Bibliografie tematiche / Mutation gain de fonction

Letteratura scientifica selezionata sul tema "Mutation gain de fonction"

Autore: Grafiati

Pubblicato: 22 giugno 2024

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Articoli di riviste sul tema "Mutation gain de fonction":

TIXIER-BOICHARD, M. "Polymorphismes moléculaires et phénotypes". INRAE Productions Animales 13, HS (22 dicembre 2000): 55–61. http://dx.doi.org/10.20870/productions-animales.2000.13.hs.3811.

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Les relations entre génotype et phénotype, initialement formalisées par la génétique mendélienne, peuvent être décrites plus précisément grâce à l’identification de la nature moléculaire d’une mutation et à l’étude des conséquences fonctionnelles de cette mutation. Sur un plan fonctionnel, les mutations peuvent être classées en trois catégories : perte de fonction, maintien partiel de la fonction avec interférences (action dominante négative), gain de fonction. Les anomalies génétiques fournissent les exemples les plus didactiques pour la compréhension de la relation génotype-phénotype. De nombreux travaux ont montré la grande diversité moléculaire des mutations responsables de maladies génétiques. Les effets sur le phénotype ne dépendent pas tant de la nature de la mutation que de sa localisation et de ses conséquences sur le fonctionnement du gène. Un polymorphisme peut affecter l’expression du gène (quantité ou structure des transcrits) ou peut modifier uniquement la structure de la protéine produite. Les conséquences fonctionnelles dépendront du mode d’action de la protéine modifiée, avec ou sans effet de dosage, avec ou sans interaction avec d’autres protéines ou des facteurs du milieu.

Lemetayer, N., J. Bouligand, J. Young e I. Beau. "Analyse du phénotype de souris mâles avec mutation gain de fonction homologue du LHCGR". Annales d'Endocrinologie 84, n. 5 (ottobre 2023): 528. http://dx.doi.org/10.1016/j.ando.2023.07.072.

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Le Scornet, T., T. Guimard, C. Picard e A. Néel. "Un champignon peut en cacher d’autres : à propos d’une mutation gain de fonction STAT1". La Revue de Médecine Interne 44 (giugno 2023): A218. http://dx.doi.org/10.1016/j.revmed.2023.04.170.

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Dereure, O. "Myofibromatose infantile sporadique : mutations avec gain de fonction de PDGFRB". Annales de Dermatologie et de Vénéréologie 144, n. 8-9 (agosto 2017): 574–75. http://dx.doi.org/10.1016/j.annder.2017.05.010.

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Olivier, Nicolas C., Fanny Morice-Picard, Franck Boralevi, Jean-Christophe Fricain e Marie-Sylvie Doutre. "Traitement par ruxolitinib d’un patient présentant une candidose cutanéo-muqueuse chronique avec mutation gain de fonction de STAT1". Annales de Dermatologie et de Vénéréologie - FMC 1, n. 8 (dicembre 2021): A91. http://dx.doi.org/10.1016/j.fander.2021.09.497.

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Dossou, E., R. Jouenne, C. Picard, B. Neven, J. Hadjadj, A. Fayand, M. Michel e E. Crickx. "Survenue d’une prolifération LGL chez une patiente avec un DICV : une mutation gain de fonction de STAT3 en cause". La Revue de Médecine Interne 41 (dicembre 2020): A132. http://dx.doi.org/10.1016/j.revmed.2020.10.221.

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Khamyath, Mélanie, Amélie Bonaud, Karl Balabanian e Marion Espéli. "La signalisation de CXCR4, un rhéostat de la réponse immunitaire à médiation humorale". médecine/sciences 39, n. 1 (gennaio 2023): 23–30. http://dx.doi.org/10.1051/medsci/2022192.

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CXCR4 est un récepteur de chimiokine qui joue un rôle central dans la migration cellulaire mais également dans d’autres mécanismes essentiels, tels que le développement du système immunitaire. De concert avec son ligand naturel, la chimiokine CXCL12, cet axe de signalisation joue un rôle important dans la biologie des lymphocytes B, des stades précoces de différenciation dans la moelle osseuse à leur activation et différenciation en cellules sécrétrices d’anticorps, aussi appelées plasmocytes. Des mutations gain de fonction de CXCR4 sont retrouvées dans une immunodéficience rare, le Syndrome WHIM. Ces mutations affectent le mécanisme de désensibilisation du récepteur et entraînent un gain de fonction en réponse à CXCL12. Cette revue résume le rôle de CXCR4 dans la réponse immune humorale et, à travers l’étude du Syndrome WHIM, souligne le rôle régulateur essentiel de la désensibilisation de CXCR4 dans ces processus. Des travaux récents rapportent en effet qu’une signalisation correcte de CXCR4 est essentielle pour limiter la réponse immune dite « extra-folliculaire » et pour permettre une protection au long terme assurée par les anticorps.

Otiniano, A., J. Gottlieb, C. Picard e O. Lambotte. "Diagnostic à l’âge adulte d’un déficit immunitaire primitif avec candidose récurrente : la mutation « gain de fonction » du gène STAT 1". La Revue de Médecine Interne 42 (giugno 2021): A129. http://dx.doi.org/10.1016/j.revmed.2021.03.083.

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Baghad, B., I. Benhsaien, F. Z. El Fatoiki, M. Migaud, A. Puel, S. Chiheb, A. A. Bousfiha e F. Ailal. "Candidose cutanéo-muqueuse chronique avec mutation gain-de-fonction du gène STAT1 associée à des infections herpétiques et à mycobactérie". Annales de Dermatologie et de Vénéréologie 147, n. 1 (gennaio 2020): 41–45. http://dx.doi.org/10.1016/j.annder.2019.09.597.

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Scard, C., C. Thomas, A. Puel, B. Vabres, H. Aubert e S. Barbarot. "Dermatoses faciales chroniques de type rosacée chez des enfants porteurs d’un déficit immunitaire primitif par mutation de gain de fonction STAT1". Annales de Dermatologie et de Vénéréologie 145, n. 12 (dicembre 2018): S204—S205. http://dx.doi.org/10.1016/j.annder.2018.09.297.

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Più fonti

Tesi sul tema "Mutation gain de fonction":

Berrabah, Sofia. "Etude de nouvelles cibles thérapeutiques dans les lymphomes compliquant la maladie cœliaque". Electronic Thesis or Diss., Université Paris Cité, 2021. http://www.theses.fr/2021UNIP5201.

