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Robert M. Tanguay - One of the best experts on this subject based on the ideXlab platform.
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Presence of three mutations in the Fumarylacetoacetate Hydrolase gene in a patient with atypical symptoms of hereditary tyrosinemia type I.
Molecular genetics and metabolism, 2019Co-Authors: Geneviève Morrow, Natacha Dreumont, Maxime Bourrelle-langlois, Vincent Roy, Robert M. TanguayAbstract:Abstract Hereditary tyrosinemia type 1 (HT1), the most severe disease of the tyrosine catabolic pathway, is caused by a deficiency of Fumarylacetoacetate Hydrolase (FAH). More than 90 disease-causing variants have been identified in the fah gene. We investigated the molecular defect in a patient who presented atypical symptoms for the disease. No immunoreactive FAH was found in the liver and RNA analysis by RT-PCR suggested the presence of splicing mutations. Indeed, the patient was revealed to be a compound heterozygote for IVS6–1 g- > t and two new variants, namely p.V259L and p.G398E. Using splicing minigene constructs transfected in HeLa cells, the c.775G > C variant (p.V259L) was shown to affect partially exon 9 splicing thereby allowing the production of some full-length double-mutant FAH transcripts. The p.G398E variant had a major impact on enzyme activity, which was worsened by the p.V259L variant. Surprisingly, the double mutant protein was expressed to similar level as the wild-type protein upon transfection in HeLa cells but was absent in the patient liver extract, suggesting a higher propensity to be degraded in the hepatocellular context.
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Molecular Aspects of the FAH Mutations Involved in HT1 Disease.
Advances in experimental medicine and biology, 2017Co-Authors: Geneviève Morrow, Francesca Angileri, Robert M. TanguayAbstract:Hereditary tyrosinemia type 1 (HT1) is caused by the lack of Fumarylacetoacetate Hydrolase (FAH), the last enzyme of the tyrosine catabolic pathway. Up to now, around 100 mutations in the FAH gene have been associated with HT1, and despite many efforts, no clear correlation between genotype and clinical phenotype has been reported. At first, it seems that any mutation in the gene results in HT1. However, placing these mutations in their molecular context allows a better understanding of their possible effects. This chapter presents a closer look at the FAH gene and its corresponding protein in addition to provide a complete record of all the reported mutations causing HT1.
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Geographical and Ethnic Distribution of Mutations of the Fumarylacetoacetate Hydrolase Gene in Hereditary Tyrosinemia Type 1
JIMD reports, 2015Co-Authors: Francesca Angileri, Anne Bergeron, Geneviève Morrow, Francine Lettre, George Gray, Tim Hutchin, Sarah Ball, Robert M. TanguayAbstract:Hereditary tyrosinemia type 1 (HT1) (OMIM 276700) is a severe inherited metabolic disease affecting mainly hepatic and renal functions that leads to a fatal outcome if untreated. HT1 results from a deficiency of the last enzyme of tyrosine catabolism, Fumarylacetoacetate Hydrolase (FAH). Biochemical findings include elevated succinylacetone in blood and urine; elevated plasma concentrations of tyrosine, methionine and phenylalanine; and elevated tyrosine metabolites in urine. The HT1 frequency worldwide is about 1 in 100,000 individuals. In some areas, where the incidence of HT1 is noticeably higher, prevalence of characteristic mutations has been reported, and the estimated incidence of carriers of a specific mutation can be as high as 1 out of 14 adults. Because the global occurrence of HT1 is relatively low, a considerable number of cases may go unrecognized, underlining the importance to establish efficient prenatal and carrier testing to facilitate an early detection of the disease. Here we describe the 95 mutations reported so far in HT1 with special emphasis on their geographical and ethnic distributions. Such information should enable the establishment of a preferential screening process for mutations most predominant in a given region or ethnic group.
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Identification of human Fumarylacetoacetate Hydrolase domain-containing protein 1 (FAHD1) as a novel mitochondrial acylpyruvase.
