficos e revelam baixa capacidade de nomeação por escrita. Desta maneira, foi possível identificar que, nessa amostra, há comprometimento de linguagem receptiva e de memória de trabalho, dificuldades em tarefas de processamento fonológico e sintático, os quais são fatores importantes para o bom desenvolvimento da leitura e da escrita

In der vorliegenden Arbeit wird eine Studie zum mentalen Lexikon bei Kindern mit Williams-Beuren-Syndrom (WBS) präsentiert. Das Lexikon junger WBS-Kinder entwickelt sich verzögert (Mervis & Robinson, 2000). Trotzdem gilt das Lexikon jugendlicher WBS-Probanden im Vergleich zu Probanden mit anderen Syndromen als elaboriert (Wang et al. 1995). Dies könnte auf sich spät entwickelnde Sprachfähigkeiten hindeuten. Es wird vermutet, dass ab 11 Jahren Veränderungen stattfinden, durch die das typische Profil des WBS erst entsteht (Rossen et al. 1996). Ziel der vorliegenden Arbeit ist es, sich der Aufholphase zu nähern, indem die lexikalischen Fähigkeiten vor dem kritischen Alter untersucht werden. Dazu werden zwei lexical constraints untersucht, die Markman (1989) für den ungestörten Lexikonerwerb postuliert. Whole object constraint (WOC): Das Kind nimmt an, dass sich ein unfamiliäres Wort auf ein ganzes Objekt bezieht. Mutual exclusivity constraint (MEC): Das Kind nimmt eine beidseitig exklusive Beziehung zwischen Wortform und Referenten an. Zum WBS gibt es eine einzige Studie zu den constraints (Stevens & Karmiloff-Smith 1997). Die WBS-Probanden sind zu alt (7;5 bis 31;5), um Aussagen über die Sprachfähigkeiten in der Zeit des Spurts machen zu können. Markman postuliert die constraints als Teil des universalen Wissens von Kindern. Dementsprechend ist die Hypothese, dass die constraints auch bei WBS-Kindern aktiv sind und in experimentellen Situationen zur Anwendung kommen. Zentral für die Hypothese ist die Untersuchung von Vorschulalkindern. Es werden 5 WBS-Kinder (3;2-7;0) und 98 chronologisch gematchte Kontrollkinder im WOC bzw. 97 im MEC untersucht. Es wird jeweils ein Versuch zum WOC (n=9) und zum MEC (n=12) durchgeführt. Beim WOC-Versuch wählen WBS-Kinder und Kontrollkinder am häufigsten das Zielitem. Die WBS-Kinder wählen häufig das Teilablenkerbild. Im Einzelfallvergleich sind 4 der 5 WBS-Kinder im Vergleich zu ihrer Kontrollgruppe auffällig. Im MEC-Versuch zeigen die ungestörten Kinder signifikant häufiger auf das Bild mit dem phonologischen Ablenker als die WBS-Kinder. In der Einzelfallanalyse liegen 4 von 5 WBS-Kindern bei der Auswahl des Zielitems oberhalb des Mittelwertes ihrer Kontrollgruppe. Insgesamt ergeben sich durch das Verhalten der WBS-Kinder in den Versuchen eher Hinweise auf defizitäre perzeptuelle Einflüsse auf die Anwendung der lexikalischen constraints als auf ihr Fehlen. Als Ursache für das Verhalten der WBS-Kinder wird die Detailpräferenzhypothese postuliert. Majerus et al.s (2003)Hypothese wird um die visuelle Verarbeitung erweitert. Diese findet lokal statt und kann nur bedingt Gattungsbegriffe aufbauen. Den überspezifizierten Wortformen stehen Teilrepräsentationen gegenüber. Die entstehenden semantischen Repräsentationen sind an konkreten Erfahrungen orientiert und verbleiben auf einer überspezifizierten Form. Mit der Hypothese der generellen Detailpräferenz wird zum ersten Mal eine einheitliche Wurzel für das Verhalten von WBS-Kindern im Vorschulalter in verschiedenen psychologischen Fakultäten aufgestellt. Majerus, S., Van der Linden, M., Mulder, L., Meulemans, T., & Peters, F. (2003). Verbal short-term memory reflects the sublexical organization of the phonological language network: evidence from an incidental phonotactic learning paradigm. Journal of Memory and Language, 51, 297-306. Markman, E. (1989). Categorization and naming in children. Cambridge MA: MIT Press. Mervis, C. B. & Robinson, B. F. (2000). Expressive vocabulary ability of toddlers with Williams syndrome or Down syndrome: a comparison. Developmental Neuropsychology, 17, 11-126. Rossen, M., Klima, E., Bellugi, U., Bihrle, A., & Jones, W. (1996). Interaction