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Johannes Häberle - One of the best experts on this subject based on the ideXlab platform.
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A rare Urea Cycle Disorder in a neonate: N-acetylglutamate synthetase deficiency.
Archivos argentinos de pediatria, 2020Co-Authors: Asburce Olgac, Çiğdem Seher Kasapkara, Mustafa Kılıç, Betül Emine Derinkuyu, Ebru Azapagasi, Selman Kesici, Gürsel Biberoğlu, Ahmet Özyazici, Meryem Karaca, Johannes HäberleAbstract:Urea Cycle Disorders (UCD), are genetically inherited diseases that may have a poor outcome due to to profound hyperammonemia. We report the case of a baby girl diagnosed as N-acetylglutamate synthase (NAGS) deficiency. The patient was evaluated due to diminished sucking and hypotonicity. Physical examination showed hepatomegaly. Complete blood count, biochemical values and blood gas analyses were normal, acute phase reactants were negative. Further laboratory analyses showed no ketones in blood and highly elevated ammonia. Metabolic tests were inconclusive. Emergency treatment was initiated immediately and she was discharged on the 15th day of admission. NAGS deficiency was confirmed by DNA-analysis. She is now without any dietary restriction or other medication, except N-carbamylglutamate (NCG). NAGS deficiency is the only UCD which can be specifically and effectively treated by NCG. Early recognition of disease will lead to early treatment that may prohibit devastating effects of hyperammonemia.
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Neurological Deterioration in Three Siblings: Exploring the Spectrum of Argininemia
The Indian Journal of Pediatrics, 2020Co-Authors: Divyani Garg, Johannes Häberle, Sunita Bijarnia-mahay, Aman Elwadhi, Sandip Ray, Suvasini SharmaAbstract:Argininemia or hyperargininemia is a Urea Cycle Disorder caused by deficiency of the enzyme arginase 1. It is inherited in an autosomal recessive fashion. It commonly leads to spastic diplegia in childhood, but other important features include cognitive deterioration and epilepsy. Unlike other Disorders of the Urea Cycle, hyperammonemia is not prominent. The authors report three siblings with genetically proven argininemia who presented with diverse phenotypes but with spasticity being a common feature. Sibling 1 developed motor regression in early childhood, sibling 2 developed delayed motor milestones from early infancy, whereas sibling 3 had global developmental delay in late infancy after a period of normal development. All siblings had mild hyperammonemia only. Early recognition is imperative, not only to initiate ammonia scavenging therapy which may lead to definite clinical improvement, but also to provide genetic counselling.
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split aav mediated gene therapy restores Ureagenesis in a murine model of carbamoyl phosphate synthetase 1 deficiency
Molecular Therapy, 2020Co-Authors: Matthew Nitzahn, Johannes Häberle, Gabriella Allegri, Suhail Khoja, Brian Truong, Georgios Makris, Gerald S LipshutzAbstract:The Urea Cycle enzyme carbamoyl phosphate synthetase 1 (CPS1) catalyzes the initial step of the Urea Cycle; bi-allelic mutations typically present with hyperammonemia, vomiting, ataxia, lethargy progressing into coma, and death due to brain edema if ineffectively treated. The enzyme deficiency is particularly difficult to treat; early recognition is essential to minimize injury to the brain. Even under optimal conditions, therapeutic interventions are of limited scope and efficacy, with most patients developing long-term neurologic sequelae. One significant encumberment to gene therapeutic development is the size of the CPS1 cDNA, which, at 4.5 kb, nears the packaging capacity of adeno-associated virus (AAV). Herein we developed a split AAV (sAAV)-based approach, packaging the large transgene and its regulatory cassette into two separate vectors, thereby delivering therapeutic CPS1 by a dual vector system with testing in a murine model of the Disorder. Cps1-deficient mice treated with sAAVs survive long-term with markedly improved ammonia levels, diminished dysregulation of circulating amino acids, and increased hepatic CPS1 expression and activity. In response to acute ammonia challenging, sAAV-treated female mice rapidly incorporated nitrogen into Urea. This study demonstrates the first proof-of-principle that sAAV-mediated therapy is a viable, potentially clinically translatable approach to CPS1 deficiency, a devastating Urea Cycle Disorder.
