Relevant bibliographies by topics / Pfic2

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Academic literature on the topic 'Pfic2'

Author: Grafiati
Published: 20 April 2024

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Journal articles on the topic "Pfic2"

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Kim, Kang Ho, Jong Min Choi, Feng Li, Armando Arizpe, Clavia Ruth Wooton-Kee, Sayeepriyadarshini Anakk, Sung Yun Jung, Milton J. Finegold, and David D. Moore. "Xenobiotic Nuclear Receptor Signaling Determines Molecular Pathogenesis of Progressive Familial Intrahepatic Cholestasis." Endocrinology 159, no. 6 (April 26, 2018): 2435–46. http://dx.doi.org/10.1210/en.2018-00110.

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Abstract Progressive familial intrahepatic cholestasis (PFIC) is a genetically heterogeneous disorder of bile flow disruption due to abnormal canalicular transport or impaired bile acid (BA) metabolism, causing excess BA accumulation and liver failure. We previously reported an intrahepatic cholestasis mouse model based on loss of function of both farnesoid X receptor (FXR; NR1H4) and a small heterodimer partner (SHP; NR0B2) [double knockout (DKO)], which has strong similarities to human PFIC5. We compared the pathogenesis of DKO livers with that of another intrahepatic cholestasis model,Bsep−/−, which represents human PFIC2. Both models exhibit severe hepatomegaly and hepatic BA accumulation, but DKO showed greater circulating BA and liver injury, andBsep−/− had milder phenotypes. Molecular profiling of BAs uncovered specific enrichment of cholic acid (CA)–derived BAs in DKO livers but chenodeoxycholate-derived BAs inBsep−/− livers. Transcriptomic and proteomic analysis revealed specific activation of CA synthesis and alternative basolateral BA transport in DKO but increased chenodeoxycholic acid synthesis and canalicular transport inBsep−/−. The constitutive androstane receptor (CAR)/pregnane X receptor (PXR)–CYP2B/CYP2C axis is activated in DKO livers but not in other cholestasis models. Loss of this axis inFxr:Shp:Car:Pxr quadruple knockouts blockedCyp2b/Cyp2c gene induction, impaired bilirubin conjugation/elimination, and increased liver injury. Differential CYP2B expression in DKO andBsep−/− was recapitulated in human PFIC5 and PFIC2 livers. In conclusion, loss of FXR/SHP results in distinct molecular pathogenesis and CAR/PXR activation, which promotesCyp2b/Cyp2c gene transcription and bilirubin clearance. CAR/PXR activation was not observed inBsep−/− mice or PFIC2 patients. These findings provide a deeper understanding of the heterogeneity of intrahepatic cholestasis.
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Kagawa, Tatehiro, Norihito Watanabe, Kaori Mochizuki, Asano Numari, Yoshie Ikeno, Johbu Itoh, Hirotoshi Tanaka, Irwin M. Arias, and Tetsuya Mine. "Phenotypic differences in PFIC2 and BRIC2 correlate with protein stability of mutant Bsep and impaired taurocholate secretion in MDCK II cells." American Journal of Physiology-Gastrointestinal and Liver Physiology 294, no. 1 (January 2008): G58—G67. http://dx.doi.org/10.1152/ajpgi.00367.2007.

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Progressive familial cholestasis (PFIC) 2 and benign recurrent intrahepatic cholestasis (BRIC) 2 are caused by mutations in the bile salt export pump (BSEP, ABCB11) gene; however, their prognosis differs. PFIC2 progresses to cirrhosis and requires liver transplantation, whereas BRIC2 is clinically benign. To identify the molecular mechanism(s) responsible for the phenotypic differences, eight PFIC2 and two BRIC2 mutations were introduced in rat Bsep, which was transfected in MDCK II cells. Taurocholate transport activity, protein expression, and subcellular distribution of these mutant proteins were studied in a polarized MDCK II monolayer. The taurocholate transport activity was approximately half of the wild-type (WT) in BRIC2 mutants (A570T and R1050C), was substantially less in two PFIC2 mutants (D482G and E297G), and was almost abolished in six other PFIC2 mutants (K461E, G982R, R1153C, R1268Q, 3767–3768insC, and R1057X). Bsep protein expression levels correlated closely with transport activity, except for R1057X. The half-life of the D482G mutant was shorter than that of the WT (1.35 h vs. 3.49 h in the mature form). BRIC2 mutants and three PFIC mutants (D482G, E297G, and R1057X) were predominantly distributed in the apical membrane. The other PFIC2 mutants remained intracellular. The R1057X mutant protein was stably expressed and trafficked to the apical membrane, suggesting that the COOH-terminal tail is required for transport activity but not for correct targeting. In conclusion, taurocholate transport function was impaired in proportion to rapid degradation of Bsep protein in the mutants, which were aligned in the following order: A570T and R1050C > D482G > E297G > K461E, G982R, R1153C, R1268Q, 3767–3768insC, and R1057X. These results may explain the phenotypic difference between BRIC2 and PFIC2.
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Mareux, Elodie, Martine Lapalus, Amel Ben Saad, Renaud Zelli, Mounia Lakli, Yosra Riahi, Marion Almes, et al. "In Vitro Rescue of the Bile Acid Transport Function of ABCB11 Variants by CFTR Potentiators." International Journal of Molecular Sciences 23, no. 18 (September 15, 2022): 10758. http://dx.doi.org/10.3390/ijms231810758.