between language and cognition: evidence from Williams syndrome. In J. H. Beitchman, N. Cohen, M. Konstantareas, & R. Tannock (Eds.), Language, learning and behavior disorders: developmental, biological, and clinical perspectives. (367-392). New York: Cambridge University Press. Stevens, T. & Karmiloff-Smith, A. (1997). Word learning in a special population: do individuals with Williams syndrome obey lexical constraints? Journal of Child Language, 24, 737-765. Wang, P. P., Doherty, S., Rourke, S. B., & Bellugi, U. (1995). Unique profile of visuo-perceptual skills in a genetic syndrome. Brain and Cognition, 29, 54-65. / This thesis presents a study on two lexical constraints in german children with Williams syndrome (WS). The lexicon ist known to be delayed in WS, however in adults the lexicon is said to be elaborated (Wang et al. 1995). This might be a hint for late developing language compenteces. Rossen et al. (1996) see a performance growth in fluency in WS children older than 11 years. The aim of the current study is to examine the lexical learning mechanisms in WS children in kindergarden age. Five WS children are matched to 97 normal children on chronological age. Two experiments (whole object constraint, mutual exclusivity constraints) are designed, following the argumentations of Markman (1989). The results show that both lexical constraints are active in WS children but act on different inputinformations than in other children. In the discussion, the detail preference hypothesis is drawn, which postulates for the first time a unique perceptual deficit which influences language acquisition without also implying a primary language disorder. Markman, E. (1989). Categorization and naming in children. Cambridge MA: MIT Press. Wang, P. P., Doherty, S., Rourke, S. B., & Bellugi, U. (1995). Unique profile of visuo-perceptual skills in a genetic syndrome. Brain and Cognition, 29, 54-65.

The complicated problem of efficient stimulation of elastic fiber production in already developed human tissues has not yet been solved. The present study introduces sodium ascorbate (SA) as a stimulator of elastogenesis in cultures of different cell types including fibroblasts isolated from patients with elastopathy genetic diseases. We then elucidated mechanisms of elastogenic action of SA. SA exercises its net elastogenic effect only after being actively transported into the cell interior through two separate mechanisms. These are the “fast effect,” which reflects the greater stability of intracellular tropoelastin, and the “late effect,” which reflects the true enhancement of the elastin gene expression occurring after SA-induced activation of c-src tyrosine kinase and the consecutive phosphorylation of IGF-1 receptor, which triggers the downstream signals leading to activation of the elastin gene expression. In conclusion, for the first time we have established that SA is a potent stimulator of elastic fiber production.

The complicated problem of efficient stimulation of elastic fiber production in already developed human tissues has not yet been solved. The present study introduces sodium ascorbate (SA) as a stimulator of elastogenesis in cultures of different cell types including fibroblasts isolated from patients with elastopathy genetic diseases. We then elucidated mechanisms of elastogenic action of SA. SA exercises its net elastogenic effect only after being actively transported into the cell interior through two separate mechanisms. These are the “fast effect,” which reflects the greater stability of intracellular tropoelastin, and the “late effect,” which reflects the true enhancement of the elastin gene expression occurring after SA-induced activation of c-src tyrosine kinase and the consecutive phosphorylation of IGF-1 receptor, which triggers the downstream signals leading to activation of the elastin gene expression. In conclusion, for the first time we have established that SA is a potent stimulator of elastic fiber production.