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coagulation disturbances in patients with argininemia
Acta Haematologica, 2018Co-Authors: Ertugrul Kiykim, Johannes Häberle, Tanyel Zubarioglu, Mehmet Serif Cansever, Tiraje Celkan, Ayse Cigdem Aktuglu ZeybekAbstract:BACKGROUND Argininemia is an autosomal recessive Urea Cycle Disorder (UCD). Unlike other UCD, hyperammonemia is rarely seen. Patients usually present in childhood with neurological symptoms. Uncommon presentations like neonatal cholestasis or cirrhosis have been reported. Although transient elevations of liver transaminases and coagulopathy have been reported during hyperammonemia episodes, a permanent coagulopathy has never been reported. METHODS In this retrospective study, coagulation disturbances are examined in 6 argininemia patients. All of the patients were routinely followed up for hepatic involvement due to argininemia. Laboratory results, including liver transaminases, albumin, prothrombin time (PT), international normalized ratio (INR), activated partial thromboplastin time (aPTT), and clotting factor levels, were assessed in all of the patients. RESULTS All of the patients had a prolonged PT and an increased INR, while none of the patients had a prolonged aPTT. Five patients had slightly elevated liver transaminases. A liver biopsy was performed in 1 patient but neither cirrhosis nor cholestasis was documented. Five of the 6 patients had low factor VII and factor IX levels, while other clotting factors were normal. CONCLUSIONS Argininemia patients should be investigated for coagulation Disorders even if there is no apparent liver dysfunction or major bleeding symptoms.
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targeting cps1 in the treatment of carbamoyl phosphate synthetase 1 cps1 deficiency a Urea Cycle Disorder
Expert Opinion on Therapeutic Targets, 2017Co-Authors: Carmen Diezfernandez, Johannes HäberleAbstract:Introduction: Carbamoyl phosphate synthetase 1 (CPS1) deficiency (CPS1D) is a rare autosomal recessive Urea Cycle Disorder (UCD), which can lead to life-threatening hyperammonemia. Unless promptly ...
Brendan Lee - One of the best experts on this subject based on the ideXlab platform.
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protein and calorie intakes in adult and pediatric subjects with Urea Cycle Disorders participating in clinical trials of glycerol phenylbutyrate
Molecular genetics and metabolism reports, 2016Co-Authors: Debra Hook, Nicola Longo, Brendan Lee, George A Diaz, James Bartley, William E Berquist, Cynthia Le Mons, Ingrid Rudolphangelich, Marty Porter, Bruce F ScharschmidtAbstract:Background Little prospectively collected data are available comparing the dietary intake of Urea Cycle Disorder (UCD) patients to UCD treatment guidelines or to healthy individuals.
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blood ammonia and glutamine as predictors of hyperammonemic crises in patients with Urea Cycle Disorder
Genetics in Medicine, 2015Co-Authors: Brendan Lee, George A Diaz, William J Rhead, Uta Lichterkonecki, Annette Feigenbaum, Susan A Berry, Cindy Le Mons, James Bartley, Nicola LongoAbstract:The aim of this study was to examine predictors of ammonia exposure and hyperammonemic crises in patients with Urea Cycle Disorders. The relationships between fasting ammonia, daily ammonia exposure, and hyperammonemic crises were analyzed in >100 patients with Urea Cycle Disorders. Fasting ammonia correlated strongly with daily ammonia exposure (r = 0.764; P 200% (P < 0.0001), respectively. The relationship between ammonia and hyperammonemic crisis risk seemed to be independent of treatment, age, Urea Cycle Disorder subtype, dietary protein intake, or blood Urea nitrogen. Fasting glutamine correlated weakly with daily ammonia exposure assessed as 24-hour area under the curve and was not a significant predictor of hyperammonemic crisis. Fasting ammonia correlates strongly and positively with daily ammonia exposure and with the risk and rate of hyperammonemic crises, suggesting that patients with Urea Cycle Disorder may benefit from tight ammonia control. Genet Med 17 7, 561–568.
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diagnosis symptoms frequency and mortality of 260 patients with Urea Cycle Disorders from a 21 year multicentre study of acute hyperammonaemic episodes
Acta Paediatrica, 2008Co-Authors: Marshall L Summar, Saul W Brusilow, Dries Dobbelaere, Brendan LeeAbstract:Aim A large longitudinal interventional study of patients with a Urea Cycle Disorder (UCD) in hyperammonaemic crisis was undertaken to amass a significant body of data on their presenting symptoms and survival.
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considerations in the difficult to manage Urea Cycle Disorder patient
Critical Care Clinics, 2005Co-Authors: Brendan Lee, William J Rhead, Rani H Singh, Lisa Sniderman King, Wendy E Smith, Marshall L SummarAbstract:Today, patients with Urea Cycle Disorder (UCD) may survive well beyond infancy. The goal of keeping them in consistent nitrogen balance can be undermined by changing metabolic needs throughout various stages of life, resulting in hyperammonemia in the short term, and poor growth and development in the long term. The specific UCD genotype can affect the risk of metabolic destabilization and management difficulties, as can variable protein tolerance secondary to changing growth demands, biochemical complications, and environmental influences. Preventing catabolic stress is as important as controlling dietary protein intake for avoiding metabolic decompensation. Optimal treatment, specifically pharmacologic therapy, possible branched chain amino acid (BCAA) supplementation, accurate laboratory monitoring, and psychosocial support, requires thorough understanding and careful application of each component.
