Le syndrome de Joubert est une maladie récessive caractérisée par une malformation congénitale distincte du tronc cérébral et du cervelet, associée à une anomalie des mouvements oculaires (apraxie oculomotrice), une respiration irrégulière, un retard de développement, et une ataxie à la démarche. Au cours de la dernière décennie, plus de 20 gènes responsables ont été identifiés, tous ayant un rôle important dans la structure et la fonction des cils primaires. Ainsi, le syndrome de Joubert est considéré une ciliopathie. Bien que le Syndrome de Joubert ait été décrit pour la première fois dans une famille canadienne-française en 1969, le(s) gène(s) causal demeurait inconnu dans presque tous les cas de syndrome de Joubert recensés en 2010 dans la population canadienne-française, soit début de mon projet doctoral. Nous avons identifié un total de 43 individus canadiens-français (35 familles) atteints du syndrome de Joubert. Il y avait un regroupement de familles dans la région du Bas-Saint-Laurent de la province de Québec, suggérant la présence d'un effet fondateur. L’objectif de ce projet était de caractériser la génétique du syndrome de Joubert dans la population canadienne-française. Notre hypothèse était qu’il existait un effet fondateur impliquant au moins un nouveau gène JBTS. Ainsi, dans un premier temps, nous avons utilisé une approche de cartographie par homozygotie. Cependant, nous n’avons pas identifié de région d’homozygotie partagée parmi les individus atteints, suggérant la présence d’une hétérogénéité génétique ou allélique. Nous avons donc utilisé le séquençage exomique chez nos patients, ce qui représente une approche plus puissante pour l’étude de conditions génétiquement hétérogènes. Nos travaux ont permis l’identification de deux nouveaux gènes responsables du syndrome de Joubert: C5orf42 et TMEM231. Bien que la localisation cellulaire et la fonction de C5orf42 soient inconnus au moment de cette découverte, nos résultats génétiques combinés avec des études ultérieures ont établi un rôle important de C5orf42 dans la structure et la fonction ciliaire, en particulier dans la zone de transition, qui est une zone de transition entre le cil et le reste de la cellule. TMEM231 avait déjà un rôle établi dans la zone de transition ciliaire et son interaction avec d’autres protéines impliquées dans le syndrome de Joubert était connu. Nos études ont également identifié des variants rares délétères chez un patient JBTS dans le gène ciliaire CEP104. Nous proposons donc CEP104 comme un gène candidat JBTS. Nous avons identifié des mutations causales dans 10 gènes, y compris des mutations dans CC2D2A dans 9 familles et NPHP1 dans 3 familles. Au total, nous avons identifié les mutations causales définitives chez 32 des 35 familles étudiées (91% des cas). Nous avons documenté un effet fondateur complexe dans la population canadienne-française avec de multiples mutations récurrentes dans quatre gènes différents (C5orf42, CC2D2A, TMEM231, NPHP1). Au début de ce projet de recherche, l’étiologie génétique était inconnue chez les 35 familles touchées du syndrome de Joubert. Maintenant, un diagnostique moléculaire définitif est identifié chez 32 familles, et probable chez les 3 autres. Nos travaux ont abouti à la caractérisation génétique du syndrome de Joubert dans la population canadienne-française grâce au séquençage exomique, et révèlent la présence d'un effet fondateur complexe avec une l'hétérogénéité allélique et intralocus importante. Ces découvertes ont éclairé la physiologie de cette maladie. Finalement, l’identification des gènes responsables ouvre de nouvelles perspectives diagnostiques ante-natales, et de conseils génétique, très précieuses pour les familles. / Joubert syndrome (JBTS) is a primarily autosomal recessive disorder characterized by a distinctive mid-hindbrain/cerebellum malformation, eye movement abnormalities (oculomotor apraxia), irregular breathing, developmental delay, and ataxia. Over the past decade, over 20 causal genes have been identified, all of which have an important role in the structure and function of the primary cilia. Thus, JBTS joins an expanding category of diseases termed “ciliopathies”. Though JBTS was first described in affected siblings of a French Canadian (FC) family in 1969, the underlying genesis basis of the disorder was unknown in the overwhelming majority of FC cases at the onset of this doctoral project in 2010. We identified a total of 43 FC individuals with JBTS from 35 families. We observed a clustering of the affected families in the Lower Saint-Lawrence region of the province of Quebec, suggesting the presence of a founder effect. The aim of this doctoral project was to characterize the genetic landscape of JBTS in the FC population, and we