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Implementation of New Strategies for Mutational and Functional Characterization of Families with Clinically Suspected Bardet-Biedl Syndrome

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Implementation of New Strategies for Mutational and Functional Characterization of Families with Clinically Suspected Bardet-Biedl Syndrome DOCTORAL DISSERTATION Implementation of new strategies for mutational and functional characterization of families with clinically suspected Bardet-Biedl syndrome Sheila Castro Sánchez 2017 “International Mention” International Doctoral School Sheila Castro Sánchez DOCTORAL DISSERTATION Implementation of new strategies for mutational and functional characterization of families with clinically suspected Bardet-Biedl syndrome Supervised by: Dr. Diana Valverde Pérez 2017 “International Mention” During the development of this doctoral thesis, Sheila Castro Sánchez has received a predoctoral fellowship from the Plan gallego de investigación, innovación y crecimiento 2011-2015/Plan I2C (Consellería de Cultura, Educación e Ordenación Universitaria, Xunta de Galicia; Ref. PRE/2012/501) and a FPU (Formación de Profesorado Universitario) predoctoral fellowship (Ministerio de Educación, Cultura y Deporte; Ref. FPU13/01835). This research work has been carried out in the Molecular Biomarkers Group (BB1) at the Department of Biochemistry, Genetics and Immunology, and has been funded by the following research projects: -Aplicación de nuevas tecnologías en la caracterización de Ciliopatías: Síndrome de Bardet-Biedl y Alström (PI12/01853). Instituto de Salud Carlos III, Fondo de Investigación Sanitaria, Ministerio de Economía y Competitividad. Period: 2013-2015. -Biomedical Capacities Support Program (BIOCAPS) (FP7 REGPOT-2012-2013. Grant agreement: 316265). European Union (7º Programa Marco). Period: 2013-2016. -Rutas de señalización coordinadas por el cilio primario: papel de los genes ciliares BBS/ALMS1 y valoración de nuevos genes candidatos (PI15/00049). Instituto de Salud Carlos III, Fondo de Investigación Sanitaria, Ministerio de Economía y Competitividad. Period: 2016-2018. In the course of this doctoral thesis, Sheila Castro Sánchez made a three-month research stay (01/09/2015 to 29/11/2015) in the Laboratorio de Genética Molecular Humana, Institut Pasteur de Montevideo (Uruguay), under the supervision of Dr. Jose Luis Badano, with funding from the Ministerio de Educación, Cultura y Deporte (Ayudas Complementarias para Beneficiarios de Ayudas FPU: Estancias Breves y Traslados Temporales (2014)). The results derived from this work have led to the following publications in scientific journals: Álvarez-Satta M*, Castro-Sánchez S*, Pereiro I, Piñeiro-Gallego T, Baiget M, Ayuso C, Valverde D. Overview of Bardet-Biedl syndrome in Spain: identification of novel mutations in BBS1, BBS10 and BBS12 genes. Clin Genet 2014; 86:601-602. (*Co-authors). Castro-Sánchez S*, Álvarez-Satta M*, Pereiro I, Piñeiro-Gallego MT, Valverde D. Algorithm for the molecular analysis of Bardet-Biedl syndrome in Spain. Med Clin (Barc) 2015; 145:147-152. (*Co-authors). Castro-Sánchez S*, Álvarez-Satta M*, Cortón M, Guillén E, Ayuso C, Valverde D. Exploring genotype-phenotype relationships in Bardet-Biedl syndrome families. J Med Genet 2015; 52:503-513. (*Co-authors). Castro-Sánchez S, Álvarez-Satta M, Tohamy Mohamed A., Beltran S, Derdak S, Valverde D. Whole exome sequencing as a diagnostic tool for patients with ciliopathy-like phenotypes. PLoS One (under revision). Castro-Sánchez S, Suárez-Bregua P, Álvarez-Satta M, Rotllant J, Valverde D. Functional analysis of BBS variants in zebrafish model. (in preparation) Castro-Sánchez S, Álvarez-Satta M, Valverde D. WES identifies DOCK6 as a novel ciliary gene. (in preparation). The results of this work have also derived in the following communications to congresses: Álvarez-Satta M, Castro-Sánchez S, Valverde, D. Resultados preliminares del análisis de los genes BBS1 y BBS12 en pacientes afectos de síndrome de Bardet-Biedl. V Jornada de Investigación Biomédica. Vigo (Spain), 2012. Castro Sánchez S, Álvarez Satta M, Pereiro Rodríguez I, Ayuso C, Valverde D. Correlación genotipo-fenotipo en pacientes con síndrome de Bardet-Biedl. XXVII Congreso Nacional de la Asociación Española de Genética Humana, AEGH. Madrid (Spain), 2013. Castro Sánchez S, Álvarez Satta M, Pereiro Rodríguez I, Valverde D. El síndrome de Bardet-Biedl: elaboración de un algoritmo de diagnóstico molecular. XXVII Congreso Nacional de la Asociación Española de Genética Humana, AEGH. Madrid (Spain), 2013. Álvarez Satta M, Castro Sánchez S, Valverde D. Implicación de los genes BBS en población española afecta del síndrome de Bardet-Biedl. BioIntegraSaúde 2013. Santiago de Compostela (Spain), 2013. Castro Sánchez S, Álvarez Satta M, Valverde D. Novel mutations involved in Bardet-Biedl syndrome. European Human Genetics Conference, ESHG. Paris (France), 2013. Castro Sánchez S, Álvarez Satta M, Valverde D. Molecular approaches in the Diagnosis of Bardet-Biedl syndrome. First International Congress on Biomedical Research and Innovation (BIOCAPS), Vigo (Spain), 2013. Castro-Sánchez S, Álvarez-Satta M, Valverde D. Genotype-phenotype correlation for BBS1 gene in Bardet-Biedl syndrome patients. 