There is evidence from family studies for the importance of genetic factors in the development of autism spectrum disorders (ASDs) but the identification of major genes has not been achieved to date. There are several reports of deletions and duplications in individuals with ASDs, some of which are not unique to an individual. In most cases, the frequencies and relevance of these abnormalities are unknown, as they have been identified serendipitously in one or a few individuals. My overall hypothesis was that such rearrangements would facilitate the identification of “culprit” genes associated with ASDs by identifying a small chromosomal region for candidate gene testing. I molecularly characterized two overlapping 2p15-2p16.1 deletions detected in unrelated individuals with confirmed autistic disorder (Subject 1) or autistic features (Subject 2), a 1.4Mb deletion on chromosome Xp22 (Subject 1) and a duplication of chromosome 7q11.23, reciprocal to the Williams-Beuren Syndrome (WBS) deletion, in one individual with an ASD (Subject 3). Using real-time semi-quantitative PCR, I screened a total of 798 individuals with an ASD and 186 healthy controls for the presence of similar abnormalities. No additional cases were identified in either group. Subsequently, I selected 6 genes [Orthodenticle homolog 1 (OTX1), Variable charge, X-linked (VCX), Neuroligin 4, X-linked (NLGN4X), Syntaxin 1A (STX1A), Cytoplasmic linker 2 (CYLN2) and General transcription factor IIi (GTF2i)], based on their function and localization within or in the vicinity of the rearrangements and tested them for association with ASDs. Although there was no evidence for association for any marker or haplotype in most of the genes tested, this was not so for GTF2i. Haplotype transmission disequilibrium testing revealed an increased transmission, from healthy parents to their affected offspring, of the common alleles of one marker and one haplotype in GTF2i (P = 0.0010 and 0.0005, respectively). This gene encodes a brain-expressed transcription factor previously implicated in the mental retardation associated with WBS. Based on these findings, I propose that, although the genomic rearrangements reported herein are not a common cause of ASDs, the GTF2i gene within the WBS critical region is important in the aetiology of autism. / Thesis (Ph.D, Physiology) -- Queen's University, 2009-11-20 00:35:11.727

El descubrimiento de las duplicaciones segmentarias (DS) o Low Copy Repeats (LCRs) ha permitido definir nuevos mecanismos evolutivos mediados, en gran parte, por duplicación génica. Las DS son responsables de reordenamientos que pueden ser submicróscopicos dando lugar a pequeñas pérdidas o ganancias de material genómico. La elucidación sobre su implicación y relación en enfermedades humanas ha generado la necesidad de crear nuevos instrumentos de medida que permitan rastrear el genoma humano a una mayor resolución que la conseguida mediante cariotipo normal. Una de estas nuevas técnicas se denomina matrices aCGH. En esta tesis doctoral se han desarrollado métodos que permiten la optimización de la técnica durante el proceso de fabricación e hibridación y que, a su vez, pueden ser aplicados sobre los métodos actuales de detección de CNVs incrementando su sensibilidad y especificidad. Además se ha realizado una comparación entre plataformas aCGH así como un análisis transcriptómico global de muestras alteradas, tomando como modelo de estudio el síndrome de Williams-Beuren que está caracterizado por una deleción parcial en la banda 7q11.23. A parte de ganancias y pérdidas de fragmentos de material génico, las DSs pueden generar copias de genes que pueden acumular cambios respecto el original (PSVs). Algunos de estas PSVs ya se han identificado como patogénicas por ello es de gran utilidad su estudio.

