Multiple Myeloma (MM) cell survival has been shown to depend on precise control of protein production and degradation. Disruption of protein catabolism through proteosomal or aggresomal blockade results in MM cell death. We hypothesized that inhibiting protein production would have a similarly toxic effect in MM. We explored the consequences of inhibiting mRNA translation in MM using silvestrol, a powerful inhibitor of ribosomal recruitment, which preferentially disrupts the production of certain cell regulatory and survival proteins. A panel of silvestrol-treated MM cell lines showed profound inhibition of growth and a rapid induction of apoptosis, as seen by MTT viability and AnnexinV flow cytometric assays respectively. The average IC50 in MM cells was determined to be 20nM while it was considerably higher in primary cultures of senescent fibroblasts. We show that silvestrol inhibits protein translation by inhibiting ribosome binding, decreasing polysome content and increasing 80S ribosomes. Western blot analyses show that silvestrol rapidly decreases the expression of c-Myc and non-canonical NF-KB signaling. Expression of anti-apoptotic proteins such as Mcl-1 and Bcl-2 decreased while pro-apoptotic proteins, such as BAX, increased with silvestrol treatment. In a novel transgenic mouse model of MM (vk*myc), which has been shown to behave clinically like human MM, silvestrol does not appear to be toxic and is therapeutically effective. Our results warrant clinical evaluation of silvestrol. / Il a été démontré que la survie des cellules cancéreuses chez les patients atteints du Myélome Multiple (MM), dépend de la régulation de la production et de la dégradation des protéines. Une perturbation du système de catabolisme des protéines, à travers un blocage proteosomale, engendre la mort de ces dernières. Nous avons donc formulé l'hypothèse que l'inhibition de la production de protéines aurait des effets toxiques similaires. Grâce à un puissant inhibiteur, le silvestrol, nous avons déterminé les conséquences liées à l'inhibition de la translation de l'ARN messager. Le silvestrol est un inhibiteur de recrutement ribosomale qui affecte de manière préférentielle certaines protéines impliquées dans la division et la survie cellulaire. Une panoplie de lignées cellulaire spécifiques au Myélome ont été susceptibles au silvestrol, ce qui s'est exprimé par une inhibition de la croissance cellulaire et une amorce rapide de l'apoptose. Cela a été observé grâce au test de viabilité MTT et par l'analyse de cytométrie en flux avec les marqueurs Annexin V et 7-AAD. La moyenne du ci50 des cellules du myélome testées a été établie à 20 nM, tandis qu'une concentration considérablement plus élevé est nécessaire pour obtenir les mêmes résultats chez les cultures primaires de fibroblaste sénescents. Nous démontrons que le silvestrol inhibe la translation des protéines en bloquant le ribosome 80S au départ du codon d'initiation de la translation. Ceci engendre une accumulation des ribosomes 80S et une décroissance du nombre de polysome par ARN messager. Nos analyses de western blot montrent que le silvestrol provoque une décroissance de l'expression de l'oncogène c-Myc et de NF-KB. De plus, l'expression de protéine anti-apoptotiques tel que Mcl-1, Bcl-Xl et Bcl-2 décroit avec un traitement de silvestrol, alors que l'expression de la protéine pro-apoptotique Bax augmente. Nos résultats montrent que le silvestrol est efficace et non toxique dans le nouveau model transgénique du MM (la souris Vk*Myc) qui est réputé pour sa similarité de caractéristiques avec le MM humain. Nous prônons une évaluation clinique du silvestrol.