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ABCB11 is responsible for biliary bile acid secretion at the canalicular membrane of hepatocytes. Variations in the ABCB11 gene cause a spectrum of rare liver diseases. The most severe form is progressive familial intrahepatic cholestasis type 2 (PFIC2). Current medical treatments have limited efficacy. Here, we report the in vitro study of Abcb11 missense variants identified in PFIC2 patients and their functional rescue using cystic fibrosis transmembrane conductance regulator potentiators. Three ABCB11 disease-causing variations identified in PFIC2 patients (i.e., A257V, T463I and G562D) were reproduced in a plasmid encoding an Abcb11-green fluorescent protein. After transfection, the expression and localization of the variants were studied in HepG2 cells. Taurocholate transport activity and the effect of potentiators were studied in Madin–Darby canine kidney (MDCK) clones coexpressing Abcb11 and the sodium taurocholate cotransporting polypeptide (Ntcp/Slc10A1). As predicted using three-dimensional structure analysis, the three variants were expressed at the canalicular membrane but showed a defective function. Ivacaftor, GLP1837, SBC040 and SBC219 potentiators increased the bile acid transport of A257V and T463I and to a lesser extent, of G562D Abcb11 missense variants. In addition, a synergic effect was observed when ivacaftor was combined with SBC040 or SBC219. Such potentiators could represent new pharmacological approaches for improving the condition of patients with ABCB11 deficiency due to missense variations affecting the function of the transporter.
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Davit-Spraul, Anne, Monique Fabre, Sophie Branchereau, Christiane Baussan, Emmanuel Gonzales, Bruno Stieger, Olivier Bernard, and Emmanuel Jacquemin. "ATP8B1 and ABCB11 analysis in 62 children with normal gamma-glutamyl transferase progressive familial intrahepatic cholestasis (PFIC): Phenotypic differences between PFIC1 and PFIC2 and natural history." Hepatology 51, no. 5 (January 28, 2010): 1645–55. http://dx.doi.org/10.1002/hep.23539.

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Lam, Ping, Claire L. Pearson, Carol J. Soroka, Shuhua Xu, Albert Mennone, and James L. Boyer. "Levels of plasma membrane expression in progressive and benign mutations of the bile salt export pump (Bsep/Abcb11) correlate with severity of cholestatic diseases." American Journal of Physiology-Cell Physiology 293, no. 5 (November 2007): C1709—C1716. http://dx.doi.org/10.1152/ajpcell.00327.2007.

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Human BSEP (ABCB11) mutations are the molecular basis for at least three clinical forms of liver disease, progressive familial intrahepatic cholestasis type 2 (PFIC2), benign recurrent intrahepatic cholestasis type 2 (BRIC2), and intrahepatic cholestasis of pregnancy (ICP). To better understand the pathobiology of these disease phenotypes, we hypothesized that different mutations may cause significant differences in protein defects. Therefore we compared the effect of two PFIC2 mutations (D482G, E297G) with two BRIC2 mutations (A570T and R1050C) and one ICP mutation (N591S) with regard to the subcellular localization, maturation, and function of the rat Bsep protein. Bile salt transport was retained in all but the E297G mutant. Mutant proteins were expressed at reduced levels on the plasma membrane of transfected HEK293 cells compared with wild-type (WT) Bsep in the following order: WT > N591S > R1050C ∼ A570T ∼ E297G >> D482G. Total cell protein and surface protein expression were reduced to the same extent, suggesting that trafficking of these mutants to the plasma membrane is not impaired. All Bsep mutants accumulate in perinuclear aggresome-like structures in the presence of the proteasome inhibitor MG-132, suggesting that mutations are associated with protein instability and ubiquitin-dependent degradation. Reduced temperature, sodium butyrate, and sodium 4-phenylbutyrate enhanced the expression of the mature and cell surface D482G protein in HEK293 cells. These results suggest that the clinical phenotypes of PFIC2, BRIC2, and ICP may directly correlate with the amount of mature protein that is expressed at the cell surface and that strategies to stabilize cell surface mutant protein may be therapeutic.
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Evason, Kimberley, Kevin E. Bove, Milton J. Finegold, A. S. Knisely, Sue Rhee, Philip Rosenthal, Alexander G. Miethke, Saul J. Karpen, Linda D. Ferrell, and Grace E. Kim. "Morphologic Findings in Progressive Familial Intrahepatic Cholestasis 2 (PFIC2)." American Journal of Surgical Pathology 35, no. 5 (May 2011): 687–96. http://dx.doi.org/10.1097/pas.0b013e318212ec87.