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La maladie cœliaque réfractaire de type II (MCRII), autrement appelé lymphome intraépithélial, est une complication rare mais sévère de la maladie cœliaque caractérisée par une expansion clonale d'une population particulière de lymphocytes intraépithéliaux (LIE) innés, présents dans l'intestin normal chez l'Homme comme chez la souris. Notre laboratoire a montré que cette population particulière de LIE innés partage des caractéristiques communes à celles des lymphocytes T et des cellules NK. Ces « LIE iCD3+ innés » sont caractérisées par une expression de CD3 au niveau intracellulaire mais pas à la surface, de récepteurs NK et présentent des réarrangements des gènes codant le récepteur T. En outre, le laboratoire a montré que ces cellules se développent dans l'épithélium intestinal à partir de précurseurs de la moëlle osseuse en réponse à une combinaison de signaux induits à travers la voie NOTCH et l'interleukine 15. Durant la lymphomagénèse, les LIE iCD3+ innés acquièrent des mutations somatiques gain-de-fonction dans JAK1et/ou STAT3. Ces mutations pourraient favoriser l'expansion clonale des LIE iCD3+ mutés aux dépens des lymphocytes T normaux résidents en leur conférant une sensibilité accrue à l'interleukine 15 (IL-15), une cytokine surexprimée dans l'intestin des patients. Ainsi, notre hypothèse est que ces mutations ont un rôle central dans l'initiation de la lymphomagénèse dans un contexte de production chronique d'IL-15 et, de ce fait, représentent une cible thérapeutique. Le premier objectif de ma thèse a été d'étudier l'intérêt des inhibiteurs de la voie JAK/STAT dans le traitement de la MCRII. Dans un premier temps, nous avons testé in vitro différents inhibiteurs de JAK/STAT sur des lignées cellulaires IL-15-dépendantes issues soit de LIE de MCRII soit de LIE T normaux. Nous avons démontré que ces drogues inhibent la prolifération et la phosphorylation de STAT3 et augmentent l'apoptose cellulaire aussi bien dans les LIE MCRII que dans les LIE T normaux. Dans un second temps, nous avons généré un modèle de xénogreffe en injectant des cellules issues de biopsies intestinales ou du sang d'un patient MCRII dans des souris immunodéficientes surexprimant l'IL-15 humaine dans l'épithélium intestinal (Rag-/-Gc-/-IL-15TgE ou IRGC) afin de tester l'efficacité des inhibiteurs de JAK/STAT in vivo. Le traitement des souris xénogreffées par le ruxolitinib, inhibiteur de JAK1/JAK2, a permis une diminution de la fréquence et du nombre ainsi que de l'activité cytotoxique des cellules tumorales humaines et une amélioration de l'état général des souris. Ces résultats encourageants restent à confirmer. Le second objectif de ma thèse a été de vérifier si la mutation pD661V de STAT3 était suffisante pour induire le développement de la MCRII dans un contexte de surproduction d'IL-15 dans des souris IRGC. Nous avons généré avec succès les LIE iCD3+ innés murins semblables aux LIE iCD3+ innés humaines à partir de précurseurs communs aux cellules lymphoïdes (CLP) en combinant un signal NOTCH et IL-15. Nous avons ensuite transduit les CLP avec un vecteur rétroviral contenant Stat3 sauvage ou muté (D661V). Les cellules transduites ont alors été injectées chez des souris IRGC suivies pendant 8 semaines. Les résultats préliminaires ont montré que les LIE iCD3+ innés se logent préférentiellement dans l'intestin mais aucun développement d'un lymphome intraépithélial n'a été observé au bout de 8 semaines suggérant que la mutation pD661V de STAT3 seule ne suffit pas en présence d'IL-15 à induire in vivo un lymphome intraépithélial. Ces résultats préliminaires sont toutefois à reproduire et à confirmer. Le modèle mise en place pour l'étude de STAT3 va désormais être utilisé afin d'évaluer la contribution respective de mutations canoniques de JAK1 et STAT3 et des autres mutations récurrentes retrouvées dans le lymphome intraépithélial
Refractory coeliac disease type II (RCDII), also called intraepithelial lymphoma, is a rare but severe complication of coeliac disease characterized by the clonal expansion of a small subset of innate intraepithelial lymphocytes (IEL), present in the normal human and murine intestine. Our lab has shown that this population displays shared features between T and natural killer (NK) cells. These so-called iCD3+ innate IEL are mainly characterized by intracellular expression of CD3, which is not detected at the cell surface, expression of NK receptors as well as DNA rearrangement of T cell receptor genes. Our lab has also shown that iCD3+ innate IEL originate from bone marrow precursors through coordinated NOTCH1 and interleukin (IL)-15 signals. During lymphomagenesis, iCD3+ innate IEL of most RCDII patients were shown to have acquired somatic gain-of-function mutations in JAK1 and/or STAT3 that confer increased sensitivity to interleukin-15, a cytokine overexpressed in the intestine of coeliac patients, thereby promoting their clonal expansion. Thus, our hypothesis is that JAK1/STAT3 mutations play a key role in initiating lymphomagenesis associated to coeliac disease in an IL-15-rich environment and that they could represent an attractive therapeutic target.The first objective of my thesis was to study the interest of JAK/STAT inhibitors for RCDII treatment. First, we have tested in vitro different JAK/STAT inhibitors on IL-15-dependent RCDII or normal IEL-T cell lines. We have shown that these inhibitors decrease the proliferation and phosphorylation of STAT3 and increase cellular apoptosis in both RCDII and normal T cell lines. Secondly, we have established a xenograft model based on the injection of cells derived from biopsy or blood from one RCDII patient into immunodeficient mice overexpressing the human IL-15 transgene in their gut epithelium (Rag-/-Gc-/- IL-15TgE; IRGC) to test the efficacy of JAK/STAT inhibitors in vivo. Treatment of xenografted mice with ruxolitinib, a potent inhibitor of JAK1/JAK2 decreased the frequency, number and cytotoxic potential of human tumoral cells and allowed clinical restoration. These preliminary results are encouraging but need to be confirmed. The second objective of my thesis was to test whether the Stat3 pD661V mutation is sufficient to induce the intraepithelial lymphoma in an IL-15-rich context in IRGC mice. We have successfully generated murine iCD3+ innate IEL in vitro, resembling their human counterparts from common lymphoid precursors by combining NOTCH and IL-15 signals. We then transduced CLP with a retroviral vector containing wild-type or mutated Stat3 pD661V. The transduced cells were injected into IRGC mice that subsequently were followed-up during a period of 8 weeks. In vitro generated iCD3+ innate IEL preferentially homed to the intestine. However, no development of intraepithelial lymphoma was observed suggesting that the Stat3 pD661V variant alone is not sufficient to induce the intraepithelial lymphoma. These preliminary results need to be reproduced and confirmed. The murine model used to test the role of STAT3 will now be used to evaluate the respective contribution of canonical mutations in JAK1 and STAT3 and of other recurrent mutations identified in RCDII

Plaud, Clément. "Mécanismes moléculaires et cellulaires des paraplégies spastiques héréditaires liées aux mutations du gène SPG4 : haploinsuffisance VS gain de fonction pathologique". Thesis, Université Paris-Saclay (ComUE), 2017. http://www.theses.fr/2017SACLE037/document.

