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Identification De Variants Génétiques Rares Aux Loci 1P13 Et 8Q22 Dans La Maladie Osseuse De Paget Les Gènes CTHRC1 Et TM7SF4 Associés À La Maladie Osseuse De Paget

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Identification De Variants Génétiques Rares Aux Loci 1P13 Et 8Q22 Dans La Maladie Osseuse De Paget Les Gènes CTHRC1 Et TM7SF4 Associés À La Maladie Osseuse De Paget Identification de variants génétiques rares aux loci 1p13 et 8q22 dans la maladie osseuse de Paget Les gènes CTHRC1 et TM7SF4 associés à la maladie osseuse de Paget Mémoire Mariejka Beauregard Maîtrise en physiologie-endocrinologie Maître ès sciences (M. Sc.) Québec, Canada © Mariejka Beauregard, 2013 ii Résumé CONTEXTE: La maladie osseuse de Paget (MOP) est transmise sur un mode autosomique dominant dans 30% des cas. Les mutations de SQSTM-1 expliquent 37% des formes familiales, ce qui suggère la présence d’autres loci. OBJECTIFS: Identifier des variants rares (VR) de gènes candidats situés aux nouveaux loci 1p13 et 8q22. Rechercher une association génétique de la MOP avec ces gènes candidats dans la population canadienne- française. MÉTHODES: Certains gènes candidats à la MOP aux loci 1p13 et 8q22 ont été sélectionnés, puis séquencés dans un échantillon de découverte. La fréquence de l’allèle mineur d’un VR devait être inférieure à 0,05. 4 VR ont été génotypés chez 240 cas et 297 témoins. RÉSULTATS: 74 VR ont été identifiés. Un VR (TM7SF4; rs62620995; Leu397Phe) était prédit dommageable par 2 outils d’analyse in silico. rs35500845 (CTHRC1) et rs62620995 (TM7SF4) étaient associés à la MOP de façon statistiquement significative. Mot clés : Maladie osseuse de Paget, Remodelage osseux, Variants rares, Polymorphismes nucléotidiques simples (SNPs), CTHRC1, TM7SF4 (DC-STAMP), Population canadienne-française, Population à effet fondateur. iii Abstract BACKGROUND: Paget's disease of bone (PDB) is transmitted through autosomal dominant mode of inheritance in 30 percent of cases. Mutations of the SQSTM-1 gene account for 37 percent of familial forms of PDB, suggesting the involvement of other loci. PURPOSE: Identify rare variants (RV) of candidate genes located on new loci 1p13 and 8q22. Search for a genetic association of PDB with these candidate genes in the French-Canadian population. METHODS: We selected candidate genes on 1p13 and 8q22 loci and sequenced them in a discovery sample. RV was defined by a minor allele frequency less than 0.05. 4 RV were genotyped in 240 PDB patients and 297 healthy individuals. RESULTS: 74 RV were identified. One RV (TM7SF4; rs62620995; Leu397Phe) was predicted to be damaging by two in silico analysis tools. rs35500845 (CTHRC1) and rs62620995 (TM7SF4) were statistically associated with PDB. KEY WORDS: Paget’s disease of bone, bone remodelling, rare variants, polymorphisms, SNP, CTHRC1, TM7SF4, DC-STAMP, French Canadian population, founder effect population v Remerciements Je tiens d’abord à remercier ma directrice de recherche, Dre Laëtitia Michou, qui m’a transmis sa passion pour la recherche. Elle a su me laisser suffisamment d’autonomie, tout en me fournissant l’encadrement requis à ma progression. Elle m’a fourni plusieurs opportunités d’apprentissage uniques et inestimables, tant aux plans clinique que scientifique (et parfois même culturel!), et m’a ainsi montré la réalité d’une chercheure-clinicienne. L’enseignement reçu de sa part dépasse largement les limites de mon projet de recherche. Je remercie Dr Jacques P Brown et Dr Jean Morissette, fondateurs du laboratoire au sein duquel j’ai réalisé mes travaux, de m’avoir fait bénéficier de leur expertise et de m’avoir prodigué de judicieux conseils. Je remercie mes évaluateurs qui ont accepté de lire ce mémoire et de contribuer à mes apprentissages en me partageant leurs commentaires. Je remercie Édith Gagnon de m’avoir montré comment réaliser les différentes manipulations nécessaires à mon projet et de m’avoir grandement aidée dans la prise en charge de mes nombreux «boulets»! Je remercie Julie Parrot d’avoir répondu, toujours aussi efficacement et agréablement, à mes multiples questions et demandes d’ordre administratif. Je remercie tous les membres de l’équipe du séquençage pour votre travail efficace et professionnel. Je remercie Claudia, Davy, Iris et Sabrina sans qui je n’aurais pu apprécier autant mes journées au sous-sol du bloc S. Nous avons bien ri ensemble! Vous me manquez déjà. Je vous souhaite bonne chance dans vos projets actuels et futurs. Merci papa pour ton aide précieuse à plusieurs étapes de la rédaction du mémoire et ta confiance inébranlable en mes capacités. Merci maman de m’avoir accompagnée en congrès, de m’avoir aidée à prendre des bonnes décisions, et d’avoir enduré nos nombreuses discussions scientifiques père-fille! Merci Ben d’avoir partagé de nombreuses heures de travail avec moi et de m’encourager à me réaliser. Merci à vous trois de m’avoir démontré votre soutien par toutes vos attentions pendant mes périodes de travail et de m’avoir distraite