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Goto, Kenji, Kohachiro Sugiyama, Tokio Sugiura, Toshihiro Ando, Fumihiko Mizutani, Koji Terabe, Kyoko Ban, and Hajime Togari. "Bile Salt Export Pump Gene Mutations in Two Japanese Patients With Progressive Familial Intrahepatic Cholestasis." Journal of Pediatric Gastroenterology and Nutrition 36, no. 5 (May 2003): 647–50. http://dx.doi.org/10.1002/j.1536-4801.2003.tb08089.x.

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ABSTRACTBackgroundIn recent years, progressive familial intrahepatic cholestasis has been classified into at least three types by genetic analysis: PFIC1, PFIC2, and MDR3. Liver transplantation is effective for treating patients with this intractable syndrome. Confirming the correct diagnosis is of paramount importance because prognosis after transplantation differs with the genetic type of the disease.MethodsSynthesis of cDNA was accomplished using RNA extracted from liver tissue of two Japanese patients with progressive familial intrahepatic cholestasis. Polymerase chain reaction was performed using 13 primer sets designed for amplification of the bile salt export pump cDNA. Direct sequencing was undertaken, and identified sequences were compared with the sequence for bile salt export pump gene registered with GenBank. In addition, gene sequences for nonprogressive familial intrahepatic cholestasis patients were analyzed.ResultsGenetic analysis of patient 1 revealed that substitutions in bile salt export pump protein sequences, namely R575X and E636G, might be the cause of the disease. In patient 2, V330X and R487H might fulfill the same role. Results of gene analysis in parents and cholestatic controls supported these conclusions.ConclusionsAbsence or presence of bile salt export protein gene mutations was confirmed as representing a useful prognostic marker for clinical course after liver transplantation.
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Gooijert, K. E. R., R. Havinga, H. Wolters, R. Wang, V. Ling, S. Tazuma, and H. J. Verkade. "The mechanism of increased biliary lipid secretion in mice with genetic inactivation of bile salt export pump." American Journal of Physiology-Gastrointestinal and Liver Physiology 308, no. 5 (March 1, 2015): G450—G457. http://dx.doi.org/10.1152/ajpgi.00391.2014.

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Human bile salt export pump ( BSEP) mutations underlie progressive familial intrahepatic cholestasis type 2 (PFIC2). In the PFIC2 animal model, Bsep−/−mice, biliary secretion of bile salts (BS) is decreased, but that of phospholipids (PL) and cholesterol (CH) is increased. Under physiological conditions, the biliary secretion of PL and CH is positively related (“coupled”) to that of BS. We aimed to elucidate the mechanism of increased biliary lipid secretion in Bsep−/−mice. The secretion of the BS tauro-β-muricholic acid (TβMCA) is relatively preserved in Bsep−/−mice. We infused Bsep−/−and Bsep+/+(control) mice with TβMCA in stepwise increasing dosages (150–600 nmol/min) and determined biliary bile flow, BS, PL, and CH secretion. mRNA and protein expression of relevant canalicular transporters was analyzed in livers from noninfused Bsep−/−and control mice. TβMCA infusion increased BS secretion in both Bsep−/−and control mice. The secreted PL or CH amount per BS, i.e., the “coupling,” was continuously two- to threefold higher in Bsep−/−mice ( P < 0.05). Hepatic mRNA expression of canalicular lipid transporters Mdr2, Abcg5, and Abcg8 was 45–55% higher in Bsep−/−mice (Abcg5; P < 0.05), as was canalicular Mdr2 and Abcg5 protein expression. Potential other explanations for the increased coupling of the biliary secretion of PL and CH to that of BS in Bsep−/−mice could be excluded. We conclude that the mechanism of increased biliary lipid secretion in Bsep−/−mice is based on increased expression of the responsible canalicular transporter proteins.
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Mushiake, S., K. Kawamoto, N. Kobayashi, Y. Etani, Y. Miyoshi, K. Ozono, T. Hasegawa, R. Sumazaki, and A. Matsui. "P0194 A CASE OF PFIC2 WHO UNDERWENT LIVING-RELATED ORTHOTOPIC LIVER TRANSPLANTATION." Journal of Pediatric Gastroenterology and Nutrition 39, Supplement 1 (June 2004): S132. http://dx.doi.org/10.1097/00005176-200406001-00318.