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Les neurones sont des cellules spécialisées dans différentes fonctions, comme le contrôle des mouvements. La transmission de l’information au sein de l’axone est comparable au trafic de voitures d’une autoroute : les informations transitent dans plusieurs directions avec parfois des bouchons. Lorsque les informations n’arrivent plus à transiter, les patients peuvent souffrir de paraplégies spastiques à caractère héréditaire (PSHs), des maladies neurodégénératives. Cette thèse étudie le rôle joué par la spastine, une protéine impliquée dans certaines PSHs, et responsable de l’entretien des autoroutes. Nos résultats montrent que l’expression d’une forme mutée ou l’absence de production de la spastine,entraîne une perturbation spécifique des routes de transport et du trafic de certains composés essentiels à la survie des neurones. Dans l’ensemble, nos résultats aident à définir es effets pathophysiologies de la spastine afin de développer de nouvelles pistes de traitements
Central motor neurons are specialized cells involved in the control of voluntary movements in human. The transmission of information along the axon of these neurons is comparable to car trafficking in a highway: information travel in both direction and sometimes traffic jam events occur. When the transit of information are slowed or impaired, patients may suffer of neurodegenerative diseases as hereditary spastic paraplegia (HSPs). In this thesis we investigated the role of spastin, a protein implicated in HSP and the maintenance of these highways. Our results showed that depletion of spastin, or expression of its mutants, lead to a disturbance of both the integrity of these « road » and the traffic of cellular components primary involved in axonal survival and growth. These results would help to elucidate the pathophysiological mechanisms implicated in the onset of this pathology and maybe in developing proficient therapeutic strategy for HSP patients

Jiang, Dadi. "Analysis of a p53 Gain-of-function Mutation in Transgenic Mouse Salivary Tumors". VCU Scholars Compass, 2007. http://scholarscompass.vcu.edu/etd_retro/103.

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p53 is an important tumor suppressor gene which is mutated in ~50% of all human cancers. Some of the p53 mutants appear to have acquired novel functions beyond merely losing wild-type functions. To investigate these gain-of-function effects in vivo, we interbred MMTV-v-Ha-ras transgenic mice to either p53-/- knock-out mice or p53R172H/+ knock-in mice to generate mice of three different genotypes: MMTV-ras, MMTV-ras/p53-/-, and MMTV-ras/p53R172H/R172H. Male mice of each of these genotypes were characterized with regard to age of salivary tumor onset and the tumors were characterized with regard to mean growth rates, proliferation fraction, apoptotic levels, and tumor histopathology, as well as responses to doxorubicin treatment. Microarray analysis was also performed to profile gene expression.The MMTV-ras/p53-/- and MMTV-ras/p53R172H/R172H mice display similar properties in age of tumor onset, tumor growth rates, and tumor histopathology, as well as response to doxorubicin. However, a subset of genes show differential expression between the two groups of tumor , and do not appear to be regulated by wild-type p53. At the same time, the MMTV-ras/p53R172H/R172H and MMTV-ras/p53+/+ tumors share similar expression levels of a group of genes that are differentially expressed in the MMTV-ras/p53-/- tumors. Thus, the gain-of-function effects may be caused in part by perturbed regulation of genes not normally regulated by wild-type p53, in addition to imbalances in the regulation of normal p53 target genes.

Lartigau, Jérôme. "Le contrôle de gestion à l’heure des réformes hospitalières : une fonction en mutation ?" Thesis, Montpellier 1, 2010. http://www.theses.fr/2010MON10036/document.

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Pris en étau entre une hausse continue de leurs dépenses et une stagnation de leurs ressources financières, les établissements publics de santé sont depuis longtemps confrontés à un problème de gestion de la rareté. Pour faire face à ce problème, beaucoup d'entre eux ont mis en œuvre un contrôle de gestion, avec les difficultés que représente une telle démarche dans une organisation traditionnellement qualifiée de « professionnelle ». Dès l'origine principalement orienté vers la maîtrise des dépenses, le contrôle de gestion hospitalier est en train de subir une profonde remise en question avec l'arrivée de la tarification à l'activité et de la mise en place de pôles d'activité médicale. Désormais, la fonction contrôle de gestion ne doit plus se cantonner à ce rôle qui lui était traditionnellement reconnu mais doit contribuer activement à l'augmentation des recettes de l'hôpital. Cette dynamique nouvelle - qui accorde une place beaucoup plus marquée aux concepts fondamentaux du contrôle de gestion - est aussi novatrice en raison de l'importance qu'elle confère aux producteurs de l'activité médicale. La mutation de la fonction contrôle de gestion dans le domaine hospitalier est un phénomène majeur pour les praticiens mais aussi un sujet particulièrement riche sur le plan théorique. Elle remet en cause les représentations traditionnellement admises du contrôle de gestion dans l'organisation professionnelle qu'est l'hôpital et donne l'occasion aux chercheurs d'utiliser de nouvelles grilles de lecture théorique
Caught between a continuous rise in spending and a stagnation of their financial resources, public hospitals have long been faced with a problem of managing scarcity. To address this problem, many of them have implemented management control, with the difficulties of such an approach in an organization traditionally described as "professional." From the beginning mainly oriented toward expenditure control, management control in hospitals is undergoing a deep challenge with the advent of prospective payment system and the implementation of clinical directorates. Now the management control function should no longer be confined to this role which was traditionally recognized, but must actively contribute to the enhancement of the hospital's revenue. This new dynamics - which gives greater importance to fundamental concepts of management control - is innovative because of the importance it gives to producers of medical activity. The mutation of the management control function in the hospital sector is a major phenomenon for practitioners but is also particularly from a theoretical point of view. It challenges the traditionally accepted representations of management control in the hospital organization and gives an opportunity for researchers to use new theoretical frames

Alouche, Nagham. "Impact d’un gain de fonction de CXCR4 sur la différenciation et la biologie plasmocytaire". Thesis, Université Paris-Saclay (ComUE), 2018. http://www.theses.fr/2018SACLS450.