The Journal of biological chemistry, 2011Co-Authors: Haymo Pircher, Robert M. Tanguay, Grit Daniela Straganz, Daniela Ehehalt, Geneviève Morrow, Pidder Jansen-dürrAbstract:The human Fumarylacetoacetate Hydrolase (FAH) domain-containing protein 1 (FAHD1) is part of the FAH protein superfamily, but its enzymatic function is unknown. In the quest for a putative enzymatic function of FAHD1, we found that FAHD1 exhibits acylpyruvase activity, demonstrated by the hydrolysis of acetylpyruvate and fumarylpyruvate in vitro, whereas several structurally related compounds were not hydrolyzed as efficiently. Conserved amino acids Asp-102 and Arg-106 of FAHD1 were found important for its catalytic activity, and Mg2+ was required for maximal enzyme activity. FAHD1 was found expressed in all tested murine tissues, with highest expression in liver and kidney. FAHD1 was also found in several human cell lines, where it localized to mitochondria. In summary, the current work identified mammalian FAHD1 as a novel mitochondrial enzyme with acylpyruvate Hydrolase activity.
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A minor alternative transcript of the Fumarylacetoacetate Hydrolase gene produces a protein despite being likely subjected to nonsense-mediated mRNA decay
BMC molecular biology, 2005Co-Authors: Natacha Dreumont, Antonella Maresca, Jean François Boisclair-lachance, Anne Bergeron, Robert M. TanguayAbstract:Coupling of alternative splicing with nonsense-mediated mRNA decay (NMD) may regulate gene expression. We report here the identification of a nonsense alternative transcript of the Fumarylacetoacetate Hydrolase (fah) gene, which produces a protein despite the fact that it is subject to NMD.
Markus Grompe - One of the best experts on this subject based on the ideXlab platform.
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Slow-onset inhibition of Fumarylacetoacetate Hydrolase by phosphinate mimics of the tetrahedral intermediate: kinetics, crystal structure and pharmacokinetics
The Biochemical journal, 2007Co-Authors: Raynard L. Bateman, Markus Grompe, John F. Witte, David E. Timm, Justin Ashworth, L.-j. Baker, Pullooru Bhanumoorthy, Thomas D. Hurley, Ronald W. McclardAbstract:FAH (Fumarylacetoacetate Hydrolase) catalyses the final step of tyrosine catabolism to produce fumarate and acetoacetate. HT1 (hereditary tyrosinaemia type 1) results from deficiency of this enzyme. Previously, we prepared a partial mimic of the putative tetrahedral intermediate in the reaction catalysed by FAH co-crystallized with the enzyme to reveal details of the mechanism [Bateman, Bhanumoorthy, Witte, McClard, Grompe and Timm (2001) J. Biol. Chem. 276, 15284–15291]. We have now successfully synthesized complete mimics CEHPOBA {4-[(2-carboxyethyl)-hydroxyphosphinyl]-3-oxobutyrate} and COPHPAA {3-[(3-carboxy-2-oxopropyl)hydroxyphosphinyl]acrylate}, which inhibit FAH in slow-onset tight-binding mode with Ki values of 41 and 12 nM respectively. A high-resolution (1.35 A; 1 A=0.1 nm) crystal structure of the FAH·CEHPOBA complex was solved to reveal the affinity determinants for these compounds and to provide further insight into the mechanism of FAH catalysis. These compounds are active in vivo, and CEHPOBA demonstrated a notable dose-dependent increase in SA (succinylacetone; a metabolite seen in patients with HT1) in mouse serum after repeated injections, and, following a single injection (1 μmol/g; intraperitoneal), only a modest regain of FAH enzyme activity was detected in liver protein isolates after 24 h. These potent inhibitors provide a means to chemically phenocopy the metabolic defects of either HT1 or FAH knockout mice and promise future pharmacological utility for hepatocyte transplantation.