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Rumbo, Carolina, Juan P. Santilli, Julio J. Trentadue, and Gabriel E. Gondolesi. "Double Heterozygous Mutation Causing PFIC2 with Synchronic Hepatocellular Carcinomas before Two Years of Age." Transplantation 102 (July 2018): S848. http://dx.doi.org/10.1097/01.tp.0000543914.64104.9e.

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Dissertations / Theses on the topic "Pfic2"

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Amzal, Rachida. "Pharmacothérapie ciblée dans la cholestase intrahépatique familiale progressive de type 2 (PFIC2)." Thesis, Université Paris-Saclay (ComUE), 2019. http://www.theses.fr/2019SACLS187.

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ABCB11/BSEP est le transporteur des acides biliaires, localisé au niveau du pôle canaliculaire des hépatocytes. Les mutations de ce gène sont responsables de la cholestase familiale intrahépatique progressive de type 2.Au cours de ma thèse, j’ai évalué la capacité des aminoglycosides et du PTC124 à induire la translecture de codons stop prématurés, l’adressage et la fonction de mutants non-sens et faux sens de Bsep ainsi que l’effet d’une bithérapie (translecture+chaperone).Dans nos modèles cellulaires, la gentamicine était capable d’induire la translecture du codon-stop prématuré du mutant non-sens BsepR1090X dans les lignées NIH3T3, HEK293 et Can 10. La protéine entière générée était partiellement détectée aux membranes plasmiques des cellules HEK293 et canaliculaires des cellules Can 10 et était partiellement fonctionnelle puisqu’elle était responsable d’une augmentation de l’activité de transport de 3H-taurocholate (3H-TC) dans les clones MDCK. Ces effets étaient potentialisés par l’addition de drogues chaperones telles que le 4-phenylbutyrate (4-PB).J’ai également mis en évidence la capacité de nouveaux composés dérivés du 4-PB (MHMPB, OTNC et HMPB) à corriger l’adressage et à augmenter le transport de 3H-TC du mutant faux sens BsepR1128C à des concentrations plus faibles que le 4-PB. Enfin, j’ai pu montrer que d'autres drogues chaperones (GPB, PA, SAHA et C18), pouvaient corriger l’adressage canaliculaire de BsepR1128C et augmenter son activité de transport de 3H-TC dans les clones MDCK
ABCB11/BSEP is the main bile acids transporter located at the canalicular pole of hepatocytes. Mutations of ABCB11 are responsible for progressive familial intrahepatic cholestasis type 2.During my phD, I evaluated the ability of aminoglycosides and PTC124 to induce readthrough of premature termination codons, targeting and function of nonsense and missense mutants of Bsep and also the effect of combined therapy (readthrough + chaperone).In our expermental models, gentamicin increased readthrough of p.R1090X mutation NIH3T3, HEK293 and Can 10 lines. The resulting full-length protein was detected at the plasma membrane of HEK293 and at the canalicular membrane of Can 10 cells; and was partially functional since it was responsible for increasing the transport activity of 3H-taurocholate (3H-TC) in MDCK clones. These effects were potentiated by the addition of chaperone drugs such as 4-phenylbutyrate (4-PB).I have also demonstrated the ability of new 4-PB derived compounds (MHMPB, OTNC and HMPB) to correct mistrafficking and to increase 3H-TC transport of BsepR1128C missense mutant at lower concentrations than 4-PB. Finally, I showed that other chaperone drugs (GPB, PA, SAHA, and C18) were able to correct mistrafiking of BsepR1128C and to increase its 3H-TC transport activity in MDCK clones
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Mareux, Elodie. "Pharmacothérapie ciblée des déficits en ABCB11." Electronic Thesis or Diss., université Paris-Saclay, 2021. http://www.theses.fr/2021UPASL083.