Translation of an mRNA begins with the recruitment of the eIF4F complex to the 5' cap of the mRNA and is completed upon start codon recognition by the preinitiation complex. Regulation of translation initiation is a major mechanism for the control of gene expression. The focus of this thesis is human 4EHP (h4EHP), a homolog of the cap-binding translation initiation factor eIF4E. 4EHP can bind to the cap structure but cannot initiate cap-dependent translation. Drosophila 4EHP functions as a translational repressor of specific mRNAs by forming a "closed loop", in which the binding partners of 4EHP determine the mRNA specificity. This study sought to investigate the function of h4EHP by identifying its interacting proteins. In total, three novel binding proteins of h4EHP have been identified: PERQ1, PERQ2, and eIF4E-Transporter (4E-T). All these proteins utilize a similar motif for h4EHP-binding. Experiments demonstrate that h4EHP:PERQ1/2 complexes are involved in translational repression. In addition, this study shows that the protein levels of PERQ1, PERQ2 and h4EHP are co-regulated. Among them, PERQ2 undergoes CUL7-mediated degradation upon h4EHP depletion. 4E-T has been shown to be involved in translational repression, eIF4E nuclear import, P-body formation and mRNA turnover. This study demonstrates that h4EHP can be localized to the nucleus. However, its nuclear localization is not affected by 4E-T depletion. The depletion of h4EHP results in a six-fold increase in the number of P-bodies but has no effect on the rate of turnover of a reporter mRNA. In conclusion, this study identifies PERQ1 and PERQ2 as two translational repressors; their function and stability are dependent on h4EHP. The function of h4EHP:4E-T interaction, however, remains elusive. / La traduction d'un ARNm commence par le recrutement du complexe eIF4F au niveau de la coiffe (ou cap) en 5' de l'ARNm et se complète lors de la reconnaissance du codon d'initiation par le complexe de pré-initiation. La régulation de l'initiation de la traduction est une étape majeure dans le contrôle de l'expression génique. Cette thèse s'intéresse à la protéine humaine 4EHP (h4EHP), un homologue du facteur d'initiation de la traduction se liant à la coiffe, eIF4E. 4EHP peut d'ailleurs s'associer à la coiffe de l'ARNm mais ne peut initier la traduction dépendante de la coiffe. L'homologue chez la drosophile, d4EHP, est un inhibiteur de la traduction de certain ARNm et agit en formant une boucle 5'-3' avec l'ARNm. Les partenaires protéiques de 4EHP définissent alors la spécificité pour l'ARNm. Cette thèse s'intéresse à la fonction de h4EHP en recherchant ses partenaires protéiques. Les trois nouveaux partenaires identifiés (PERQ1, PERQ2 et 4E-T) utilisent un même motif de liaison à h4EHP. Mes expériences démontrent non seulement, que les complexes h4EHP:PERQ1/2 sont impliqués dans la répression de la traduction, mais aussi qu'il existe une co-régulation des niveaux relatifs des protéines h4EHP, PERQ1 et PERQ2. Ce dernier est d'ailleurs dégradé par CUL7 après la déplétion de h4EHP. La protéine 4E-T est connu pour son rôle dans l'inhibition de la traduction, l'import nucléaire d'eIF4E, la formation des « P-Bodies » et le renouvellement des ARNm. Cette étude démontre que h4EHP a une localisation nucléaire et indépendante de 4E-T. La suppression de 4E-T augmente cependant de six fois le nombre de « P-Bodies », sans pour autant affecter le taux de renouvellement d'un ARNm reporteur. En conclusion, cette étude identifie PERQ1 et PERQ2 comme deux inhibiteurs de la traduction dont la fonction et la stabilité sont dépendantes de h4EHP. Cependant, le rôle de l'inter

To elucidate the structure and the function of the prolactin receptor, I have used molecular biological techniques. After unsuccessful screening of expression cDNA libraries with poly- and monoclonal antibodies, synthetic oligonucleotide probes, deduced from tryptic fragment sequences of the purified receptor, were used to isolate the rat liver prolactin receptor cDNA. Using this cDNA, the regulation of prolactin receptor expression by estrogen treatment and during ontogenesis was studied in female rat liver and revealed both pre-translational and translational control of the receptor. Finally, the human prolactin receptor cDNA was isolated. It encodes a long form of receptor (598 aa) compared to the rat liver receptor (291 aa). Both forms present regions of strong identity with the growth hormone receptor, suggesting that prolactin and growth hormone receptor genes form a family.

Pitx2 is a homeodomain transcription factor. Three functional protein isoforms are encoded by the Pitx2 gene that differ only in their N-terminus. Functional studies have demonstrated that the Pitx2c isoform is the most downstream component of the left-right patterning cascade that is responsible for positioning the internal organs relative to the midline. / In all vertebrates, mRNA for the Pitx2c isoform is expressed asymmetrically in the left lateral plate mesoderm and in organs that become asymmetrically positioned. A Pitx2c isoform specific antibody was created and used to determine the pattern of Pitx2c protein expression in the chick embryo. Pitx2c protein expression appears to be identical to the pattern of Pitx2c mRNA expression. / I hypothesized that the Pitx2c N-terminus would be able to independently act as a dominant negative and interfere with the left-right patterning activity of endogenous Pitx2c protein. To test this hypothesis, the Pitx2c N-terminus was overexpressed in the left lateral plate mesoderm. The first morphological sign of left-right asymmetry is the rightward looping of the heart. The heart looped to the left side in 30% of the infected embryos suggesting that the Pitx2c N-terminus was acting as a dominant negative protein and interfering with the activity of the endogenous Pitx2c. Mutation analysis indicated that the amino acid residues 41 to 45, LAMAT, were required for the dominant negative activity of Pitx2cN.