hypothesized the presence of a founder effect in novel JBTS gene(s). Therefore, we initially used a homozygosity mapping approach. However, we did not identify any shared regions of homozygosity amongst affected individuals, suggesting the presence of genetic and/or allelic heterogeneity. We therefore primarily used a whole exome sequencing approach in our JBTS patients, a strategy that is better suited for the study of genetically heterogeneous conditions. Our work has resulted in the identification of two novel JBTS genes: C5orf42 and TMEM231. In total, we have identified causal mutations in C5orf42 in 14 families (including the original JBTS family described in 1969), and TMEM231 in 2 families. Though the function and cellular localization of C5orf42 was not known at the time of the publication of our manuscript, our genetic findings combined with subsequent animal and cellular work establish the important role of C5orf42 in ciliary structure and function, particularly at the ciliary transition zone. TMEM231 had been previously shown to localize to the ciliary transition zone and interact with several JBTS gene products. We also identified deleterious rare variants in one JBTS patient in the ciliary gene CEP104, implicating CEP104 as a strong candidate JBTS gene. We identified causal mutations in 10 JBTS genes, including CC2D2A in 9 families and NPHP1 in 3 families. Definite causal mutations were identified in 32 of 35 families (91% of cases). We documented a complex founder effect in the FC population with multiple recurrent mutations in 4 different genes (C5orf42, CC2D2A, TMEM231, NPHP1). Prior to the start of this research endeavor, the underlying genetic etiology of Joubert syndrome was unknown in all 35 families. Now, a definite molecular diagnosis has been identified in 32 families, and a probable molecular diagnosis in the remaining 3. Therefore, our work has resulted in the unraveling of the genetic basis of JBTS in the French-Canadian population using WES, and reveals the presence of a complex founder effect with substantial locus and allelic heterogeneity.

Ph.D. / A central tradition within the art of novel-writing is that of realism. Reality cannot be duplicated, and the illusion of reality in literature depends on narrative conventions. Within the perspective of the age-old tradition of realism one would have to view the bent and the emphasis of modern prose in the light of what has been described as "realism with documentary woof", "faction" , and "the new realism". The link with the reality of the day is often such that one cannot merely talk about "illusion of reality" - it pertinently becomes "illusion of actuality". The "political" noveI that wants to play in upon an actual situation, brings about an important change in the character of the literary work: the fictional is subdued, so to speak. In this study the question concerning the relation between work of art and actuality strikingly comes to the fore as a problem. The author increasingly addresses himself to the portrayal of the actual. Two methods of portrayal are identified: i) the actuality situation is fictionalised and ii ) a semblance of authenticity is given to the fictitious situation. In this thesis the different strategies employed in each of the two methods of portrayal of actuality are examined. The concepts "actuality", "illusion", and "involvement" are demarcated. Then note is taken of portrayal of actuality in older Afrikaans prose, before proceeding to an analysis of the different strategies employed in three "exemplary" works: Die swerfjare van Poppie Nongena (Elsa Joubert), 'n Droë wit seisoen (André P. Brink), and Dagboek van 'n verraaier (J.C. Steyn). The conclusion eventually drawn, is that novels with a fictitious world as a point of departure, have potentially richer literary posibilities than novels in which the actual situation serves as a point of departure. However, notwithstanding the fact that Dagboek van 'n verraaier has the fictional situation as point of departure, it does not succeed novel-wise. Despite the relatively weaker technique being used in Die swerfjare van Poppie Nongena, the novel is a success. The respective success or failure of these works is determined by the extent to which the concrete author manages to make full-fledged, blood-warm human beings of his characters. 'n Droë wit seisoen serves as an illustration of what· can be achieved when the fictitious world is used as point of departure and the characters are rendered true to life. The latter is, novelwise, the greatest success of the three. Contributing to this, in particular, are narrator's perspective, colloquial usage and tonality, the convincing manipulation of documentation, period location and characterization.