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ABCB11/BSEP (Bile Salt Export Pump) est exprimé à la membrane canaliculaire des hépatocytes. Sa fonction de transport d’acides biliaires dans la bile est essentielle à la sécrétion biliaire. Près de 400 variations du gène ABCB11 ont été identifiées et sont associées à des maladies hépatobiliaires rares, la plus sévère étant la cholestase intrahépatique progressive familiale de type 2 (PFIC2). L’efficacité des traitements médicaux est limitée. Par conséquent, une transplantation hépatique est indiquée avant l’âge adulte pour près de deux tiers des patients. Dans ce contexte, l’identification de thérapies alternatives est un enjeu capital.Cette thèse s’intéresse à la recherche de stratégies thérapeutiques personnalisées permettant de corriger les conséquences pathologiques de certaines variations d’ABCB11 identifiées chez des patients. Dans le cadre d’une stratégie de traitement par des molécules potentiatrices, nous avons étudié les variations A257V, G562D et T463I d’ABCB11 par modélisation moléculaire 3D. L’étude de l’expression et de la fonction de ces variants dans différents modèles cellulaires a confirmé que ces variations étaient responsables d’un défaut de fonction du transporteur Abcb11. L’ivacaftor (VX 770, Kalydeco®), approuvé cliniquement pour le traitement de la mucoviscidose, corrigeait le défaut d’activité de ces trois variants.Des effets similaires ont été observés avec les molécules GLPG1837, SBC040 et SBC219, connues comme potentiateurs de CFTR (Cystic Fibrosis Transmembrane conductance Regulator). Dans une optique de thérapie combinatoire, nous avons également mis en évidence la capacité de ces potentiateurs à corriger le défaut de fonction des variants R1090C et R1090W, produits potentiels de la translecture du variant non-sens R1090X. Nous avons également évalué les molécules correctrices elexacaftor (VX-445) et tezacaftor (VX-661). Ces correcteurs, en monothérapie ou en combinaison, permettaient de restaurer l’adressage du variant R1128C, s’accompagnant d’une augmentation significative du transport de taurocholate. De façon intéressante, l’addition de molécules potentiatrices réduisait ces effets.L’ensemble de ces travaux constitue une preuve de concept que les défauts de certains variants d’ABCB11 peuvent être corrigés par ces molécules potentiatrices à haut potentiel thérapeutique. Ce type de traitements pourrait être envisagé pour les patients atteints de déficit en ABCB11 et permettrait ainsi d’augmenter la pharmacopée disponible pour traiter ce genre de pathologies et ainsi repousser voir palier à la transplantation hépatique pour les cas les plus sévères
ABCB11/BSEP (Bile Salt Export Pump) is expressed at the canalicular membrane of hepatocytes. It ensures bile acids secretion into bile which is essential for biliary secretion. Nearly 400 variations of the ABCB11 gene have been identified and are associated with rare hepatobiliary diseases, the most severe being progressive familial intrahepatic cholestasis type 2 (PFIC2). The effectiveness of medical treatments is limited. Consequently, liver transplantation is required before adulthood for almost 2/3 of PFIC2 patients. In this context, the identification of alternative therapies is a major challenge.This thesis focuses on personalized therapeutic strategies to correct the pathological consequences of some ABCB11 variations identified in patients. The A257V, G562D and T463I variations of ABCB11 were studied by 3D molecular modelling. These variations were responsible for a defect in Abcb11 transport function. Ivacaftor (VX-770, Kalydeco®), a clinically approved cystic fibrosis treatment, corrects the activity defect of the three variants.Similar effects were observed with GLPG1837, SBC040 and SBC219, known as potentiators of CFTR (Cystic Fibrosis Transmembrane Conductance Regulator).From a combinatory therapy perspective, we also demonstrated the ability of these potentiators to correct the transport defect of the R1090C and R1090W variants, potential readthrough products of the R1090X nonsense variant. We also evaluated the ability of Elexacaftor (VX-445) and Tezacaftor (VX 661) correctors of CFTR. These correctors, alone or in combination, restored trafficking of the R1128C missense variant, leading to a significant increase in the transport function. Interestingly, the addition of potentiators abolishes this effect.Altogether, this thesis constitutes a proof of concept that molecules with high therapeutic potential can correct the molecular defects of ABCB11 variants. These treatments could increase the pharmacopoeia available for patients with ABCB11 deficiency and thus delay or even suppress the need for liver transplantation
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De, Vulpillieres Quitterie. "Rôle de l'extrémité C-terminale d'ABCB4/MDR3 : Interaction avec la protéine à domaines PDZ EBP50." Thesis, Paris 6, 2015. http://www.theses.fr/2015PA066038.

