6 results on '"Genetic liver disease"'
Search Results
2. Ivacaftor-Mediated Potentiation of ABCB4 Missense Mutations Affecting Critical Motifs of the NBDs: Repositioning Perspectives for Hepatobiliary Diseases
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Jean-Louis Delaunay, Ahmad Elbahnsi, Alix Bruneau, Claire Madry, Anne-Marie Durand-Schneider, Anne Stary, Chantal Housset, Jérémie Gautheron, Isabelle Callebaut, and Tounsia Aït-Slimane
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bile secretion ,genetic liver disease ,PFIC3 ,ABC transporter ,potentiators ,ivacaftor ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
ABCB4 (ATP-binding cassette subfamily B member 4) is a hepatocanalicular floppase involved in biliary phosphatidylcholine (PC) secretion. Variations in the ABCB4 gene give rise to several biliary diseases, including progressive familial intrahepatic cholestasis type 3 (PFIC3), an autosomal recessive disease that can be lethal in the absence of liver transplantation. In this study, we investigated the effect and potential rescue of ten ABCB4 missense variations in NBD1:NBD2 homologous positions (Y403H/Y1043H, K435M/K1075M, E558K/E1200A, D564G/D1206G and H589Y/H1231Y) all localized at the conserved and functionally critical motifs of ABC transporters, six of which are mutated in patients. By combining structure analysis and in vitro studies, we found that all ten mutants were normally processed and localized at the canalicular membrane of HepG2 cells, but showed dramatically impaired PC transport activity that was significantly rescued by treatment with the clinically approved CFTR potentiator ivacaftor. Our results provide evidence that functional ABCB4 mutations are rescued by ivacaftor, paving the way for the repositioning of this potentiator for the treatment of selected patients with PFIC3 caused by mutations in the ATP-binding sites of ABCB4.
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- 2023
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3. Analysis of the mechanism underlying liver diseases using human induced pluripotent stem cells
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Sei Kakinuma and Mamoru Watanabe
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Cholangiocytes ,genetic liver disease ,hepatitis B virus ,hepatic stellate cells ,hepatocytes ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Results of recent studies have shown that disease models using human induced pluripotent stem (iPS) cells have recapitulated the pathophysiology of genetic liver diseases, viral hepatitis and hepatic fibrosis. The utilization of human iPS cells as a model of liver diseases has several substantial advantages compared with primary hepatocytes and cancer cell lines, such as the potential for unlimited expansion and similarity of biological characteristics to normal liver cells. In this review, we have focused on modeling liver diseases using human iPS cells and discussed the experimental evidence that supports the utility of such disease models, including that in our recent studies. Genetically modified or patient-derived human iPS cells can mimic congenital liver disease phenotypes. Human iPS-derived hepatic cells can be infected with the hepatitis viruses. The co-culture of human iPS-derived hepatocytes and mesenchyme partially mimics the process of liver fibrosis. Human iPS cell-derived hepatic cells and the co-culture system of such cells will contribute to the progress of studies on the pathophysiology of genetic and non-genetic liver diseases and development of novel therapeutic strategies for treating liver diseases.
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- 2019
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4. Jaundice revisited: recent advances in the diagnosis and treatment of inherited cholestatic liver diseases
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Huey-Ling Chen, Shang-Hsin Wu, Shu-Hao Hsu, Bang-Yu Liou, Hui-Ling Chen, and Mei-Hwei Chang
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Cholestasis ,Genetic liver disease ,Pediatric ,Progressive familial intrahepatic cholestasis ,Next generation sequencing ,Bile acids ,Medicine - Abstract
Abstract Background Jaundice is a common symptom of inherited or acquired liver diseases or a manifestation of diseases involving red blood cell metabolism. Recent progress has elucidated the molecular mechanisms of bile metabolism, hepatocellular transport, bile ductular development, intestinal bile salt reabsorption, and the regulation of bile acids homeostasis. Main body The major genetic diseases causing jaundice involve disturbances of bile flow. The insufficiency of bile salts in the intestines leads to fat malabsorption and fat-soluble vitamin deficiencies. Accumulation of excessive bile acids and aberrant metabolites results in hepatocellular injury and biliary cirrhosis. Progressive familial intrahepatic cholestasis (PFIC) is the prototype of genetic liver diseases manifesting jaundice in early childhood, progressive liver fibrosis/cirrhosis, and failure to thrive. The first three types of PFICs identified (PFIC1, PFIC2, and PFIC3) represent defects in FIC1 (ATP8B1), BSEP (ABCB11), or MDR3 (ABCB4). In the last 5 years, new genetic disorders, such as TJP2, FXR, and MYO5B defects, have been demonstrated to cause a similar PFIC phenotype. Inborn errors of bile acid metabolism also cause progressive cholestatic liver injuries. Prompt differential diagnosis is important because oral primary bile acid replacement may effectively reverse liver failure and restore liver functions. DCDC2 is a newly identified genetic disorder causing neonatal sclerosing cholangitis. Other cholestatic genetic disorders may have extra-hepatic manifestations, such as developmental disorders causing ductal plate malformation (Alagille syndrome, polycystic liver/kidney diseases), mitochondrial hepatopathy, and endocrine or chromosomal disorders. The diagnosis of genetic liver diseases has evolved from direct sequencing of a single gene to panel-based next generation sequencing. Whole exome sequencing and whole genome sequencing have been actively investigated in research and clinical studies. Current treatment modalities include medical treatment (ursodeoxycholic acid, cholic acid or chenodeoxycholic acid), surgery (partial biliary diversion and liver transplantation), symptomatic treatment for pruritus, and nutritional therapy. New drug development based on gene-specific treatments, such as apical sodium-dependent bile acid transporter (ASBT) inhibitor, for BSEP defects are underway. Short conclusion Understanding the complex pathways of jaundice and cholestasis not only enhance insights into liver pathophysiology but also elucidate many causes of genetic liver diseases and promote the development of novel treatments.