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Le récepteur CXCR4 et son ligand chimiokinique CXCL12 jouent un rôle essentiel dans le développement des cellules B et contribuent à la migration des plasmocytes (PCs) vers la moelle osseuse (MO) où ces cellules persistent dans des niches particulières et produisent des anticorps au long cours. Des mutations hétérozygotes du gène codant CXCR4 ont été identifiées dans un déficit immunitaire rare appelé le syndrome WHIM (SW) et récemment dans la macroglobulinémie de Waldenström (MW), un lymphoplasmacytome B caractérisé par l’expansion d’un clone IgM+ qui s’accumule dans la MO. Ces mutations affectent l’étape de désensibilisation du récepteur en réponse à CXCL12 et mènent donc à un gain de fonction. Mes travaux de thèse ont porté sur l’étude de l’impact du gain de fonction de Cxcr4 sur la biologie plasmocytaire par le moyen d’un unique modèle murin porteur de la mutation Cxcr4+/1013 précédemment identifié chez certains patients. Afin de mieux comprendre un défaut de vaccination présent chez les patients atteints du SW, la première partie de ma thèse s’est basé sur l’étude de la réponse humorale Thymo-dépendent du modèle murin Cxcr4+/1013. Nous avons mis en évidence un défaut de maintien de la réponse vaccinale probablement lié à l’absence des PCs spécifiques de l’antigène dans la MO des souris mutantes. En revanche, une population de plasmablastes (PBs) immatures dérivée de la réponse extra-folliculaire (EF), s’accumulent de façon aberrante suggérant une occupation des niches qui pourrait être à l’origine de la réponse vaccinale défectueuse. D’une autre part, dans la MW, les mutations CXCR4 sont toujours retrouvées en association avec des mutations gain de fonction du gène MYD88, la deuxième partie de ma thèse a donc porté sur l’étude de la réponse Myd88-dependante dans le modèle Cxcr4+/1013. Nos résultats révèlent une entrée en cycle accrue des cellules B Cxcr4+/1013 qui s’accompagne d’une augmentation de la différentiation plasmocytaire après activation de Myd88. De plus, nos résultats suggèrent, que le gain de fonction de Cxcr4 affecte la maturation des PBs ainsi que leur code migratoire ce qui pourrait expliquer leur migration exacerbée vers la moelle osseuse. L’ensemble de mes travaux a permis de mettre en évidence que la désensibilisation de Cxcr4 était un mécanisme clé régulant la réponse EF ainsi que la différentiation et la maturation plasmocytaire
CXCR4 plays an essential role in B cell development and controls partially plasma cell (PCs) homing to the bone marrow (BM). Heterozygous gain-of-function mutations of CXCR4 affecting its desensitization in response to the chemokine CXCL12 have been reported in a severe immune-deficiency disorder called WHIM syndrome (WS) and recently identified in Waldenström’s macroglobulinemia (WM), a B lympho-plasmacytoma characterized by the expansion of proliferative clonal malignant lymphoplasmacytic cells which secrete IgM Abs and mainly persist in the BM. Here we used a unique knock-in mice harboring the mutation Cxcr4+/1013 previously described in patients to assess how a gain-of-Cxcr4-function impacts PC biology and antibody (Ab) production. Following vaccination, WS patients mount a normal immune response but fail to maintain Ab titers over time. Therefore, the first part of my PhD was focused on studying the T-dependent humoral response in Cxcr4+/1013 mice. We showed that a strong reduction of antigen (Ag)-specific long-lived PCs in the BM of Cxcr4+/1013 mice could be the cause of the defective maintenance of Ab titers. Moreover, an aberrant accumulation of extra-follicular (EF) derived immature plasmablasts (PBs) was observed in this tissue potentially hampering the homing or maintenance of the Ag-specific PCs. Interestingly, in WM, mutations of CXCR4 are systematically associated with MYD88 mutations. Thus, the second part of my PhD focused on the study of the MyD88-dependent response in Cxcr4+/1013 mice. We showed that the Cxcr4 gain of function led to an increased cell cycle entry of splenic B cells that was associated with an enhanced PC differentiation. Finally, our findings showed that the desensitization of Cxcr4 is an essential break limiting the EF response as well as PC differentiation and maturation and suggest that an accumulation of mutated PB in the BM is not only due to the gain of function of Cxcr4 but to a more global change in the migratory code of these cells controlled by the exacerbated Cxcr4/Cxcl12 signaling

Verleyen, Stijn. "Fonction, forme et variation : analyse métathéorique de trois modèles du changement phonique au XXe siècle, 1929-1982 /". Leuven ; Paris ; Dudley : Ma : Peeters, 2008. http://catalogue.bnf.fr/ark:/12148/cb414383627.

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Morin, Denis. "Le récepteur V2 humain de la vasopressine : perte de fonction et gain de fonction. Du Diabète Insipide Néphrogénique à un récepteur V2 constitutivement actif". Montpellier 1, 1999. http://www.theses.fr/1999MON1T007.

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Biajoux, Vincent. "Impact d’un gain de fonction de Cxcr4 sur le développement et la compartimentalisation périphérique des lymphocytes". Thesis, Paris 11, 2013. http://www.theses.fr/2013PA114825/document.

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Le syndrome WHIM (SW) est un déficit immuno-hématologique rare causé principalement par des mutations autosomales dominantes du gène CXCR4 qui entrainent une troncation du domaine C-terminal (C-Ter) du récepteur. Les formes mutantes de CXCR4 associées au SW génèrent des altérations de la désensibilisation et de l’internalisation du récepteur en réponse à CXCL12, qui se traduisent par une hypersensibilité à l’action chimiotactique du ligand. CXCR4 est un récepteur de chimiokine exprimé sur les leucocytes dont le rôle dans l’hématopoïèse et le trafic leucocytaire à l’état basal suggère que la lympho-neutropénie des patients atteints du SW est due à des défauts de production et/ou de domiciliation périphérique des leucocytes causés par le gain de fonction de CXCR4. Néanmoins, la validation de cette hypothèse est difficile chez les patients. En générant une souche de souris (Cxcr4+/1013), porteuse d’une mutation rapportée chez une famille de patients par une stratégie de knock-in, nous avons mis en évidence le rôle du domaine C-Ter de Cxcr4 dans le développement, la domiciliation périphérique des lymphocytes et l’immunité adaptative à médiation humorale.Les principaux résultats issus de notre travail, obtenus en combinant des approches biochimiques, fonctionnelles, de reconstitution de l’hématopoïèse par compétition, de transferts adoptifs et d’injection d’anticorps anti-CD45 in vivo, sont : 1) La mutation Cxcr41013 tronquant le domaine C-Ter se comporte différemment en terme de signalisation, selon qu’elle soit présente à l’état hétérozygote ou homozygote, et perturbe respectivement les transitions double-négatif (DN) 2-DN3 et proB-preB de la lymphopoïèse dans le thymus et la moelle osseuse (MO). Au contraire, elle ne génère pas d’effets sur le développement des cellules NK et la myélopoïèse ; 2) La lymphopénie qui touche les lymphocytes B (LB) et T (LT) est un processus intrinsèque aux cellules porteuses de la mutation Cxcr41013 et suit un modèle allèle-dose-dépendant ; 3) Le défaut de désensibilisation de Cxcr41013 empêche le relargage des lymphocytes NK et B immatures de la MO et celui des LB et LT matures des ganglions lymphatiques dans le sang. A l’inverse, le gain de fonction exacerbe la migration des LB recirculants et LT matures et leur rétention dans le parenchyme médullaire ; et 4) malgré l’absence de follicules primaires dans les ganglions lymphatiques, les souris mutantes sont capables de mettre en place une réponse immunitaire humorale efficace et spécifique d’un antigène T-dépendant, comme en témoigne l’augmentation des LB du centre germinatif et des plasmocytes ayant effectué une commutation isotypique. En conclusion, nous démontrons que la signalisation fine médiée par Cxcr4 est nécessaire pour le développement, la compartimentalisation périphérique et la fonction des lymphocytes
The WHIM Syndrome (WS) is a rare combined immuno-hematological disorder caused by inherited heterozygous autosomal dominant mutations in CXCR4, which result in most cases in the distal truncation of the receptor’s Carboxyl-terminal tail (C-Tail). Mutants of CXCR4 associated with WS display impaired desensitization and internalization of the receptor upon CXCL12 exposure, leading to enhanced migratory response. Because CXCR4 is expressed on leukocytes, we hypothesized that circulating pan-leukopenia could arise from altered CXCR4-mediated signalling that would skew tissue distribution and differentiation of leukocytes. This assumption was obviously difficult to address in patients. By generating a knock-in mouse strain (Cxcr4+/1013) that harbors a WS-linked gain-of-Cxcr4-function mutation, we establish that the C-tail domain in Cxcr4-mediated signalling is a pivotal regulator of lymphocyte development, peripheral trafficking and humoral immunity. The essential findings of our work, obtained by combining biochemical, bone marrow (BM)-mixed chimeras, in vivo labelling, adoptive co-transfers and functional approaches, are: 1) the C-tail truncating Cxcr41013 mutation caused differential signalling capacities depending on its heterozygous versus homozygous status and inhibited double-negative (DN) 2-to-DN3 and pro-B-to-pre-B developmental transitions during lymphopoiesis. In contrast, it had no effect on NK lymphopoiesis and granulopoiesis; 2) the resulting circulating B and T lymphopenia was due to hematopoietic cell-intrinsic defects and followed a mutated allele dose-dependent pattern; 3) impaired Cxcr41013 desensitization prevented the release of immature BM NK and B cells and mature lymph node (LN) B and T lymphocytes into the blood. Conversely, it forced homing and retention of mature recirculating B and T cells in the BM parenchyma; and 4) despite the absence of primary B-cell follicles in LNs, mutant mice produced efficient humoral responses upon immunization as illustrated by increased antigen-specific germinal center B cells and isotype-switched plasma cells. Collectively, our findings demonstrate that fine-tuning of Cxcr4 signal strength is required for optimal trafficking, egress and fitness of lymphocytes