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Mechanistic Inferences from the Crystal Structure of Fumarylacetoacetate Hydrolase with a Bound Phosphorus-based Inhibitor
The Journal of biological chemistry, 2001Co-Authors: Raynard L. Bateman, Markus Grompe, P. Bhanumoorthy, John F. Witte, Ronald W. Mcclard, David E. TimmAbstract:Abstract Fumarylacetoacetate Hydrolase (FAH) catalyzes the hydrolytic cleavage of a carbon–carbon bond in Fumarylacetoacetate to yield fumarate and acetoacetate as the final step of Phe and Tyr degradation. This unusual reaction is an essential human metabolic function, with loss of FAH activity causing the fatal metabolic disease hereditary tyrosinemia type I (HT1). An enzymatic mechanism involving a catalytic metal ion, a Glu/His catalytic dyad, and a charged oxyanion hole was previously proposed based on recently determined FAH crystal structures. Here we report the development and characterization of an FAH inhibitor, 4-(hydroxymethylphosphinoyl)-3-oxo-butanoic acid (HMPOBA), that competes with the physiological substrate with aK i of 85 μm. The crystal structure of FAH complexed with HMPOBA refined at 1.3-A resolution reveals the molecular basis for the competitive inhibition, supports the proposed formation of a tetrahedral alkoxy transition state intermediate during the FAH catalyzed reaction, and reveals a Mg2+ bound in the enzyme's active site. The analysis of FAH structures corresponding to different catalytic states reveals significant active site side-chain motions that may also be related to catalytic function. Thus, these results advance the understanding of an essential catabolic reaction associated with a fatal metabolic disease and provide insight into the structure-based development of FAH inhibitors.
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Liver repopulation and correction of metabolic liver disease by transplanted adult mouse pancreatic cells.
The American journal of pathology, 2001Co-Authors: Xin Wang, Milton J Finegold, Muhsen Al-dhalimy, Eric Lagasse, Markus GrompeAbstract:The emergence of cells with hepatocellular properties in the adult pancreas has been described in several experimental models. To determine whether adult pancreas contains cells that can give rise to therapeutically useful and biochemically normal hepatocytes, we transplanted suspensions of wild-type mouse pancreatic cells into syngeneic recipients deficient in Fumarylacetoacetate Hydrolase and manifesting tyrosinemia. Four of 34 (12%) mutant mice analyzed were fully rescued by donor-derived cells and had normal liver function. Ten additional mice (29%) showed histological evidence of donor-derived hepatocytes in the liver. Previous work has suggested that pancreatic liver precursors reside within or close to pancreatic ducts. We therefore performed additional transplantations using either primary cell suspensions enriched for ducts or cultured ducts. Forty-four mutant mice were transplanted with cells enriched for pancreatic duct cells, but only three of the 34 (9%) recipients analyzed displayed donor-derived hepatocytes. In addition, 28 of the Fumarylacetoacetate Hydrolase-deficient mice were transplanted with cultured pancreatic duct cells, but no donor-derived hepatocytes were observed. Our results demonstrate for the first time that adult mouse pancreas contains hepatocyte progenitor cells capable of significant therapeutic liver reconstitution. However, contrary to previous reports, we were unable to detect these cells within the duct compartment.
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EX VIVO HEPATIC GENE THERAPY OF A MOUSE MODEL OF HEREDITARY TYROSINEMIA TYPE I
Human gene therapy, 1998Co-Authors: Ken Overturf, Milton J Finegold, Muhsen Al-dhalimy, Kara Manning, Markus GrompeAbstract:Previously, this lab has reported the use of hepatocyte transplantation and in vivo gene therapy for the correction of a mouse model of Hereditary Tyrosinemia Type I (HT1). Here, we demonstrate repopulation of Fumarylacetoacetate Hydrolase (FAH)-deficient livers with cultured hepatocytes. Correction of the disease phenotype was achieved by retrovirally transducing cultured FAH- hepatocytes ex vivo, followed by transplantation and selective repopulation. Treated mice were phenotypically normal and had corrected plasma amino acid levels and liver function tests. Our results demonstrate that efficient hepatic repopulation using ex vivo genetically manipulated hepatocytes is feasible.
