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GENOME-WIDE APPROACHES TO INVESTIGATE RARE NEUROLOGICAL DISORDERS IN FRENCH CANADIANS Karine Choquet Department of Human Genetics McGill University, Montréal, Canada April 2018 A thesis submitted to McGill University in partial fulfillment of the requirements of the degree of Doctor of Philosophy © Karine Choquet, 2018 ABSTRACT The French Canadian population of Québec is defined by a unique history and genetic heritage, which has led to the regional clustering of a large number of Mendelian diseases. This includes several types of cerebellar ataxias, a heterogeneous group of neurological disorders characterized by impaired balance and coordination. In the past 20 years, the causative genes have been identified for the major forms of autosomal recessive cerebellar ataxias (ARCA) in Québec. However, approximately 30% of French Canadian ARCA patients remain without a definite molecular diagnosis. We combined whole exome and targeted sequencing and identified the underlying genetic defect in 13 families, representing more than 40% of our unresolved ARCA cohort. Specifically, we uncovered pathogenic SPG7 mutations in 12 families, demonstrating that this is an important cause of spastic ataxia in Québec. In the last family, we found a homozygous mutation in the gene PMPCA, a recently described novel cause of ARCA. In order to improve the number of available treatments for cerebellar ataxias, it is crucial to gain a better understanding of the pathogenic mechanisms responsible for these diseases. Thus, we next focused on one specific ataxia-related disorder, Pol III-related hypomyelinating leukodystrophy (POLR3-HLD), and on unraveling its pathophysiological processes. POLR3- HLD is characterized by deficient cerebral myelin formation and is caused by recessive mutations in the genes POLR3A, POLR3B and POLR1C, encoding three subunits of RNA Polymerase III (Pol III). Pol III is an essential enzyme responsible for the synthesis of transfer RNAs (tRNA) and many small non-coding RNAs. First, we generated two knock-in mouse models and performed an in-depth phenotypic and molecular characterization. We found that the Polr3a c.2015G>A (p.G672E) mutation does not lead to a neurological phenotype in mouse, contrary to what is observed in human homozygotes, and that the G672E mutation causes only a mild defect in Pol III function in human cells. Next, using CRISPR-Cas9 gene editing and two complementary RNA-sequencing approaches, we observed that mutations in POLR3A lead to decreased expression of a subset of Pol III transcripts in human cell lines, with the most potent impact on nuclear-encoded tRNAs, the signal recognition particle 7SL RNA and the brain cytoplasmic BC200 RNA. Furthermore, expression profiling in patient-derived fibroblasts and genomic deletion of BC200 in an oligodendroglial cell line provide the first evidence linking this non-coding RNA to POLR3-HLD pathogenesis. Overall, our findings contribute to a better understanding of the genetic and molecular basis of three distinct ataxia-related disorders in 2 French Canadians, while providing insights into the role of an essential enzyme in mouse and human. 3 RÉSUMÉ La population canadienne française du Québec est caractérisée par une histoire et un héritage génétique uniques ayant mené au regroupement régional de nombreuses maladies héréditaires. Celles-ci incluent diverses formes d’ataxies cérébelleuses, un groupe hétérogène de maladies neurologiques définies par un défaut d’équilibre et de coordination. Au cours des vingt dernières années, les gènes causant les formes majeures d’ataxies cérébelleuses autosomiques récessives (ACAR) au Québec ont été identifiés. Pourtant, environ 30% de patients canadiens français atteints d’ACAR n’ont toujours pas de diagnostic moléculaire. En combinant des méthodes de séquençage exomique et ciblé, nous avons identifié le défaut génétique chez 13 familles, ce qui représente plus de 40% de notre cohorte de cas d’ACAR non résolus. Précisément, nous avons découvert des mutations pathogéniques dans le gène SPG7 chez 12 familles, démontrant ainsi qu’il s’agit d’une cause importante d’ataxie spastique au Québec. Chez la dernière famille, nous avons trouvé une mutation homozygote dans le gène PMPCA, une nouvelle cause d’ACAR récemment identifiée. Afin d’améliorer le nombre insuffisant de traitements disponibles pour les ataxies cérébelleuses, il est indispensable de mieux comprendre les mécanismes pathogéniques à l’origine de ces maladies. Ainsi, nous nous sommes ensuite concentrés sur la résolution des processus pathophysiologiques présents dans les leucodystrophies hypomyélinisantes reliées à l’ARN polymérase III (LDH-POLR3). Ce groupe de maladies caractérisé par un déficit de formation de la myéline dans le système nerveux central est aussi associé à la présence d’ataxie