Ovarian cancer is the leading cause of death from a gynecological malignancy in North America. It is an incomplete understanding of the early molecular events in ovarian carcinogenesis which limit our ability to diagnose and effectively treat this disease at a stage when it is still curable. The Wnt/beta-catenin canonical signaling pathway is involved in development, wound repair, and tumorigenesis. Studies examining the involvement of Wnt/canonical signaling in ovarian carcinogenesis, however, have only recently begun to emerge. In this study, we hypothesize that ovarian cancer cells exhibit aberrations in Wnt/canonical signaling, which may cause and/or effect ovarian tumorigenesis. Our objectives were therefore to (1) determine whether ovarian cancer cells exhibit alterations in the expression patterns of Wnt signaling pathway components, (2) determine whether ovarian cancer cells exhibit functional aberrations in response to Wnt/canonical stimulation and (3) determine whether these aberrations affect cell proliferation and cadherin expression. Our study shows that ovarian cancer cells exhibit alterations in the expression profiles of Wnt signaling pathway components and that these cells display aberrations at different levels of the Wnt/canonical signaling pathway, which in turn, modulate cell proliferation, and cadherin expression. These results suggest that Wnt/canonical signaling may be involved in ovarian tumorigenesis and that further study of this involvement may contribute to a better understanding of early molecular events in ovarian cancer.

Nuclear receptors are transcription factors that regulate gene expression in response to small lipophilic molecules, including steroid hormones, thyroid hormone, and vitamin A and D metabolites. RORalpha is an orphan nuclear receptor that was initially cloned based on its similarities with the retinoic acid receptor. The term orphan was coined in reference to a nuclear receptor whose discovery has preceded that of its ligand. Genetic ablation of the Rora gene in mice leads to severe cerebellar ataxia, known as the staggerer phenotype. RORalpha regulates a myriad of genes involved in cellular differentiation, including myogenesis and adipogenesis, as well as various metabolic pathways. Nuclear receptors control the expression of their target genes by binding to short DNA sequences, referred to as hormone response elements, as monomers, homodimers, or heterodimers with the common partner RXR. RORalpha is strictly a monomeric DNA binding protein, lacking key molecular determinants in its DNA binding domain essential for cooperative homodimer formation. This orphan receptor is a potent transcriptional activator, whose activity is dependent on an endogenous ligand and is controlled by the concerted action of coactivator and corepressor proteins. The product of the thyroid hormone-regulated mammalian gene hairless (Hr) is a strong repressor of RORalpha transcriptional activity. In contrast to other corepressor-nuclear receptor interactions, Hr utilizes LxxLL motifs to mediate interaction with RORalpha, a mechanism associated with coactivator interaction. Strikingly, Hr specificity is dictated by the RORalpha AF-2 helix. Moreover, corepressor action is maintained in the presence of ligand, suggesting that Hr is a ligand-oblivious corepressor. The RORalpha AF-2 helix plays a dynamic role in controlling both corepressor and coactivator interactions. The interaction of Hr with RORalpha provides a molecular link converging the thyroid hormone and RO

The 3' poly(A) tail of eukaryotic mRNAs and the poly(A) binding protein (PABP) play key roles in the regulation of translation. Recently, our group identified two human PABP-interacting proteins (Paip), Paip1 and Paip2, which stimulate and repress translation, respectively. Paip2 also inhibits the binding of PABP to the poly(A) tail and competes with Paip1 for binding to PABP. My research project was divided into two parts to allow me to gain a greater understanding of the roles of these two PABP-interacting proteins. First, in order to study the mechanism of interaction of Paip1 and PABP, their binding sites were mapped by Far Western and GST pull-downs experiments. The Paip1-PABP interaction involves two distinct binding regions in each protein. The PABP interacting motif-1 (PAM1) of Paip1 is rich in acidic amino acids and is located in the C-terminus (a.a. 440--479). PAM1 interacts with the RNA recognition motifs (RRMs) 1 and 2 of PABP. PAM2 consists of a 15 amino acid stretch residing in the N-terminus of Paip1 (a.a. 123--137) and interacts with the C-terminal domain of PABP. In addition, the stoichiometry and the kinetic and thermodynamic