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ADENOVIRUS-MEDIATED GENE THERAPY IN A MOUSE MODEL OF HEREDITARY TYROSINEMIA TYPE I
Human gene therapy, 1997Co-Authors: Ken Overturf, Robert M. Tanguay, Muhsen Al-dhalimy, Milton J Finegold, André Lieber, Mark A. Kay, Markus GrompeAbstract:ABSTRACT Mice lacking the enzyme Fumarylacetoacetate Hydrolase (FAH) have symptoms similar to humans with the disease hereditary tyrosinemia type I (HT1). FAH-deficient mice were injected with a fi...
Jacques Poudrier - One of the best experts on this subject based on the ideXlab platform.
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A missense mutation (Q279R) in the Fumarylacetoacetate Hydrolase gene, responsible for hereditary tyrosinemia, acts as a splicing mutation.
BMC genetics, 2001Co-Authors: Natacha Dreumont, Anne Bergeron, Faouzi Baklouti, Jacques Poudrier, Harvey Louis Levy, Robert M. TanguayAbstract:Tyrosinemia type I, the most severe disease of the tyrosine catabolic pathway is caused by a deficiency in Fumarylacetoacetate Hydrolase (FAH). A patient showing few of the symptoms associated with the disease, was found to be a compound heterozygote for a splice mutation, IVS6-1g->t, and a putative missense mutation, Q279R. Analysis of FAH expression in liver sections obtained after resection for hepatocellular carcinoma revealed a mosaic pattern of expression. No FAH was found in tumor regions while a healthy region contained enzyme-expressing nodules. Analysis of DNA from a FAH expressing region showed that the expression of the protein was due to correction of the Q279R mutation. RT-PCR was used to assess if Q279R RNA was produced in the liver cells and in fibroblasts from the patient. Normal mRNA was found in the liver region where the mutation had reverted while splicing intermediates were found in non-expressing regions suggesting that the Q279R mutation acted as a splicing mutation in vivo. Sequence of transcripts showed skipping of exon 8 alone or together with exon 9. Using minigenes in transfection assays, the Q279R mutation was shown to induce skipping of exon 9 when placed in a constitutive splicing environment. These data suggest that the putative missense mutation Q279R in the FAH gene acts as a splicing mutation in vivo. Moreover FAH expression can be partially restored in certain liver cells as a result of a reversion of the Q279R mutation and expansion of the corrected cells.
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Genotyping of a case of tyrosinaemia type I with normal level of succinylacetone in amniotic fluid
Prenatal diagnosis, 1999Co-Authors: Jacques Poudrier, Francine Lettre, Maryse St.-louis, Robert M. TanguayAbstract:Tyrosinaemia type I is caused by a deficiency of Fumarylacetoacetate Hydrolase and mainly affects the liver. This disease is characterized by the presence of a high level of succinylacetone. This metabolite has been used for prenatal diagnosis from amniotic fluid samples. One case with a normal level of succinylacetone in amniotic fluid has recently been described (Grenier et al., 1996). Here, we report that this patient is a compound heterozygote for two known mutations: E364X and IVS6-1g-->t. The low level of succinylacetone cannot be explained by these mutations.