Bouis, Delphine. "Etude des conséquences d’un gain de fonction de Sting chez la souris : modèle STING V154M/WT". Thesis, Strasbourg, 2018. http://www.theses.fr/2018STRAJ063.

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Des mutations gains de fonction du gène STING chez l’Homme (telles que V155M) déclenchent une pathologie autoinflammatoire sévère de type interféronopathie, le SAVI (Sting associated vasculopathy with onset in infancy), une vasculopathie associée à une fibrose pulmonaire et des symptômes lupus-like. Afin de comprendre la physiopathologie du SAVI, nous avons généré un modèle murin porteur de la mutation correspondante grâce à la technologie CRISPR/Cas9. Ces souris STING V154M/WT développent un phénotype SCID (déficit immunitaire combiné sévère) avec diminution des LT, des LB et des NK en périphérie, et une expansion du compartiment myéloïde. Ce défaut de développement est observé précocement dès le stade pré-proB dans la moelle osseuse, et au stade DN2 dans le thymus, et semble intrinsèque aux cellules hématopoïétiques. De plus, ces souris présentent une hypogammaglobulinémie sévère. Les LT et LB matures présentent également des défauts intrinsèques. Enfin, les souris présentent une signature IFN, mais leur phénotype SCID est IFN de type I-indépendant. Ces résultats mettent en évidence un rôle important de STING dans le développement lymphoïde
In humans, point mutations in STING gene, such as V155M, lead to a severe autoinflammatory disease called SAVI (Sting associated vasculopathy with onset in infancy), classified as interferonopathy and characterized by vasculopathy, pulmonary fibrosis and a lupus-like pathology. In order to better understand the pathophysiology of SAVI, we generated a mouse model with the corresponding mutation, using CRISPR/Cas9 technology. These STING V154M/WT mice develop a SCID (severe combined immunodeficiency disease) with decrease of peripheral T, B and NK cells, and expansion of myeloid compartment. This defect seems to be present since the early stages, i.e. pre-proB cells stage in bone marrow and DN2 stage in thymus, and seems intrinsic to hematopoiectic cells. In addition, these mice present a strong hypogammaglobulinemia. Mature T and B cells also present intrinsic defaults. Finally, these mice present an IFN signature but their phenotype is independent of the IFN pathway. These results highlight an important role of STING in lymphoid development

Pronier, Elodie. "Etude de la fonction de TET2 dans l'hématopoïese normale et pathologique". Paris 7, 2013. http://www.theses.fr/2013PA077035.

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Les hémopathies myéloïdes sont des maladies clonales de la cellule souche hématopoïétique. Récemment de nombreuses études ont démontré l'implication des facteurs épigénétiques dans l'apparition de ces maladies. En effet, le séquençage d'ADN de patients atteints de diverses hémopathies malignes a permis l'identification de mutations dans le gène TET2 (TET methylcytosïne dioxygenase 2). Cette enzyme convertit les 5-méthylcytosines en 5-hydroxyméthylcytosines (5hmC). L'impact biologique de cette nouvelle base de l'ADN ainsi que la fonction des protéines TET sont encore mal connus. Les objectifs de ma thèse ont donc consisté à déterminer la ou les fonction(s) de TET2 au cours de l'hématopoïèse humaine et son implication dans la transformation maligne. Mes travaux ont confirmé, dans les cellules de patients atteints de NMP, que la mutation de TET2 induit une diminution du taux global de 5hmC génomique. Puis nous avons montré qu'une haploinsuffisance en TET2 dans des cellules CD34+ induisait un biais de différenciation vers le lignage myéloïde aux dépens des lignages lymphoïdes et érythrocytaires. Elle influence aussi les étapes terminales des trois lignages myéloïdes. Nous avons également démontré que l'inhibition de TET2 induit la surexpression de MIF (Macrophage Migration Inhibitory Factor}, TET2 est capable de se fixer au niveau de son site d'initiation de la transcription (TSS) et d'influencer sa transcription par recrutement d'EGR-1 et de la polymerase II activée. Enfin, l'haploinsuffisance de TET2 confère un avantage sélectif aux cellules CD34+ permettant une reconstitution supérieure du système hématopoïétique de souris immunodéficientes dans un modèle de xénogreffe
Myeloid malignancies are clonal disease of the hematopoietic stem cell develop following a skewed of the differentiation toward myeloid lineages associated with increased proliferation. Recently, many studies have demonstrated the involvement epigenetic factors in malignant transformation. Indeed, DNA sequencing of patients with diverse malignancies identified mutations in TET2 (TET methylcytosïne dioxygenase 2) gene. This gene encodes an enzyme that couverts 5-methylcytosines to 5-hydroxyméthylcytosines (5hmC). The biological impact of this new modification of DNA bases and the TET protein function during hematopoiesis is poorly understood. The objectives of my thesis were to determine the function(s) of TET2 in human hematopoiesis and involvement in malignant transformation. My results confirmed in the cells from MPN patients that TET2 mutation induces a decrease in the overall rate of 5hmC. Then we hâve shown that TET2 haploinsufficiency after infection of CD34+ using a specific shRNA induces differentiation skewed toward myeloid lineage. This haploinsufficiency also affects the terminal stages of myeloid three lineages. We also demonstrated that TET2 inhibition induces expression of several inflammatory cytokines such as MIF (Macrophage Migration Inhibitory Factor}. TET2 binds to it promoter regions and influence their transcription through the recruitment of EGR1 and active polymerase II. Finally, haploinsufficiency of TET2 induces a selective advantage of CD34+ cells for reconstitution of the hematopoietic System of highly immunodeficient mice. TET2 is involved in several steps of tumor transformation but these functions factor transcription remain poorly understood

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Libri sul tema "Mutation gain de fonction":

Ontario. Esquisse de cours 12e année: Sciences de l'activité physique pse4u cours préuniversitaire. Vanier, Ont: CFORP, 2002.

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Ontario. Esquisse de cours 12e année: Technologie de l'information en affaires btx4e cours préemploi. Vanier, Ont: CFORP, 2002.