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ABCB4/MDR3 est le transporteur canaliculaire de la phosphatidylcholine. Il est exprimé à la membrane canaliculaire des hépatocytes et est essentiel à la sécrétion biliaire. Un défaut d’ABCB4 entraîne des pathologies hépatobiliaires, dont la PFIC3 (cholestase intrahépatique familiale progressive de type 3), caractérisée par une cholestase précoce qui progresse vers la cirrhose et l’insuffisance hépatique avant l’âge adulte. Dans la majorité des cas, la seule thérapie efficace est la transplantation hépatique. Cette thèse s’intéresse aux rôles de l’extrémité C-terminale dans la régulation de la stabilité et l’expression de ce transporteur au canalicule biliaire. Nous avons délété le motif Q-N-L de cette extrémité et montré que cette délétion affecte la stabilité d’ABCB4/MDR3 en augmentant son endocytose. Son interaction avec des protéines à domaines PDZ est alors étudiée. Nous avons montré une interaction par le motif Q-N-L avec la protéine à domaines PDZ, EBP50. Cette interaction est nécessaire pour l’expression canaliculaire et la stabilité du transporteur
ABCB4 is a phosphatidylcholine translocator specifically expressed at the bile canalicular membrane of hepatocytes. Mutations of the ABCB4 gene cause progressive familial intrahepatic cholestasis type 3 (PFIC3), a rare genetic disease characterized by early onset of cholestasis and evolution to cirrhosis and liver failure before adulthood. Little is known regarding the molecular mechanisms which control the canalicular expression and membrane stabilization of ABCB4 in hepatocytes. The aim of this work was to study the role of the C-terminal domain of ABCB4 for its expression and stability. potential interaction with EBP50, a PDZ protein highly expressed in hepatocytes. The experimental approach consisted in the deletion of the QNL motif at the C-terminus of ABCB4. The truncation of the QNL motif leds to a reduction of ABCB4 stability by increasing its endocytosis. ABCB4 co-precipitated with EBP50, an interaction that required the QNL motif. This interaction plays a critical role in the canalicular expression and stabilization of ABCB4
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Siew, Susan Mei-Ling. "Recombinant AAV-mediated Gene Therapy Approaches to Treat Progressive Familial Intrahepatic Cholestasis Type 3." Thesis, The University of Sydney, 2014. http://hdl.handle.net/2123/12409.

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Among contemporary gene transfer vehicles, non-pathogenic recombinant adeno-associated viral vectors (rAAV) show exceptional promise for liver-targeted therapeutic approaches. The broad focus of studies described in this thesis was the development of rAAV-mediated gene therapy to treat Progressive Familial Intrahepatic Cholestasis type 3. This autosomal recessive condition, caused by mutations of ABCB4, results in deficient hepatocanalicular phosphatidylcholine translocation and leads to progressive cholestatic liver disease with approximately 50% of patients requiring liver transplantation before reaching adulthood. Using an Abcb4-knockout mouse model, in vivo liver transduction with rAAV2/8 vectors encoding hABCB4 led to increased biliary phosphatidylcholine in disease-free heterozygous, but not in homozygous adults with established liver disease, despite varying vector genome size and routes of administration. Maximal transduction was achieved prior to onset of liver disease, optimally in neonates. However, loss of transgene expression occurs following neonatal vector delivery, due to rAAV episomal degradation during rapid liver growth. A novel, hybrid rAAV-piggyBac transposon vector strategy was devised to sustain hABCB4 expression in neonatally-treated homozygotes. Successful correction of liver disease was demonstrated in Abcb4-/- mice up to 9 months post-inoculation, with preliminary results indicating reduction in disease-related hepatocarcinogenic risk. These results demonstrate that rAAV-mediated gene therapy has the potential to offer patients with this heritable cholestatic liver disease an effective alternative treatment to liver transplantation, but also illustrate the importance of addressing challenges, such as the impact of liver pathology on vector performance, which is vital before this potential can be realised for this and related conditions.
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MATARAZZO, LORENZA. "“STUDIO MULTICENTRICO PER LA CARATTERIZZAZIONE GENOTIPICA E FENOTIPICA DELLE COLESTASI EREDITARIE”." Doctoral thesis, Università degli Studi di Trieste, 2020. http://hdl.handle.net/11368/2961248.