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FREQUENCY OF THE IVS12+5G→A SPLICE MUTATION OF THE Fumarylacetoacetate Hydrolase GENE IN CARRIERS OF HEREDITARY TYROSINAEMIA IN THE FRENCH CANADIAN POPULATION OF SAGUENAY‐LAC‐ST‐JEAN
Prenatal diagnosis, 1996Co-Authors: Jacques Poudrier, Maryse St.-louis, Francine Lettre, Karine Gibson, Claude Prévost, Jean Larochelle, Robert M. TanguayAbstract:Hereditary tyrosinaemia type I (HTI), an autosomal recessive inborn error of metabolism, is caused by a deficiency of the enzyme Fumarylacetoacetate Hydrolase. The highest incidence of HTI is observed in the Saguenay-Lac-St-Jean region (SLSJ) (Quebec, Canada), where 1 out of 22 individuals is thought to be a carrier. A splice mutation (IVS12+5G|adA) has recently been identified in this particular region. Here, we have determined the frequency of this mutation in a population of obligate carriers from the SLSJ region by allele-specific oligonucleotide hybridization and a method using a restriction enzyme digestion. Over 95 per cent of the HTI carriers were found to have the IVS12+5G|adA splice mutation. Screening for this mutation based on the two methods reported here is thus a reliable and rapid way of detecting carriers of hereditary tyrosinaemia type I in that region at high risk.
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frequency of the ivs12 5g a splice mutation of the Fumarylacetoacetate Hydrolase gene in carriers of hereditary tyrosinaemia in the french canadian population of saguenay lac st jean
Prenatal Diagnosis, 1996Co-Authors: Jacques Poudrier, Francine Lettre, Karine Gibson, Claude Prévost, Jean Larochelle, Maryse Stlouis, Robert M. TanguayAbstract:Hereditary tyrosinaemia type I (HTI), an autosomal recessive inborn error of metabolism, is caused by a deficiency of the enzyme Fumarylacetoacetate Hydrolase. The highest incidence of HTI is observed in the Saguenay-Lac-St-Jean region (SLSJ) (Quebec, Canada), where 1 out of 22 individuals is thought to be a carrier. A splice mutation (IVS12+5G|adA) has recently been identified in this particular region. Here, we have determined the frequency of this mutation in a population of obligate carriers from the SLSJ region by allele-specific oligonucleotide hybridization and a method using a restriction enzyme digestion. Over 95 per cent of the HTI carriers were found to have the IVS12+5G|adA splice mutation. Screening for this mutation based on the two methods reported here is thus a reliable and rapid way of detecting carriers of hereditary tyrosinaemia type I in that region at high risk.
Maryse St.-louis - One of the best experts on this subject based on the ideXlab platform.
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Genotyping of a case of tyrosinaemia type I with normal level of succinylacetone in amniotic fluid
Prenatal diagnosis, 1999Co-Authors: Jacques Poudrier, Francine Lettre, Maryse St.-louis, Robert M. TanguayAbstract:Tyrosinaemia type I is caused by a deficiency of Fumarylacetoacetate Hydrolase and mainly affects the liver. This disease is characterized by the presence of a high level of succinylacetone. This metabolite has been used for prenatal diagnosis from amniotic fluid samples. One case with a normal level of succinylacetone in amniotic fluid has recently been described (Grenier et al., 1996). Here, we report that this patient is a compound heterozygote for two known mutations: E364X and IVS6-1g-->t. The low level of succinylacetone cannot be explained by these mutations.
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Mutations in the Fumarylacetoacetate Hydrolase gene causing hereditary tyrosinemia type I: Overview
Human mutation, 1997Co-Authors: Maryse St.-louis, Robert M. TanguayAbstract:Tyrosinemia type I is an inborn error of metabolism caused by a deficiency in the last enzyme of the tyrosine catabolic pathway, Fumarylacetoacetate Hydrolase (FAH). The disease has been reported worldwide with varying incidence. Recently, there has been considerable progress in identifying mutations in the FAH gene. At present 26 mutations have been reported, all consisting of single base substitutions resulting in 16 amino acid replacements, one silent mutation causing a splicing defect, five nonsense codons, and four putative splicing defects. The location of these mutations is spread over the entire FAH gene, with a particular clustering between amino acid residues 230 and 250. The identification of these mutations in subpopulations and groups at high risk should help in the diagnosis of, and genetic counseling for, HT1. We describe all these 26 mutations reported so far and their implication in diagnosis and carrier detection.