constants for the Paip1-PABP interaction were determined using a Surface Plasmon Resonance (SPR)-biosensor. Paip1 interacts with PABP with an apparent KD of 1.9 nM and with a 1:1 stoichiometry. In the second part of my thesis research, the Drosophila Paip2 (dPaip2) was isolated and characterized in order to ascertain a biological role for Paip2. dPaip2 was found to be the bona fide homologue of human Paip2 since it interacts with the Drosophila PABP (dPABP) via two independent binding sites, interferes with the ability of dPABP to bind to poly(A), and represses translation. Ectopic overexpression of dPaip2 in wings resulted in a size reduction phenotype, which was due to a decrease in the cell number but not to a difference in cell size. Clones of cells overexpressing dPaip2 in wing discs also contai

Iron is an essential but potentially harmful metal element. Iron regulatory protein 1 and IRP2 posttranscriptionally control cellular iron homeostasis by binding to iron-responsive elements (IREs). Binding of IRPs to single IRE within 5'-untranslated region (5'-UTR) of ferritin mRNA attenuates biosynthesis of the iron-storage protein by translational repression, while their binding to multiple IREs within 3'-UTR of transferrin receptor 1 (TfR1) mRNA stimulates that of the iron-acquisition protein through mRNA stabilization. IRP1 and IRP2 share extensive homology, but respond to levels of cellular iron by distinct mechanisms. According to cellular iron status, IRP1 is switched between the states of RNA-binding and cytosolic (c-)aconitase by reversible assembly of a cubane [4Fe-4S] cluster. In contrast, IRP2 is mainly regulated through iron-dependent proteasomal degradation. Previous studies have identified constitutive IRP mutants. Substitution of any IRP1 cluster-coordinating cysteine residue with serine rendered the mutant (such as IRP1C437S) constitutively active for IRE-binding. In the case of IRP2, replacement of cysteines at positions of 168, 174 and 178 within an IRP2-specific, 73-amino-acid fragment (73 aa) was reported to yield an apparently stable mutant (IRP23CS). This project was initially designed to study the functional characteristics of IRPs in vivo by stably expressing constitutive IRP mutants in human cells. To this end, we first established clones of human lung (H1299) and breast (MCF7) cancer cells that express epitope-tagged IRP1C437S in a tetracycline-dependent manner and characterized the biological effects associated with IRP1C437S expression (Chapter II). In agreement with the commonly accepted regulatory model of IRE/IRP regulatory system, we demonstrated that IRP1C437S stimulates TfR1 by stabilizing its mRNA, resulting in increased uptake of cellular iron from 59Fe-transferrin. However, we observed a more complex

Synercid® is used to treat infections caused by vancomycin resistant Enterococcus faecium, methicillin resistant Staphylococcus species and some Streptococcus species. It belongs to a class of antimicrobials, known as streptogramins, which is comprised of Group A (e.g. dalfopristin) and Group B (e.g. quinupristin) compounds. Independently, these compounds are bacteriostatic against Gram-positive bacteria, however, in combination they exhibit synergistic bactericidal effects due to permanent inhibition of the bacterial 50S ribosomal subunit. Resistance to the Group B streptogramins is conferred enzymatically by streptogramin B lyases (Vgb), which cleave the ring structure of these peptide drugs. / Here we present the first crystal structure of a streptogramin B lyase from Staphylococcus aureus to a resolution of 1.65 Å. High-resolution data sets were collected for both the native and L-selenomethionine substituted Vgb and the structure was solved using a combination of MAD and molecular replacement techniques. The structure of Vgb, is that of a beta-propeller consisting of seven blades made of highly twisted beta-sheets arranged in a circular array. A similar fold has been observed in the WD40, Kelch, YWTD, PQQ and AxSPD families, however, Vgb has no sequence similarity to these proteins. This identifies Vgb as possessing a novel beta-propeller motif. Initial attempts to crystallize Vgb with a catalytically inactive mutant were met with limited success due to problems with crystal packing. Using structure-inspired loop mutagenesis, we were able to crystallize Vgb in a new crystal form conducive to substrate binding. This structure reveals that the antibiotic, quinupristin, binds in a large depression on the top face of Vgb. Guided by the structure, we propose a reaction mechanism in which the initial proton abstraction is facilitated by a Mg2+ linked conjugated system, with His270, His228, Try18, Glu268, and