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La colestasi intraepatica è una sindrome clinica e bioumorale secondaria a disturbi congeniti o acquisiti della formazione e secrezione canalicolare degli acidi biliari. Le colestasi progressive familiari intraepatiche (PFIC) rappresentano la causa di colestasi nel 10-15% dei casi e mutazioni in tre geni sono state classicamente identificate: le PFIC tipo 1 e 2, causate da mutazioni nei geni ATP8B1 e ABCB11, caratterizzate da livelli normali di GGT e la PFIC di tipo 3, causata da mutazioni nel gene ABCB4, con GGT elevate. Negli ultimi anni, le tecniche di Next Generation Sequencing hanno permesso di identificare e caratterizzare nuovi geni coinvolti nelle colestasi ereditarie sia nella forme a GGT normali (TJP2, FXR, MYO5B), che elevate (CLDN1, DCDC2). A partire da tali premesse, è stato condotto uno studio multicentrico, retrospettivo e prospettico, con l’obiettivo di arruolare pazienti affetti da colestasi e caratterizzarli fenotipicamente e genotipicamente. I pazienti sono stati studiati mediante sequenziamento dell’esoma e conferma con tecnica Sanger nei probandi e, qualora disponibili, nei genitori. Sono stati arruolati 25 pazienti con i seguenti risultati: una predominanza del sesso maschile (19/25, 76%) ed un’età mediana all’esordio di 0.8 anni (range 0 - 15.1). Il 68% dei pazienti (17/25) era di origine italiana. La durata media del follow-up è stata di 3.7 anni (range 0.1 - 25.6). Le manifestazioni cliniche all’esordio comprendevano epatomegalia (68%), ittero (57%), prurito (43%), scarsa crescita (33%), feci ipocoliche (33%) e splenomegalia (28%). Il valore mediano delle ALT era 184 U/L (range 54 - 650), della bilirubina totale e diretta rispettivamente 5.5 mg/dl e 3.2 mg/dl. Gli acidi biliari erano aumentati nell’81% dei pazienti. Una lieve predominanza delle forme a GGT elevate (64%) è stata riscontrata. La biopsia epatica, eseguita in 16/25 (64%) pazienti, mostrava un’ istologia compatibile con colestasi intraepatica nelle forme a GGT normali e con colangiopatia per le forme a GGT elevate.La terapia medica all’esordio consisteva nell’utilizzo di acido ursodesossicolico, supplementazione con vitamine liposolubili e trattamento del prurito. Quattro pazienti (16%) hanno ricevuto trapianto epatico. I risultati completi delle analisi genetiche, disponibili per 8 pazienti, hanno mostrato una prevalenza di mutazioni a carico del gene della miosina 5B (MYO5B), presenti in 6 pazienti; 2 pazienti avevano mutazioni a carico del gene ABCB4 (PFIC tipo 3), mentre per i restanti pazienti le analisi genetiche sono ancora in corso.
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Books on the topic "Pfic2"

1

O'Donnell, Thomas A. PFICs. [Washington, D.C.]: Tax Management, 2006.

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Pfin2. South Western Educational Publishing, 2011.

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Wali, Sami. Applied Nanomedicine. Membrane Microdomain Disorganization Disorders. Volume 17. ADPKD and PFIC1: Diseases with Persistent or Impaired Raft Building. Wali, Sami, 2021.

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Book chapters on the topic "Pfic2"

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Davit-Spraul, Anne, Marine Beinat, Dominique Debray, Agnes Rötig, Abdelhamid Slama, and Emmanuel Jacquemin. "Secondary Mitochondrial Respiratory Chain Defect Can Delay Accurate PFIC2 Diagnosis." In JIMD Reports, 17–21. Berlin, Heidelberg: Springer Berlin Heidelberg, 2013. http://dx.doi.org/10.1007/8904_2013_278.

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Braun-Falco, Markus, Henry J. Mankin, Sharon L. Wenger, Markus Braun-Falco, Stephan DiSean Kendall, Gerard C. Blobe, Christoph K. Weber, et al. "PFIC Type 1." In Encyclopedia of Molecular Mechanisms of Disease, 1633. Berlin, Heidelberg: Springer Berlin Heidelberg, 2009. http://dx.doi.org/10.1007/978-3-540-29676-8_7852.

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Braun-Falco, Markus, Henry J. Mankin, Sharon L. Wenger, Markus Braun-Falco, Stephan DiSean Kendall, Gerard C. Blobe, Christoph K. Weber, et al. "PFIC Type 2." In Encyclopedia of Molecular Mechanisms of Disease, 1633. Berlin, Heidelberg: Springer Berlin Heidelberg, 2009. http://dx.doi.org/10.1007/978-3-540-29676-8_7853.

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Braun-Falco, Markus, Henry J. Mankin, Sharon L. Wenger, Markus Braun-Falco, Stephan DiSean Kendall, Gerard C. Blobe, Christoph K. Weber, et al. "PFIC Type 3." In Encyclopedia of Molecular Mechanisms of Disease, 1633. Berlin, Heidelberg: Springer Berlin Heidelberg, 2009. http://dx.doi.org/10.1007/978-3-540-29676-8_7854.

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"PFIC." In Encyclopedia of Clinical Neuropsychology, 1930. New York, NY: Springer New York, 2011. http://dx.doi.org/10.1007/978-0-387-79948-3_5248.