Submitted by Marta Toyoda (1144061@mackenzie.br) on 2017-01-18T16:59:58Z No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Ismael Lima Junior.pdf: 2867869 bytes, checksum: 23357746ee679899accbb9bb5f6431fa (MD5) / Approved for entry into archive by Eliezer Santos (eliezer.santos@mackenzie.br) on 2017-02-02T17:22:00Z (GMT) No. of bitstreams: 2 Ismael Lima Junior.pdf: 2867869 bytes, checksum: 23357746ee679899accbb9bb5f6431fa (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Made available in DSpace on 2017-02-02T17:22:00Z (GMT). No. of bitstreams: 2 Ismael Lima Junior.pdf: 2867869 bytes, checksum: 23357746ee679899accbb9bb5f6431fa (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2015-08-04 / The aim of this study is to produce and evaluate an informative video and guidance to parents and caregivers about the behavioral management of people with Williams-Beuren syndrome. And also answer to the problem: "how to contribute scientific and socially with the public who lives and works with individuals with WBS?". The research allows possession of information on the SWB contained in the work done by researchers related to our Theoretical Framework. The syndrome is rare and is associated with neurocognitive and behavioral phenotypes that should be understood as the basis for the research of behavioral, emotional and cognitive patterns, without disregarding the influence of the environment and its connection with intellectual deficit. Through knowledge of symptoms, it is possible to help in the early diagnosis, providing better handling with the individual and improved quality of life. To contribute to this, we develop and produce a video guidance report for parents / caregivers, whose central purpose is the dissemination of information and care for individuals with Williams-Beuren syndrome. The video is available to parents and caregivers, after being evaluated by professionals, undergraduates and graduate students. This process finds an answer to the question "How to donate?" and has come to an end after evaluation of all the groups, who answered to questions about the effectiveness of information. The evaluation was carried out with the participation of forty-six judges who answered to ten objective questions about its content and development. We have as judges: three professionals working in the area, eight graduate students, eleven graduates in Psychology and twenty-four parents / caregivers of children / adolescents with WBS. In eight questions of evaluation we obtained 100% approval by 46 forty-six judges, revealing that the video has fulfilled its main objective to contribute scientific and socially, to inform and guide parents / caregivers of people with SWB. In conclusion, we can consider that the video produced and evaluated in this thesis presents relevant guidelines and meets the information needs of the target audience, with a proposal of easy understanding. We understand that with this production, we can really contribute to social development and information for parents and caregivers. / O objetivo do presente estudo foi o de produzir e avaliar um vídeo informativo e de orientação direcionado a pais e cuidadores sobre o manejo comportamental de pessoas com Síndrome de Williams-Beuren. E, também, responder à problemática: “como contribuir científica e socialmente com o público que convive e trabalha com indivíduos com a SWB?”. A revisão (pesquisa) bibliográfica permitiu a posse de informações sobre a SWB que constam nos trabalhos realizados por pesquisadores relacionados em nosso Referencial Teórico. A Síndrome é rara e está associada a fenótipos neurocognitivos e comportamentais que devem ser entendidos como a base para a pesquisa de padrões comportamentais, emocionais e cognitivos, sem desconsiderar a influência do ambiente e sua ligação com o déficit intelectual. Através do conhecimento dos sintomas, é possível ajudar no diagnóstico precoce, proporcionando melhor manejo com o indivíduo e melhora na qualidade de vida. Para contribuir, desenvolvemos e produzimos um vídeo reportagem de orientação para pais/cuidadores, tendo como objeto central a disseminação de informações e cuidados com indivíduos com a Síndrome de Williams-Beuren. O vídeo foi disponibilizado a pais e cuidadores, após ser avaliado pelos profissionais, graduandos e pós-graduandos. O processo que teve por objetivo encontrar resposta para a questão “Como contribuir ?” Chegou ao seu término após a avaliação de todos os grupos, que responderam a perguntas sobre a eficácia das informações. A avaliação foi efetuada com a participação de quarenta e seis juízes, que responderam a dez questões objetivas sobre seu conteúdo e desenvolvimento. Como juízes: três profissionais que atuam na área, oito pós-graduandos, onze graduandos em Psicologia e vinte e quatro pais/cuidadores de crianças/adolescentes com SWB. Em oito questões de avaliação do conteúdo obteve-se 100% de aprovação pelos 46 quarenta e seis juízes, revelando que o vídeo cumpriu seu principal objetivo, contribuir científica e socialmente, ao informar e orientar pais/cuidadores de pessoas com SWB. Concluindo, pode-se ponderar que o vídeo produzido e avaliado na presente tese apresenta relevantes orientações através da forma televisiva, e atende às necessidades informativas do público alvo, com uma proposta de fácil acesso. Entendemos que com esta produção, podemos contribuir de forma marcante com o desenvolvimento social e informativo a pais e cuidadores.