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Ontario. Esquisse de cours 12e année: Études informatiques ics4m cours préuniversitaire. Vanier, Ont: CFORP, 2002.

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Ontario. Esquisse de cours 12e année: Mathématiques de la technologie au collège mct4c cours précollégial. Vanier, Ont: CFORP, 2002.

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Ontario. Esquisse de cours 12e année: Sciences snc4m cours préuniversitaire. Vanier, Ont: CFORP, 2002.

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Ontario. Esquisse de cours 12e année: English eae4e cours préemploi. Vanier, Ont: CFORP, 2002.

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Ontario. Esquisse de cours 12e année: Le Canada et le monde: une analyse géographique cgw4u cours préuniversitaire. Vanier, Ont: CFORP, 2002.

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Ontario. Esquisse de cours 12e année: Environnement et gestion des ressources cgr4e cours préemploi. Vanier, Ont: CFORP, 2002.

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Ontario. Esquisse de cours 12e année: Histoire de l'Occident et du monde chy4c cours précollégial. Vanier, Ont: CFORP, 2002.

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Ontario. Esquisse de cours 12e année: Géographie mondiale: le milieu humain cgu4u cours préuniversitaire. Vanier, Ont: CFORP, 2002.

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Capitoli di libri sul tema "Mutation gain de fonction":

Das, Priyanka, Rajeev N. Bahuguna, Rohit Joshi, Sneh Lata Singla-Pareek e Ashwani Pareek. "In search of mutants for gene discovery and functional genomics for multiple stress tolerance in rice." In Mutation breeding, genetic diversity and crop adaptation to climate change, 444–50. Wallingford: CABI, 2021. http://dx.doi.org/10.1079/9781789249095.0045.

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Abstract Mutation breeding is a commanding tool, which has been adapted to generate altered genetic material to study functional genomics, including understanding the molecular basis of stress tolerance. Hitherto, several rice lines have been generated through mutagenesis and the mutated genes responsible for the 'gain of function' in terms of plant architecture, stress tolerance, disease resistance and grain quality have been characterized. Oryza sativa L. cv. IR64 is a high-yielding rice cultivar but sensitive to abiotic stresses such as acute temperatures, salinity and drought. In this study, a population of rice IR64 mutants was generated using gamma irradiation. The population was then subjected to a preliminary phenotypic screening under abiotic stresses such as heat and salinity at the seedling stage. On the basis of root length, shoot length, fresh weight, dry weight and chlorophyll measurements, we identified eight 'gain-of-function' mutant lines and used them for further biochemical and molecular characterization. Phenotyping results demonstrated that the identified mutant plants have gained the potential to thrive under heat and salinity conditions. This information would be of wide scientific interest and helpful for developing novel cultivars able to maintain yield in saline, hot and dry areas.

Corne, David W., Martin J. Oates e Douglas B. Kell. "On Fitness Distributions and Expected Fitness Gain of Mutation Rates in Parallel Evolutionary Algorithms". In Parallel Problem Solving from Nature — PPSN VII, 132–41. Berlin, Heidelberg: Springer Berlin Heidelberg, 2002. http://dx.doi.org/10.1007/3-540-45712-7_13.

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Brandão, Maíra Pontual, Elaine Maria Frade Costa, Maki Fukami, Mariza Gerdulo, Natalia P. Pereira, Sorahia Domenice, Tsutomu Ogata e Berenice B. Mendonca. "MAMLD1 (Mastermind-Like Domain Containing 1) Homozygous Gain-of-Function Missense Mutation Causing 46,XX Disorder of Sex Development in a Virilized Female". In Advances in Experimental Medicine and Biology, 129–31. New York, NY: Springer New York, 2011. http://dx.doi.org/10.1007/978-1-4419-8002-1_28.

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"Gain-of-Function Mutation". In Encyclopedia of Cancer, 1489. Berlin, Heidelberg: Springer Berlin Heidelberg, 2011. http://dx.doi.org/10.1007/978-3-642-16483-5_2303.

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Allendorf, Fred W., W. Chris Funk, Sally N. Aitken, Margaret Byrne e Gordon Luikart. "Mutation". In Conservation and the Genomics of Populations, 253–68. Oxford University Press, 2022. http://dx.doi.org/10.1093/oso/9780198856566.003.0012.

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Mutations are errors in the transmission of genetic information from parents to progeny, and an understanding of mutation assists in interpreting patterns of genetic variation to inform conservation. Mutation is the source of all variation, and can be neutral, beneficial, or detrimental. Mutation rates vary across the nuclear genome, and are generally higher in animal mitochondrial genomes, but much lower in chloroplast and plant mitochondrial genomes. Mutation contributes to variation within populations, population subdivision, and the rate of recovery from bottlenecks. Mutations can be detected using genomic analysis, or through effects on morphological, physiological, or behavioral traits. The amount of standing genetic variation within populations is a balance between the gain of genetic variation from mutations and loss from genetic drift. Natural selection acts to keep mutations that have a detrimental effect on fitness from increasing in frequency, and genetic drift aids the survival of advantageous mutations.

Brochier, Damien, e Nathalie Quintero. "20 - Encadrant courrier : une fonction en pleine mutation". In Les professions intermédiaires, 259. Armand Colin, 2013. http://dx.doi.org/10.3917/arco.guit.2013.01.0259.

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Squverer, Amos. "La psychologie clinique au défi des symptômes contemporains". In La psychologie clinique au défi des symptômes contemporains, 25–40. In Press, 2018. http://dx.doi.org/10.3917/pres.vavas.2018.01.0026.

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Notre époque donne à voir une mutation dans une des institutions les plus anciennes et les plus intimes qu’est la famille. Ce chapitre propose de penser la fonction de la famille dans la structuration du sujet. Pour ce faire, il déploie un concept majeur de la psychanalyse : le complexe d’Œdipe. En réactualisant ce concept, ce chapitre met le concept en travail pour penser l’actualité de la famille.

Miraoui, Hichem, Kimberly W. Keefe, Gerasimos Sykiotis, Lacey Plummer, Taneli Raivio, Andrew A. Dwyer, Yisrael Sidis, Pei Tsai, Moosa Mohammadi e Nelly Pitteloud. "Gain-of-Function Mutation in FGFR1 in Human GnRH Deficiency". In TRANSLATIONAL - Genetics & Epigenetics in GnRH Regulation, OR05–4—OR05–4. The Endocrine Society, 2011. http://dx.doi.org/10.1210/endo-meetings.2011.part1.or6.or05-4.

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Do, Marine. "Chapitre 7. Fonction de tuteur : continuité, transformation ou mutation du processus de professionnalisation". In Accompagner le changement dans le champ de la santé, 97–111. Vuibert, 2015. http://dx.doi.org/10.3917/vuib.basti.2015.01.0097.

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Kasim, Nader, Antoinette Moran e Amir Moheet. "Case 37: “Do I Really Need Insulin?” The Role of Insulin Therapy in Cystic Fibrosis–Related Diabetes (CFRD)". In Diabetes In Practice: Case Studies with Commentary, 155–57. American Diabetes Association, 2021. http://dx.doi.org/10.2337/9781580407663.37.