cérébelleuse et est causé par des mutations récessives dans les gènes POLR3A, POLR3B et POLR1C, codant pour trois sous-unités de l’ARN polymérase III (Pol III). Pol III est une enzyme essentielle qui synthétise les ARNs de transfert (ARNt) ainsi que de nombreux petits ARNs non codants. D’abord, nous avons généré deux modèles de souris et les avons caractérisés de façon détaillée aux niveaux phénotypique et moléculaire. Nos résultats montrent que la mutation c.2015G>A (p.G672E) dans Polr3a ne cause pas de phénotype neurologique chez la souris, contrairement à ce qui est observé chez les patients humains homozygotes. De plus, la mutation G672E n’entraîne qu’un défaut léger de la fonction de Pol III dans des cellules humaines. Ensuite, à l’aide de la technologie d’édition du génome CRISPR-Cas9 et de deux méthodes complémentaires de séquençage de l’ARN, nous avons découvert que des mutations dans POLR3A mènent à une diminution de l’expression d’un sous-groupe de transcrits Pol III dans des 4 lignées cellulaires humaines. Parmi les transcrits les plus affectés, nous retrouvons les ARNt, l’ARN 7SL de la particule de reconnaissance du signal et l’ARN cytoplasmique du cerveau BC200. De plus, à l’aide de mesures d’expression dans des fibroblastes de patients et de la délétion génomique de BC200 dans une lignée cellulaire oligodendrocytaire, nous démontrons un premier lien entre cet ARN non codant et la pathogénèse de la LDH-POLR3. En conclusion, nos données contribuent à une meilleure compréhension des bases génétiques et moléculaires de trois différentes maladies reliées à l’ataxie chez les Canadiens français, tout en approfondissant le rôle d’une enzyme essentielle chez la souris et l’humain. 5 Table of Contents ABSTRACT ................................................................................................................................... 2 RÉSUMÉ ........................................................................................................................................ 4 LIST OF ABBREVIATIONS ....................................................................................................... 9 LIST OF FIGURES ..................................................................................................................... 13 LIST OF TABLES ....................................................................................................................... 15 ACKNOWLEDGEMENTS ........................................................................................................ 16 PREFACE .................................................................................................................................... 18 Contribution of Authors ......................................................................................................... 19 Original Contribution to Knowledge ..................................................................................... 21 CHAPTER 1: General Introduction .......................................................................................... 22 1.1 Genetics of autosomal recessive cerebellar ataxias ........................................................ 23 1.1.1 Cerebellar ataxias ......................................................................................................... 23 1.1.2 Autosomal recessive cerebellar ataxias (ARCA) ......................................................... 24 1.1.3 ARCAs in the French Canadian population ................................................................. 24 1.1.4 Next-generation sequencing in the genetic diagnosis of ARCAs ................................ 26 1.2 Pol III-related leukodystrophies ...................................................................................... 28 1.2.1 Myelination in the central nervous system ................................................................... 28 1.2.2 Leukodystrophies ......................................................................................................... 30 1.2.3 Pol III-related leukodystrophy: a new disease entity ................................................... 32 1.2.4 Expansion of the phenotypic spectrum associated with POLR3A and POLR3B mutations ............................................................................................................................... 33 1.3 Function and regulation of RNA Polymerase III and its transcripts ........................... 35 1.3.1 Pol III transcription machinery and associated proteins ............................................... 35 1.3.2 Functions of Pol III transcripts ..................................................................................... 36 1.3.3 Regulation of Pol III transcription ...............................................................................
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