47th European Human Genetics Conference. Milan (Italy), 2014. Castro-Sánchez S, Álvarez-Satta M, Valverde D. Performing Whole-Exome Sequencing in Bardet-Bie syndrome. Cilia 2014. Paris (France), 2014. Castro-Sánchez S, Álvarez-Satta M, Cortón M, Ayuso C, Valverde D. Herencia trialélica en dos familias diagnosticadas de síndrome de Bardet-Biedl. XXVIII Congreso Nacional de Genética Humana, AEGH. Palma de Mallorca (Spain), 2015. Castro-Sánchez S, Suárez-Bregua P, Álvarez-Satta M, Rotllant J, Valverde D. Caracterización de mutaciones en el gen BBS5 mediante análisis funcional en el pez cebra. III Xornadas de Investigación BioIntegraSaúde 2015. Vigo (Spain), 2015. Castro-Sánchez S, Suárez-Bregua P, Álvarez-Satta M, Rotllant P, Valverde D. Characterization of mutations in BBS5 gene by functional analysis in zebrafish model. 48th European Human Genetics Conference. Glasgow (Escocia), 2015. Castro-Sánchez S, Lepanto P, Novas R, Suárez-Bregua P, Álvarez-Satta M, Rotllant J, Badano J, Valverde D. Zebrafish: a useful model for functional characterization of BBS variants. EMBO Conference Cilia 2016. Amsterdam (Netherlands), 2016. Castro-Sánchez S, Álvarez-Satta M, Valverde D. DOCK6: nuevo gen implicado en ciliopathies. I Congreso Interdisciplinar en Genética Humana. Madrid (Spain), 2017. TABLE OF CONTENTS TABLE OF CONTENTS ABBREVIATIONS .......................................................................................................................... 1 ABSTRACT ..................................................................................................................................... 9 GENERAL INTRODUCTION ..................................................................................................... 21 2. CILIOPATHIES .......................................................................................................... 27 3. BARDET-BIEDL SYNDROME .................................................................................... 30 3.1 Epidemiology ........................................................................................................... 30 3.2. Clinical spectrum and diagnosis ............................................................................ 31 3.3. Genetics and heredity ............................................................................................ 34 3.4. BBS proteins and related functions ...................................................................... 36 3.5. Management, prognosis and counselling ............................................................ 40 OBJECTIVES ................................................................................................................................. 43 CHAPTER I: Mutational analysis of BBS1 gene in Spanish BBS patients: an attempt of genotype-phenotype correlation ..................................................................................... 47 1. INTRODUCTION ...................................................................................................... 49 2. PATIENTS AND METHODS ..................................................................................... 53 2.1 Patients ...................................................................................................................... 53 2.2 Direct sequencing of BBS1 gene ............................................................................. 54 3. RESULTS .................................................................................................................. 65 3.1 Identification and characterization of predicted pathogenic variants ............. 65 3.2 Genotype-phenotype correlation .......................................................................... 69 4. DISCUSSION............................................................................................................ 83 4.1 Contribution of BBS1 gene in a Spanish bbs cohort ............................................ 83 4.2 Improvement of diagnostic algorithm for Spanish BBS patients ....................... 85 4.3 Genotype-phenotype relationships in Spanish BBS families ............................. 89 CHAPTER II: Functional analysis of BBS variants in zebrafish............................................ 95 1. INTRODUCTION ...................................................................................................... 97 2. PATIENTS AND METHODS ...................................................................................... 99 2.1 Study cohort .............................................................................................................. 99 2.2 Mutational analysis .................................................................................................
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