En aquest treball es presenta l'evolució molecular i estudi funcional de gens localitzats a les duplicacions segmentàries de la regió 7q11.23, implicada en la Síndrome de Williams-Beuren (SWB). S'ha datat l'aparició d'aquestes duplicacions en els últims 25 milions d'anys d'evolució i s'ha proposat un model evolutiu amb reordenaments específics i mecanismes de generació. Correlacions clínico-moleculars en els pacients amb la SWB han permès determinar que l'haploinsuficiència per NCF1, un gen localitzat a les duplicacions, és un factor protector per hipertensió. S'ha proposat un model patogènic per la hipertensió, implicant l'oxidasa NAD(P)H i estrès oxidatiu, suggerint que noves estratègies terapèutiques podrien ser utilitzades. A més, s'ha caracteritzat parcialment la funció de GTF2IRD2, un altre gen de les duplicacions. GTF2IRD2 interacciona amb altres factors de transcripció relacionats, té una localització subcel·lular variable i no s'uneix a ADN. Aquests resultats contribueixen a conèixer millor els mecanismes mutacionals i patogènics de la SWB. / This work presents the molecular evolution along with the functional analysis of the genes located in the segmental duplications flanking the 7q11.23 region, involved in Williams-Beuren syndrome (WBS). The generation of the segmental duplications has been dated to the last 25 million years of evolution and an evolutionary model with specific rearrangements and mechanisms has been proposed. Clinical-molecular correlations in WBS patients have allowed to determine that haploinsufficiency at NCF1, a gene located in the duplications, is a protective factor for hypertension. A pathogenic model for hypertension has been proposed, implicating NAD(P)H oxidase and oxidative stress, and suggesting that novel therapeutic strategies could be used. In addition, the functional characterization of another gene of the duplications, GTF2IRD2, has been partially achieved. GTF2IRD2 has been shown to interact with other related transcription factors, to display variable subcellular localization and to lack DNA binding properties. These results contribute to a better knowledge of the mutational and pathogenic mechanisms of the WBS.

Williams-Beuren syndrome (WBS) is a neurodevelopmental disorder caused by the common deletion of 26-28 contiguous genes in the 7q11.23 region, which poses difficulties to the establishment of genotype-phenotype correlations. The use of mouse models would broader the knowledge of the syndrome, the role of deleted genes, affected pathways and possible treatments. In this thesis project, several mouse models, tissues and cells have been used to define the phenotypes at different levels, the deregulated genes and pathways and to discover modifying elements and novel treatments for the cardiovascular phenotype. In addition, a new binding motif has been described for Gtf2i, a deleted gene encoding a transcription factor with a major role in WB, providing new target genes from deregulated pathways. The obtained results reveal the essential role of mouse models for the study of Williams-Beuren syndrome and provide new treatments options and affected pathways and genes which could be future treatment targets. / La síndrome de Williams-Beuren és una malaltia del neurodesenvolupament causada per una deleció comú d’entre 26 i 28 gens contigus a la regió 7q11.23, dificultant l’establiment de relacions genotip-fenotip. L’ús de models de ratolí pot augmentar el coneixement sobre la malaltia, el paper dels gens delecionats, les vies moleculars afectades i els futurs tractaments. En aquesta tesi s’han usat diversos models de ratolí, les seves cèl·lules i teixits per tal de descriure i definir fenotips, gens i vies moleculars desregulades i per descobrir elements modificadors i nous tractaments. Per últim, s’ha definit un nou motiu d’unió per Gtf2i, uns dels gens delecionats que codifica per un factor de transcripció amb un rol central en la síndrome, proporcionats possible nous gens diana de vies moleculars desregulades. Els resultats obtinguts revelen el paper essencial dels models de ratolí per a l’estudi de la síndrome de Williams-Beuren, proporcionen noves opcions terapèutiques i defineixen nous gens i vies moleculars afectades que podrien suposar noves dianes terapèutiques.