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- 2018
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5. Promoterless gene targeting without nucleases rescues lethality of a Crigler‐Najjar syndrome mouse model
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Fabiola Porro, Giulia Bortolussi, Adi Barzel, Alessia De Caneva, Alessandra Iaconcig, Simone Vodret, Lorena Zentilin, Mark A Kay, and Andrés F Muro
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brain damage ,genetic liver disease ,homologous recombination ,hyperbilirubinemia ,kernicterus ,Medicine (General) ,R5-920 ,Genetics ,QH426-470 - Abstract
Abstract Crigler‐Najjar syndrome type I (CNSI) is a rare monogenic disease characterized by severe neonatal unconjugated hyperbilirubinemia with a lifelong risk of neurological damage and death. Liver transplantation is the only curative option, which has several limitations and risks. We applied an in vivo gene targeting approach based on the insertion, without the use of nucleases, of a promoterless therapeutic cDNA into the albumin locus of a mouse model reproducing all major features of CNSI. Neonatal transduction with the donor vector resulted in the complete rescue from neonatal lethality, with a therapeutic reduction in plasma bilirubin lasting for at least 12 months, the latest time point analyzed. Mutant mice, which expressed about 5–6% of WT Ugt1a1 levels, showed normal liver histology and motor‐coordination abilities, suggesting no functional liver or brain abnormalities. These results proved that the promoterless gene therapy is applicable for CNSI, providing therapeutic levels of an intracellular ER membrane‐bound enzyme responsible for a lethal liver metabolic disease.
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- 2017
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6. Mild Iron Overload as Seen in Individuals Homozygous for the Alpha-1 Antitrypsin Pi*Z Variant Does Not Promote Liver Fibrogenesis in HFE Knockout Mice
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Nurdan Guldiken, Karim Hamesch, Shari Malan Schuller, Mahmoud Aly, Cecilia Lindhauer, Carolin V. Schneider, Malin Fromme, Christian Trautwein, and Pavel Strnad
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iron metabolism ,α1-antitrypsin deficiency ,rare liver disease ,genetic liver disease ,serpina1 ,hfe ,liver fibrosis ,Cytology ,QH573-671 - Abstract
The presence of the homozygous ‘Pi*Z’ variant of alpha-1 antitrypsin (AAT) (‘Pi*ZZ’ genotype) predisposes to liver fibrosis development, but the role of iron metabolism in this process remains unknown. Therefore, we assessed iron metabolism and variants in the Homeostatic Iron Regulator gene (HFE) as the major cause of hereditary iron overload in a large cohort of Pi*ZZ subjects without liver comorbidities. The human cohort comprised of 409 Pi*ZZ individuals and 254 subjects without evidence of an AAT mutation who were recruited from ten European countries. All underwent a comprehensive work-up and transient elastography to determine liver stiffness measurements (LSM). The corresponding mouse models (Pi*Z overexpressors, HFE knockouts, and double transgenic [DTg] mice) were used to evaluate the impact of mild iron overload on Pi*Z-induced liver injury. Compared to Pi*Z non-carriers, Pi*ZZ individuals had elevated serum iron, transferrin saturation, and ferritin levels, but relevant iron overload was rare. All these parameters were higher in individuals with signs of significant liver fibrosis (LSM ≥ 7.1 kPa) compared to those without signs of significant liver fibrosis. HFE knockout and DTg mice displayed similar extent of iron overload and of fibrosis. Loss of HFE did not alter the extent of AAT accumulation. In Pi*ZZ individuals, presence of HFE mutations was not associated with more severe liver fibrosis. Taken together, Pi*ZZ individuals display minor alterations in serum iron parameters. Neither mild iron overload seen in these individuals nor the presence of HFE mutations (C282Y and H63D) constitute a major contributor to liver fibrosis development.
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- 2019
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