Glu284 playing roles in the catalytic mechanism. Since Mg2+ is only indirectly involved in the opening of the lactone ring, this represents a novel enzymatic mechanism. / A comparison of Vgb and the ribosome structures reveals that Mg2+ facilitates the binding of the antibiotic through the 3-hydroxypicolinic acid moiety in both targets, however, the predominant associations are due to van der Waals interactions. In Vgb, interactions between the enzyme and the substrate are predominantly through interactions parallel to the plane of the lactone, while in the ribosome the antibiotic bound is at the periphery of the ring. This allows for extension of the antibiotic at the L-phenylglycine moiety when bound to the ribosome, while such an alteration would preclude efficient binding to Vgb. Lastly, we have characterized an engineered Group B streptogramin that has a variation at the L-phenylglycine position and we find that this new ligand retains antibacterial properties while it is a much weaker substrate for Vgb. This information has laid out the foundation
 for further structure-based drug design of Group B streptogramins that will bind the ribosome with greater affinity and not be susceptible to inactivation by Vgb. / Le Synercide® est utilisé pour traiter les infections causées par Enterococcus faecium résistant à la vancomycine, les espèces de Staphylocoques résistantes à la méthicilline, ainsi que certaines espèces de Streptocoques. Il appartient à une catégorie d'antibiotiques dénommée streptogramines. Cette dernière est composée de deux sous-groupes d'antibiotiques, notamment Groupe A (ex. dalfopristine) et Groupe B (e.x. quinopristine). Utilisés indépendamment, ces composés ont un effet bactériostatique contre les bactéries à Gram positif. Cependant, en combinaison, elles exercent un effet synergique bactéricide grâce à l'inhibition permanente de l'unité 50S du ribosome. La résistance aux streptogramines du Groupe B est conférée par des enzymes lyases streptogramine B(Vgb), qui scindent la structure cyclique de ces antibiotique. / Dans ce thèse, nous présentons la première structure cristallographique d'une lyase streptogramine B de Staphylococcus aureus à une résolution de 1.65 Å. Des données à haute résolution ont été obtenues pour la protéine Vgb native, ainsi que celle qui contenait des substitutions de L-sélénométhionine. La structure a été résolue en utilisant une combinaison des techniques de MAD et de remplacements moléculaires. La structure de Vgb est celle d'une hélice β composée de sept ailettes de feuillets β tordus et arrangés en formation circulaire. Un pli semblable fut observé dans les familles WD40, Kelch, YWTD, PQQ et AxSPD, cependant Vgb ne possède aucune similarité au niveau de sa séquence avec ces protéines. Ceci indique que Vgb possède une hélice β inédite. Les efforts initiaux pour cristalliser Vgb avec un mutant catalytiquement inactif ont été limités par des problèmes d'empaquetage de cristaux. En utilisant la mutagenèse d'une boucle, nous avons réussi à cristalliser Vgb dans une nouvelle configuration qui permet la liaison de son substrat. Cette structure révèle que la quinupristine se lie dans un large creux situé sur la surface supérieure de Vgb. Guidés par la structure, nous proposons un mécanisme de réaction dans lequel le départ initiale du proton est favorisée par un système conjugué lié au Mg2+, avec His270, His228, Tyr 18, Glu268 et Glu284 jouant des rôles clés dans le mécanisme catalytique. Étant donné que le Mg2+ est impliqué de manière indirecte dans l'ouverture de l'anneau du lactone, ceci représente un nouveau mécanisme enzymatique. / En comparant Vgb et le ribosome, on observe que le Mg2+ favorise la liaison de l'antibiotique par le biais de l'acide 3-hydroxypicolinique aux deux sites, cependant, les interactions van der Waals représentent le mécanisme principal de liaison. Au niveau de Vgb, les interactions entre l'enzyme et son substrat sont favorisées par des interactions van der Waals parallèle au plan de la lactone, quant au ribosome, la liaison de l'antibiotique a lieu à la périphérie de l'anneau. Ceci permet l'extension de l'antibiotique sur la moitié L-phénylglycine lorsque lié au ribosome, mais un changement pareil empêcherait la liaison efficace à Vgb. Nous avons caractérisé une streptogramine B modifiée qui possède une variation à cette position et nous avons remarqué que cette nouvelle streptogramine garde son action antibactérienne tout en étant un faible substrat de Vgb. Cette information forme une base pour la création d'autres streptogramines de Groupe B qui se fixeront avec plus d'efficacité au ribosome sans être susceptibles à l'inactivation par Vgb.