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A 23-year-old female with cystic fibrosis (CF) (homozygous for the F508del mutation), history of pancreatic insufficiency, and history of poor weight gain underwent an oral glucose tolerance test (OGTT) per routine screening for cystic fibrosis–related diabetes (CFRD).

Atti di convegni sul tema "Mutation gain de fonction":

Peeters, Janneke GC, Stephanie Silveria, Merve Ozdemir, Grigorios Georgolopoulos e Michel DuPage. "951 An Ezh2 gain of function mutation gives regulatory T cells a gain of function". In SITC 38th Annual Meeting (SITC 2023) Abstracts. BMJ Publishing Group Ltd, 2023. http://dx.doi.org/10.1136/jitc-2023-sitc2023.0951.

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Lin, Jie, Youyan Guo, Zuo Wang, Fengru Shi, Ya Yang, Qiang Yong, Xiaodong Pan, Zhisheng Jiang e Luya Wang. "R306S gain-of-function mutation enhances PCSK9-mediated lowering of LDL-R expression". In 2011 4th International Conference on Biomedical Engineering and Informatics (BMEI). IEEE, 2011. http://dx.doi.org/10.1109/bmei.2011.6098587.

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Jung, Seunghwan, Sejoon Lee, Sangwoo Kim e Hojung Nam. "Identification of Genomic Features in the Classification of Loss- and Gain-of-Function Mutation". In the ACM 8th International Workshop. New York, New York, USA: ACM Press, 2014. http://dx.doi.org/10.1145/2665970.2665977.

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Brockmann, Knut, Renate Brackmann, Angela Abicht, Ingo Kurth, Jianying Huang, Stephen Waxman e Sulayman Dib-Hajj. "Episodic Pain Syndrome Associated with a Novel Heterozygous Gain-of-Function SCN11A Missense Mutation". In Abstracts of the 45th Annual Meeting of the Society for Neuropediatrics. Georg Thieme Verlag KG, 2019. http://dx.doi.org/10.1055/s-0039-1698164.

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Wang, Jin, Yuan Hu, Cassandra Gonzalez, Lin Tang, Bingbing Wang, Adel El-Naggar, Jeffrey Myers e Carlos Caulin. "Abstract A14: The p53R172H gain-of-function mutation promotes resistance to oral cancer immunoprevention". In Abstracts: AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; April 29-30, 2019; Austin, TX. American Association for Cancer Research, 2020. http://dx.doi.org/10.1158/1557-3265.aacrahns19-a14.

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Perkins, R., L. M. Bartnikas e A. M. H. Casey. "Bronchiectasis Reversal with Tofacitinib Therapy in a Patient with STAT 3 Gain of Function Mutation". In American Thoracic Society 2020 International Conference, May 15-20, 2020 - Philadelphia, PA. American Thoracic Society, 2020. http://dx.doi.org/10.1164/ajrccm-conference.2020.201.1_meetingabstracts.a1979.

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Gonzalez-Mancera, M. S., B. Johnson, M. Murthi, G. E. Holt, M. A. Campos e M. Mirsaeidi. "STAT3 Gain-of-Function Mutation in a Patient with Recurrent Bronchopulmonary Infections and Multi-Organ Involvement". In American Thoracic Society 2020 International Conference, May 15-20, 2020 - Philadelphia, PA. American Thoracic Society, 2020. http://dx.doi.org/10.1164/ajrccm-conference.2020.201.1_meetingabstracts.a1362.

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Lees, Robert, Nicola Wyatt, Stephen Boag, Siobhan Burns, Chris Lamb e Ally Speight. "P89 A case of enteropathy secondary to STAT1 gain-of-function mutation successfully treated with tofacitinib". In BSG LIVE’23, 19–22 June, ACC Liverpool. BMJ Publishing Group Ltd and British Society of Gastroenterology, 2023. http://dx.doi.org/10.1136/gutjnl-2023-bsg.161.

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Hu, Zhongqian, Haoshu Fang e Siying Wang. "Abstract 3634: A gain-of-function mutation in tyrosine phosphatase SHP-2 enhances breast carcinoma malignant phenotypes". In Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA. American Association for Cancer Research, 2015. http://dx.doi.org/10.1158/1538-7445.am2015-3634.

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Acin, Sergio, e Carlos Caulin. "Abstract 4158: The p53 gain-of-function mutation p53R172Hpromotes oral cancer progression in response to DNA damage". In Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC. American Association for Cancer Research, 2010. http://dx.doi.org/10.1158/1538-7445.am10-4158.

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Rapporti di organizzazioni sul tema "Mutation gain de fonction":

McClure, Michael A., Yitzhak Spiegel, David M. Bird, R. Salomon e R. H. C. Curtis. Functional Analysis of Root-Knot Nematode Surface Coat Proteins to Develop Rational Targets for Plantibodies. United States Department of Agriculture, ottobre 2001. http://dx.doi.org/10.32747/2001.7575284.bard.

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The goal of this research was to provide a better understanding of the interface between root-knot nematodes, Meloidogyne spp., and their host in order to develop rational targets for plantibodies and other novel methods of nematode control directed against the nematode surface coat (SC). Specific objectives were: 1. To produce additional monoclonal SC antibodies for use in Objectives 2, 3, and 4 and as candidates for development of plantibodies. 2. To determine the production and distribution of SC proteins during the infection process. 3. To use biochemical and immunological methods to perturbate the root-knot nematode SC in order to identify SC components that will serve as targets for rationally designed plantibodies. 4. To develop SC-mutant nematodes as additional tools for defining the role of the SC during infection. The external cuticular layer of nematodes is the epicuticle. In many nematodes, it is covered by a fuzzy material termed "surface coat" (SC). Since the SC is the outermost layer, it may playa role in the interaction between the nematode and its surroundings during all life stages in soil and during pathogenesis. The SC is composed mainly of proteins, carbohydrates (which can be part of glycoproteins), and lipids. SC proteins and glycoproteins have been labeled and extracted from preparasitic second-stage juveniles and adult females of Meloidogyne and specific antibodies have been raised against surface antigens. Antibodies can be used to gain more information about surface function and to isolate genes encoding for surface antigens. Characterization of surface antigens and their roles in different life-stages may be an important step towards the development of alternative control. Nevertheless, the role of the plant- parasitic nematode's surface in plant-nematode interaction is still not understood. Carbohydrates or carbohydrate-recognition domains (CROs) on the nematode surface may interact with CROs or carbohydrate molecules, on root surfaces or exudates, or be active after the nematode has penetrated into the root. Surface antigens undoubtedly play an important role in interactions with microorganisms that adhere to the nematodes. Polyclonal (PC) and monoclonal (MC) antibodies raised against Meloidogyne javanica, M. incognita and other plant-parasitic nematodes, were used to characterize the surface coat and secreted-excreted products of M. javanica and M. incognita. Some of the MC and PC antibodies raised against M. incognita showed cross-reactivity with the surface coat of M. javanica. Further characterization, in planta, of the epitopes recognized by the antibodies, showed that they were present in the parasitic juvenile stages and that the surface coat is shed during root penetration by the nematode and its migration between root cells. At the molecular level, we have followed two lines of experimentation. The first has been to identify genes encoding surface coat (SC) molecules, and we have isolated and characterized a small family of mucin genes from M. incognita. Our second approach has been to study host genes that respond to the nematode, and in particular, to the SC. Our previous work has identified a large suite of genes expressed in Lycopersicon esculentum giant cells, including the partial cDNA clone DB#131, which encodes a serine/threonine protein kinase. Isolation and predicted translation of the mature cDNA revealed a frame shift mutation in the translated region of nematode sensitive plants. By using primers homologous to conserved region of DB#131 we have identified the orthologues from three (nematode-resistant) Lycopersicon peruvianum strains and found that these plants lacked the mutation.