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FREQUENCY OF THE IVS12+5G→A SPLICE MUTATION OF THE Fumarylacetoacetate Hydrolase GENE IN CARRIERS OF HEREDITARY TYROSINAEMIA IN THE FRENCH CANADIAN POPULATION OF SAGUENAY‐LAC‐ST‐JEAN
Prenatal diagnosis, 1996Co-Authors: Jacques Poudrier, Maryse St.-louis, Francine Lettre, Karine Gibson, Claude Prévost, Jean Larochelle, Robert M. TanguayAbstract:Hereditary tyrosinaemia type I (HTI), an autosomal recessive inborn error of metabolism, is caused by a deficiency of the enzyme Fumarylacetoacetate Hydrolase. The highest incidence of HTI is observed in the Saguenay-Lac-St-Jean region (SLSJ) (Quebec, Canada), where 1 out of 22 individuals is thought to be a carrier. A splice mutation (IVS12+5G|adA) has recently been identified in this particular region. Here, we have determined the frequency of this mutation in a population of obligate carriers from the SLSJ region by allele-specific oligonucleotide hybridization and a method using a restriction enzyme digestion. Over 95 per cent of the HTI carriers were found to have the IVS12+5G|adA splice mutation. Screening for this mutation based on the two methods reported here is thus a reliable and rapid way of detecting carriers of hereditary tyrosinaemia type I in that region at high risk.
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A Single Mutation of the Fumarylacetoacetate Hydrolase Gene in French Canadians with Hereditary Tyrosinemia Type I
The New England journal of medicine, 1994Co-Authors: Markus Grompe, Muhsen Al-dhalimy, Maryse St.-louis, Sylvie I. Demers, Barbara Leclerc, Robert M. TanguayAbstract:Background Hereditary tyrosinemia type I is an autosomal recessive inborn error of metabolism caused by a deficiency of the enzyme Fumarylacetoacetate Hydrolase. The disorder clusters in the Saguenay-Lac-St.-Jean area of Quebec. In this region, 1 of 1846 newborns is affected and 1 of every 22 persons is thought to be a carrier. Recently, we identified a splice mutation and two nonsense mutations in the Fumarylacetoacetate Hydrolase gene in two patients from Quebec with tyrosinemia type I. Methods We used allele-specific-oligonucleotide hybridization to examine the frequency of these three candidate mutations in patients with tyrosinemia type I and in the population of Quebec. Results The splice mutation was found in 100 percent of patients from the Saguenay-Lac-St.-Jean area and in 28 percent of patients from other regions of the world. Of 25 patients from the Saguenay-Lac-St.-Jean region, 20 (80 percent) were homozygous for this mutation, a guanine-to-adenine change in the splice-donor sequence in intron...
Muhsen Al-dhalimy - One of the best experts on this subject based on the ideXlab platform.
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Liver repopulation and correction of metabolic liver disease by transplanted adult mouse pancreatic cells.
The American journal of pathology, 2001Co-Authors: Xin Wang, Milton J Finegold, Muhsen Al-dhalimy, Eric Lagasse, Markus GrompeAbstract:The emergence of cells with hepatocellular properties in the adult pancreas has been described in several experimental models. To determine whether adult pancreas contains cells that can give rise to therapeutically useful and biochemically normal hepatocytes, we transplanted suspensions of wild-type mouse pancreatic cells into syngeneic recipients deficient in Fumarylacetoacetate Hydrolase and manifesting tyrosinemia. Four of 34 (12%) mutant mice analyzed were fully rescued by donor-derived cells and had normal liver function. Ten additional mice (29%) showed histological evidence of donor-derived hepatocytes in the liver. Previous work has suggested that pancreatic liver precursors reside within or close to pancreatic ducts. We therefore performed additional transplantations using either primary cell suspensions enriched for ducts or cultured ducts. Forty-four mutant mice were transplanted with cells enriched for pancreatic duct cells, but only three of the 34 (9%) recipients analyzed displayed donor-derived hepatocytes. In addition, 28 of the Fumarylacetoacetate Hydrolase-deficient mice were transplanted with cultured pancreatic duct cells, but no donor-derived hepatocytes were observed. Our results demonstrate for the first time that adult mouse pancreas contains hepatocyte progenitor cells capable of significant therapeutic liver reconstitution. However, contrary to previous reports, we were unable to detect these cells within the duct compartment.