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"Byler Disease (PFIC1, 18q21)." In Encyclopedia of Genetics, Genomics, Proteomics and Informatics, 244. Dordrecht: Springer Netherlands, 2008. http://dx.doi.org/10.1007/978-1-4020-6754-9_2132.

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Pandey, Chandra, Soumya Nath, and Mukesh Tripathi. "Progressive Familial Intrahepatic Cholestasis (PFIC)." In Hepatic and Biliary Diseases: Anesthesiologists’ Perspective, 298. Jaypee Brothers Medical Publishers (P) Ltd., 2012. http://dx.doi.org/10.5005/jp/books/11585_33.

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Gissen, Paul, and Eamonn R. Maher. "VPS33B and the Arthrogryposis, Renal Dysfunction, and Cholestasis Syndrome." In Inborn Errors Of Development, 1410–15. Oxford University PressNew York, NY, 2008. http://dx.doi.org/10.1093/oso/9780195306910.003.0161.

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Abstract Arthrogryposis, renal dysfunction, and cholestasis (ARC) syndrome (OMIM 208085) is a severe multisystem autosomal recessive disorder 2rst described in the 1970s, and to date, approximately 50 cases of ARC have been reported (see Gissen et al., 2006 and references within). Although the variability in liver biopsy 2ndings initially suggested possible genetic heterogeneity, Horslen et al., 1994 coined the eponym of ARC syndrome and reported that although the hepatic changes may show intrafamilial variability, the other features were usually consistent. Subsequently a high prevalence of ichthyosis, abnormal platelet morphology, intracranial defects, and diarrhea was noted. Many reported families were consanguineous, consistent with autosomal recessive inheritance. Although the hepatic features of ARC and progressive familial intrahepatic cholestasis (PFIC) overlap, linkages to PFIC-1 and PFIC-2 loci were excluded, and the locus for ARC syndrome was mapped to chromosome 15q26.1 using autozygosity mapping approach and germline mutations were identi2ed in VPS33B (Gissen et al., 2004). VPS33B is a homologue of yeast vps33 gene involved in vacuolar biogenesis and in vesicular traf2cking at different stages of the endocytosis and exocytosis (Gallwitz et al., 2003). Yeast vps33 encodes a class C vacuolar protein sorting (vps) protein whose inactivation results in severe cellular defects including temperature-sensitive growth restriction, abnormalities in the amino acid pool, and vacuolar biogenesis defects. VPS33B contains a Sec1- like domain and belongs to the family of SM (Sec1/Munc18) proteins that bind tightly to members of the syntaxin family of target-SNAREs (soluble N-ethylmaleimide-sensitive factor attachment protein receptors or SNAP receptor proteins). SM proteins can exert inMuence upon the SNARE-complex formation and may provide speci2city to the vesicular fusion events.
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Keitel-Anselmino, Verena. "Behandlung progressiv-familiärer intrahepatischer Cholestasen (PFIC)." In Therapie-Handbuch - Gastroenterologie und Hepatologie, 356–61. Elsevier, 2021. http://dx.doi.org/10.1016/b978-3-437-23847-5.00050-8.

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Conference papers on the topic "Pfic2"

1

Grimps, P., S. Hametner-Schreil, I. Soellradl, M. Weitersberger, and D. Schiller. "Die Krux der PFIC–Differentialdiagnose zum (vorgetäuschten) Mb. Wilson–Ein Fallbericht." In 55. Jahrestagung & 32. Fortbildungskurs der Österreichischen Gesellschaft für Gastroenterologie & Hepatologie–ÖGGH (Hybrid Veranstaltung). Georg Thieme Verlag, 2022. http://dx.doi.org/10.1055/s-0042-1755765.

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Behrendt, Annika, Jan Stindt, Eva-Doreen Pfister, Kathrin Grau, Stefanie Brands, Carola Dröge, Amelie Stalke, et al. "Impaired transitioning from an inactive to an active state of FXR underlies a PFIC5 phenotype." In 40. Jahrestagung der Deutschen Arbeitsgemeinschaft zum Studium der Leber. Georg Thieme Verlag, 2024. http://dx.doi.org/10.1055/s-0043-1777501.

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Özen, Hasan, Etienne Sokal, Florence Lacaille, Buket Dalgic, Quanhong Ni, Lise Kjems, and Patrick Horn. "L2 Efficacy and safety outcomes with odevixibat in children with progressive familial intrahepatic cholestasis due to deficiencies in multidrug resistance protein 3 (PFIC type 3) or myosin 5B (PFIC type 6)." In Abstracts of the BSPGHAN Annual Meeting, 25–27 April 2022. BMJ Publishing Group Ltd, 2022. http://dx.doi.org/10.1136/flgastro-2022-bspghan.65.

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