This dissertation is a report on a study about autobiography as genre, focusing on the voice of the white, Afrikaans-speaking woman. The point of departure for this study was a survey of the number of autobiographies written in Afrikaans by these women. With the focus on the limited number of such autobiographies three autobiographies were studied, namely, Met die Boere in die veld (Sarah Raal), My beskeie deel (M.E.R.) and 'n Wonderlike geweld (Elsa Joubert). Within the framework of the complexity systems theory the role of the observer (author/reader) was studied to determine the possibility of demonstrating that when reading/writing an autobiography, some epistemological changes may occur, manifesting as conceptual changes in the mind of the observer. It could be demonstrated that because of women's sensitivity to interpersonal relationships they are capable of acting as unique registers of the complexity of individual existence, while remaining aware of the constant influence, effect and needs of the other. / AFRIKAANS & THEORY OF LIT / MA (AFRIKAANS)

This dissertation is a report on a study about autobiography as genre, focusing on the voice of the white, Afrikaans-speaking woman. The point of departure for this study was a survey of the number of autobiographies written in Afrikaans by these women. With the focus on the limited number of such autobiographies three autobiographies were studied, namely, Met die Boere in die veld (Sarah Raal), My beskeie deel (M.E.R.) and 'n Wonderlike geweld (Elsa Joubert). Within the framework of the complexity systems theory the role of the observer (author/reader) was studied to determine the possibility of demonstrating that when reading/writing an autobiography, some epistemological changes may occur, manifesting as conceptual changes in the mind of the observer. It could be demonstrated that because of women's sensitivity to interpersonal relationships they are capable of acting as unique registers of the complexity of individual existence, while remaining aware of the constant influence, effect and needs of the other. / AFRIKAANS and THEORY OF LIT / MA (AFRIKAANS)

Text in Afrikaans / ’n Merkbare opbloei in die publikasie van literêre niefiksietekste wêreldwyd het gelei tot die klassifikasie van sodanige tekste as ’n vierde genre. Die politieke oorgang in Suid-Afrika in 1994 het gelei tot ’n soortgelyke toename in outobiografiese tekste waarin kommentaar gelewer word op die Suid-Afrikaanse politieke werklikheid deur die vertel van sowel persoonlike as kollektiewe geskiedenisse. Daymond en Visagie (2012) identifiseer outo-etnografie, apologie en belydenis as kenmerke van die Suid-Afrikaanse outobiografie ná 1994. In hierdie navorsingsverslag word enkele resente skrywersoutobiografieë van onderskeidelik Elsa Joubert (’n Wonderlike geweld: jeugherinneringe (2005); Reisiger (2009)), André P. Brink (’n Vurk in die pad (2009)) en Koos Kombuis (Seks & drugs & boeremusiek: die memoirs van ‘n volksverraaier (2000); Die tyd van die Kombi’s: ‘n persoonlike blik op die Afrikaanse rock-rebellie (2009)) gemeet aan die kriteria wat deur Daymond en Visagie voorgestel word. Die beskrywing en interpretasie van verskeie outo-etnografiese merkers lei daartoe dat hierdie outobiografieë as ’n vorm van kulturele introspeksie beskou kan word. / A marked proliferation in the publication of literary nonfiction globally led to the classification of such texts as a fourth genre. The political transition in South Africa in 1994 caused a similar increase in autobiographical texts in which commentary is offered on the South African political reality through the telling of both personal and collective histories. Daymond and Visagie (2012) identify autoethnography, apologia and confession as characteristics of post-1994 South African autobiographies. In this research report some contemporary writers’ autobiographies, respectively those of Elsa Joubert (’n Wonderlike geweld: jeugherinneringe (2005); Reisiger (2009)), André P. Brink (’n Vurkin die pad (2009)) and Koos Kombuis (Seks & drugs & boeremusiek: die memoirs van ‘n volksverraaier (2000); Die tyd van die Kombi’s: ‘n persoonlike blik op die Afrikaanse rock-rebellie (2009)) are evaluated using the criteria proposed by Daymond and Visagie. The description and interpretation of various autoethnographical markers confirm that these autobiographies can be considered a form of cultural introspection. / Afrikaans and Theory of Literature / M.A. (Afrikaans)