Weller, Joel I., Derek M. Bickhart, Micha Ron, Eyal Seroussi, George Liu e George R. Wiggans. Determination of actual polymorphisms responsible for economic trait variation in dairy cattle. United States Department of Agriculture, gennaio 2015. http://dx.doi.org/10.32747/2015.7600017.bard.

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The project’s general objectives were to determine specific polymorphisms at the DNA level responsible for observed quantitative trait loci (QTLs) and to estimate their effects, frequencies, and selection potential in the Holstein dairy cattle breed. The specific objectives were to (1) localize the causative polymorphisms to small chromosomal segments based on analysis of 52 U.S. Holstein bulls each with at least 100 sons with high-reliability genetic evaluations using the a posteriori granddaughter design; (2) sequence the complete genomes of at least 40 of those bulls to 20 coverage; (3) determine causative polymorphisms based on concordance between the bulls’ genotypes for specific polymorphisms and their status for a QTL; (4) validate putative quantitative trait variants by genotyping a sample of Israeli Holstein cows; and (5) perform gene expression analysis using statistical methodologies, including determination of signatures of selection, based on somatic cells of cows that are homozygous for contrasting quantitative trait variants; and (6) analyze genes with putative quantitative trait variants using data mining techniques. Current methods for genomic evaluation are based on population-wide linkage disequilibrium between markers and actual alleles that affect traits of interest. Those methods have approximately doubled the rate of genetic gain for most traits in the U.S. Holstein population. With determination of causative polymorphisms, increasing the accuracy of genomic evaluations should be possible by including those genotypes as fixed effects in the analysis models. Determination of causative polymorphisms should also yield useful information on gene function and genetic architecture of complex traits. Concordance between QTL genotype as determined by the a posteriori granddaughter design and marker genotype was determined for 30 trait-by-chromosomal segment effects that are segregating in the U.S. Holstein population; a probability of <10²⁰ was used to accept the null hypothesis that no segregating gene within the chromosomal segment was affecting the trait. Genotypes for 83 grandsires and 17,217 sons were determined by either complete sequence or imputation for 3,148,506 polymorphisms across the entire genome. Variant sites were identified from previous studies (such as the 1000 Bull Genomes Project) and from DNA sequencing of bulls unique to this project, which is one of the largest marker variant surveys conducted for the Holstein breed of cattle. Effects for stature on chromosome 11, daughter pregnancy rate on chromosome 18, and protein percentage on chromosome 20 met 3 criteria: (1) complete or nearly complete concordance, (2) nominal significance of the polymorphism effect after correction for all other polymorphisms, and (3) marker coefficient of determination >40% of total multiple-regression coefficient of determination for the 30 polymorphisms with highest concordance. The missense polymorphism Phe279Tyr in GHR at 31,909,478 base pairs on chromosome 20 was confirmed as the causative mutation for fat and protein concentration. For effect on fat percentage, 12 additional missensepolymorphisms on chromosome 14 were found that had nearly complete concordance with the suggested causative polymorphism (missense mutation Ala232Glu in DGAT1). The markers used in routine U.S. genomic evaluations were increased from 60,000 to 80,000 by adding markers for known QTLs and markers detected in BARD and other research projects. Objectives 1 and 2 were completely accomplished, and objective 3 was partially accomplished. Because no new clear-cut causative polymorphisms were discovered, objectives 4 through 6 were not completed.

Cahaner, Avigdor, Sacit F. Bilgili, Orna Halevy, Roger J. Lien e Kellye S. Joiner. effects of enhanced hypertrophy, reduced oxygen supply and heat load on breast meat yield and quality in broilers. United States Department of Agriculture, novembre 2014. http://dx.doi.org/10.32747/2014.7699855.bard.

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Abstract (sommario):

Original objectivesThe objectives of this project were to evaluate the growth performance, meat yield and quality attributes of broiler strains widely differing in their genetic potential under normal temperature vs. warm temperature (short and long-term) conditions. Strain differences in breast muscle accretion rate, metabolic responses under heat load and, gross and histopathological changes in breast muscle under thermal load was also to be characterized. BackgroundTremendous genetic progress has been made in broiler chicken growth rate and meat yield since the 1950s. Higher growth rate is driven by higher rates of feed intake and metabolism, resulting in elevated internal heat production. Hot rearing conditions negatively affect broiler growth by hindering dissipation of heat and may lead to a lethal elevation in body temperature. To avoid heat-induced mortality, broilers reduce feed intake, leading to depressed growth rate, lower weight gain, reduce breast meat yield and quality. Thus, the genetic potential of contemporary commercial broilers (CCB) is not fully expressed under hot conditions. Major conclusions, solutions, and achievementsResearch conducted in Israel focused on three broiler strains – CCB, Featherless, Feathered sibs (i.e., sharing similar genetic background). Complimentary research trials conducted at Auburn utilized CCB (Cobb 500, Cobb 700, Ross 308, Ross 708), contrasting their performance to slow growing strains. Warm rearing conditions consistently reduced feed intake, growth rate, feed efficiency, body weight uniformity and breast muscle yield, especially pronounced with CCB and magnified with age. Breast meat quality was also negatively affected, as measured by higher drip loss and paler meat color. Exposure to continuous or short-term heat stress induced respiratory alkalosis. Breast muscle histomorphometrics confirmed enhanced myofiber hypertrophy in CCB. Featherless broilers exhibited a significant increase in blood-vessel density under warm conditions. Rapid growth and muscle accretion rate was correlated to various myopathies (white striping, woody and necrotic) as well as to increases in plasma creatinekinase levels. Whether the trigger(s) of muscle damage is loss of cellular membrane integrity due to oxidative damage or tissue lactate accumulation, or to loss of inter-compartmental cation homeostasis is yet to be determined. Based on genome-wide single-nucleotide polymorphism array genotyping, identification of the gene with the recessive mutation Scaleless (sc) facilitated the development a dCAPS assay to discriminate between sc carrier (sc/+) and non-carrier (+/+) individuals. ImplicationsThis project confirmed that featherless broiler strains grow efficiently with high yield and quality of breast meat, even under warm rearing conditions that significantly depress the overall performance of CCB. Therefore, broiler meat production in hot regions and climates can be substantially improved by introducing the featherless gene into contemporary commercial broiler stocks. This approach has become more feasible with the development of dCAPS assay. A novel modification of the PCR protocol (using whole blood samples instead of extracted DNA) may contribute to the efficient development of commercial featherless broiler strains. Such strains will allow expansion of the broiler meat production in developing countries in warm climates, where energy intensive environmental control of rearing facilities are not economical and easily achievable.