Kidney cancer is a complex disease comprising several types of renal carcinomas, which are classified in different subtypes based on their histological characteristics. A small number of cases of renal cancers are due to hereditary predispositions and nearly all the knowledge on the molecular pathogenesis of kidney cancers was learned by the investigation of these hereditary forms of renal carcinomas. In this thesis, we studied two hereditary diseases predisposing to the development of kidney cancer, von Hippel Lindau (VHL) and Birt-Hogg-Dubé (BHD) syndromes, and their causative genes, VHL and FLCN respectively. First, we investigated the role of the extracellular matrix (ECM) regulation by VHL during tumorigenesis and angiogenesis, and we demonstrated that inactivation of the VHL-ECM assembly pathway results in highly vascularized tumors with a disrupted ECM. We concluded that loss of the ECM assembly promotes and maintains tumor angiogenesis by providing a way for new blood vessels to invade the tumor tissue. In the second part of this thesis, we developed a novel VHL mouse model to investigate the possible cooperation between VHL and p53 during tumorigenesis. We observed that inactivation of both tumor suppressor genes accelerate the formation of liver hemangiomas and splenic hemangiosarcomas. Furthermore, concomitant deletion of VHL and p53 abolished the development of lymphoma usually associated with loss of p53. Our results indicate that the phenotypes arising following the inactivation of VHL and p53 is organ-dependent. Finally, to study the pathogenesis of the BHD syndrome, we developed a new mouse model using an established embryonic stem cell line. We described the murine Flcn expression pattern and noticed that homozygous disruption of Flcn was embryonically lethal early during development. Furthermore, we observed a continuum of kidney lesions from renal tubules hyperproliferation to rare adenoma. FLCN tumor suppressor role was also substantiated usi / Le cancer du rein est une maladie complexe qui comprend différents types de cancers classifiés selon leurs caractéristiques histologiques. Certains cas de cancers rénaux sont attribuables à une prédisposition héréditaire et l'étude de ces formes héréditaires de cancer a largement contribué au développement des connaissances concernant la pathogenèse des cancers rénaux. Le travail décrit dans cette thèse porte sur deux maladies héréditaires prédisposant au développement de tumeurs rénales soit la maladie de Von Hippel-Lindau (VHL) et le syndrome de Birt-Hogg-Dubé (BHD) ainsi que les gènes associés à ces dernières, VHL et FLCN respectivement. Premièrement, nous avons étudié le rôle de la régulation de l'assemblage de la matrice extracellulaire (MEC) par VHL durant la tumorigénèse et nous avons démontré que l'assemblage inadéquat de la MEC corrèle avec une croissance tumorale accrue et induit la formation de tumeurs fort vascularisées. Nous avons conclu que la perte de l'intégrité de la MEC favorise l'angiogénèse tumorale en fournissant une voie permettant aux vaisseaux sanguins d'infiltrer la tumeur. Deuxièmement, nous avons développé un modèle murin pour étudier la coopération potentielle entre VHL et p53 durant le développement tumoral. Nous avons observé que l'inactivation simultanée de VHL et p53 accélère la progression d'hémangiomes du foie et d'hémangiosarcomes de la rate. De plus, la perte concomitante de VHL et p53 inhibe le développement de lymphomes normalement associés à l'inactivation de p53. Nos résultats indiquent que les phénotypes apparaissant suite à l'inactivation de VHL et p53 varient selon l'organe étudié. Finalement, nous avons développé un modèle murin pour étudier de la pathologie associée au syndrome BHD et à avons observé la formation d'un continuum de lésions rénales allant de l'hyperprolifération des tubules rénaux à de rares adénomes. Finalement, nous avons conf