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EX VIVO HEPATIC GENE THERAPY OF A MOUSE MODEL OF HEREDITARY TYROSINEMIA TYPE I
Human gene therapy, 1998Co-Authors: Ken Overturf, Milton J Finegold, Muhsen Al-dhalimy, Kara Manning, Markus GrompeAbstract:Previously, this lab has reported the use of hepatocyte transplantation and in vivo gene therapy for the correction of a mouse model of Hereditary Tyrosinemia Type I (HT1). Here, we demonstrate repopulation of Fumarylacetoacetate Hydrolase (FAH)-deficient livers with cultured hepatocytes. Correction of the disease phenotype was achieved by retrovirally transducing cultured FAH- hepatocytes ex vivo, followed by transplantation and selective repopulation. Treated mice were phenotypically normal and had corrected plasma amino acid levels and liver function tests. Our results demonstrate that efficient hepatic repopulation using ex vivo genetically manipulated hepatocytes is feasible.
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ADENOVIRUS-MEDIATED GENE THERAPY IN A MOUSE MODEL OF HEREDITARY TYROSINEMIA TYPE I
Human gene therapy, 1997Co-Authors: Ken Overturf, Robert M. Tanguay, Muhsen Al-dhalimy, Milton J Finegold, André Lieber, Mark A. Kay, Markus GrompeAbstract:ABSTRACT Mice lacking the enzyme Fumarylacetoacetate Hydrolase (FAH) have symptoms similar to humans with the disease hereditary tyrosinemia type I (HT1). FAH-deficient mice were injected with a fi...
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Serial transplantation reveals the stem-cell-like regenerative potential of adult mouse hepatocytes.
The American journal of pathology, 1997Co-Authors: Ken Overturf, Milton J Finegold, Muhsen Al-dhalimy, Markus GrompeAbstract:Previous work has shown that adult mouse hepatocytes can divide at least 18 times in vivo. To test whether this represents the upper limit of their regenerative capacity, we performed serial transplantation of hepatocytes in the Fumarylacetoacetate Hydrolase deficiency murine model of liver repopulation. Hepatocytes from adult donors were serially transplanted in limiting numbers six times and resulted in complete repopulation during each cycle. This corresponds to a minimal number of 69 cell doublings or a 7.3 x 10(20)-fold expansion. No evidence for abnormal liver function or altered hepatic architecture was found in repopulated animals. We conclude that a fraction of adult mouse hepatocytes have growth potential similar to that of hematopoietic stem cells.
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Pharmacological correction of neonatal lethal hepatic dysfunction in a murine model of hereditary tyrosinaemia type I.
Nature genetics, 1995Co-Authors: Markus Grompe, Muhsen Al-dhalimy, Nancy G Kennaway, Sven Lindstedt, John Papaconstantinou, Carlos A. Torres-ramos, Milton J FinegoldAbstract:Hereditary tyrosinaemia type I, a severe autosomal recessive metabolic disease, affects the liver and kidneys and is caused by deficiency of Fumarylacetoacetate Hydrolase (FAH). Mice homozygous for a FAH gene disruption have a neonatal lethal phenotype caused by liver dysfunction and do not represent an adequate model of the human disease. Here we demonstrate that treatment of affected animals with 2–(2–nitro–4–trifluoro–methylbenzyol)–1,3–cyclohexanedione abolished neonatal lethality, corrected liver function and partially normalized the altered expression pattern of hepatic mRNAs. The prolonged lifespan of affected animals resulted in a phenotype analogous to human tyrosinaemia type I including hepatocellular carcinoma. The adult FAH−/− mouse will serve as useful model for studies of the pathophysiology and treatment of hereditary tyrosinaemia type I as well as hepatic cancer.