aux moments opportuns! Finalement, j’aimerais remercier les organismes suivants sans lesquels ce projet n’aurait pu être réalisé : le Fonds de recherche du Québec – Santé, les Instituts de recherche en santé du Canada, la fondation du CHUQ, le Groupe de Recherche en Maladies Osseuses, la Fondation canadienne pour l’innovation, l’université Laval et le Centre de Recherche du CHUQ (CHUL). vii Table des matières Résumé .............................................................................................................................................................. iii Abstract .............................................................................................................................................................. v Remerciement ................................................................................................................................................... vii Table des matières ............................................................................................................................................. ix Liste des tableau .............................................................................................................................................. xiii Liste des figures ................................................................................................................................................ xv Liste des annexes ........................................................................................................................................... xvii 1. MISE EN CONTEXTE ET REVUE DE LA LITTÉRATURE ........................................................................... 1 1.1. GÉNÉTIQUE DES MALADIES COMPLEXES; Un défi imposant ....................................................... 1 1.1.1. Composition et diversité du génome ............................................................................................. 1 1.1.2. Variations génétiques ................................................................................................................... 2 1.1.3. Maladies monogéniques ............................................................................................................... 3 1.1.4. Maladies complexes ..................................................................................................................... 3 1.1.4.1. Maladies communes – Variants communs ........................................................................ 3 1.1.4.2. Maladies communes – Variants rares ............................................................................... 4 1.1.4.2.1. Influence de la sélection naturelle sur la fréquence des variants génétiques ................. 4 1.1.4.2.2. Impact fonctionnel des variants rares ............................................................................. 5 1.1.4.2.3. Méthodes de détection des variants rares ...................................................................... 6 1.1.4.2.4. Maladies à début tardif et variants rares......................................................................... 8 1.1.4.2.5. Population canadienne-française et variants rares ......................................................... 9 1.2. MALADIE DE PAGET; Une maladie du remodelage osseux ............................................................. 9 1.2.1. Tissu osseux normal ..................................................................................................................... 9 1.2.2. Aperçu général de la maladie osseuse de Paget ....................................................................... 11 1.2.3. Épidémiologie ............................................................................................................................. 11 1.2.4. Présentation clinique .................................................................................................................. 13 1.2.5. Caractéristiques de l’os et des cellules osseuses pagétiques .................................................... 14 ix 1.2.6. Étiologie ...................................................................................................................................... 17 1.2.6.1. Composante environnementale ....................................................................................... 17 1.2.6.1.1. Hypothèse virale ........................................................................................................... 17 1.2.6.1.2. Alimentation .................................................................................................................. 19 1.2.6.1.3. Substances toxiques ..................................................................................................... 20 1.2.6.2. Composante génétique .................................................................................................... 20 1.2.6.2.1. Régions chromosomiques liées à la MOP ...................................................................
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