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effect of alternative pathway therapy on branched chain amino acid metabolism in Urea Cycle Disorder patients
Molecular Genetics and Metabolism, 2004Co-Authors: Fernando Scaglia, Brendan Lee, Susan Carter, William E ObrienAbstract:Urea Cycle Disorders (UCDs) are a group of inborn errors of hepatic metabolism caused by the loss of enzymatic activities that mediate the transfer of nitrogen from ammonia to Urea. These Disorders often result in life-threatening hyperammonemia and hyperglutaminemia. A combination of sodium phenylbutyrate and sodium phenylacetate/benzoate is used in the clinical management of children with Urea Cycle defects as a glutamine trap, diverting nitrogen from Urea synthesis to alternatives routes of excretion. We have observed that patients treated with these compounds have selective branched chain amino acid (BCAA) deficiency despite adequate dietary protein intake. However, the direct effect of alternative therapy on the steady state levels of plasma branched chain amino acids has not been well characterized. We have measured steady state plasma branched chain and other essential non-branched chain amino acids in control subjects, untreated ornithine transcarbamylase deficiency females and treated null activity Urea Cycle Disorder patients in the fed steady state during the course of stable isotope studies. Steady-state leucine levels were noted to be significantly lower in treated Urea Cycle Disorder patients when compared to either untreated ornithine transcarbamylase deficiency females or control subjects (P<0.0001). This effect was reproduced in control subjects who had depressed leucine levels when treated with sodium phenylacetate/benzoate (P<0.0001). Our studies suggest that this therapeutic modality has a substantial impact on the metabolism of branched chain amino acids in Urea Cycle Disorder patients. These findings suggest that better titration of protein restriction could be achieved with branched chain amino acid supplementation in patients with UCDs who are on alternative route therapy.
Carmen Diezfernandez - One of the best experts on this subject based on the ideXlab platform.
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targeting cps1 in the treatment of carbamoyl phosphate synthetase 1 cps1 deficiency a Urea Cycle Disorder
Expert Opinion on Therapeutic Targets, 2017Co-Authors: Carmen Diezfernandez, Johannes HäberleAbstract:Introduction: Carbamoyl phosphate synthetase 1 (CPS1) deficiency (CPS1D) is a rare autosomal recessive Urea Cycle Disorder (UCD), which can lead to life-threatening hyperammonemia. Unless promptly ...
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targeting cps1 in the treatment of carbamoyl phosphate synthetase 1 cps1 deficiency a Urea Cycle Disorder
Expert Opinion on Therapeutic Targets, 2017Co-Authors: Carmen Diezfernandez, Johannes HäberleAbstract:ABSTRACTIntroduction: Carbamoyl phosphate synthetase 1 (CPS1) deficiency (CPS1D) is a rare autosomal recessive Urea Cycle Disorder (UCD), which can lead to life-threatening hyperammonemia. Unless promptly treated, it can result in encephalopathy, coma and death, or intellectual disability in surviving patients. Over recent decades, therapies for CPS1D have barely improved leaving the management of these patients largely unchanged. Additionally, in many cases, current management (protein-restriction and supplementation with citrulline and/or arginine and ammonia scavengers) is insufficient for achieving metabolic stability, highlighting the importance of developing alternative therapeutic approaches.Areas covered: After describing UCDs and CPS1D, we give an overview of the structure- function of CPS1. We then describe current management and potential novel treatments including N-carbamoyl-L-glutamate (NCG), pharmacological chaperones, and gene therapy to treat hyperammonemia.Expert opinion: Probably, the f...
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targeting cps1 in the treatment of carbamoyl phosphate synthetase 1 cps1 deficiency a Urea Cycle Disorder
Expert Opinion on Therapeutic Targets, 2017Co-Authors: Carmen Diezfernandez, Johannes HäberleAbstract:ABSTRACTIntroduction: Carbamoyl phosphate synthetase 1 (CPS1) deficiency (CPS1D) is a rare autosomal recessive Urea Cycle Disorder (UCD), which can lead to life-threatening hyperammonemia. Unless promptly treated, it can result in encephalopathy, coma and death, or intellectual disability in surviving patients. Over recent decades, therapies for CPS1D have barely improved leaving the management of these patients largely unchanged. Additionally, in many cases, current management (protein-restriction and supplementation with citrulline and/or arginine and ammonia scavengers) is insufficient for achieving metabolic stability, highlighting the importance of developing alternative therapeutic approaches.Areas covered: After describing UCDs and CPS1D, we give an overview of the structure- function of CPS1. We then describe current management and potential novel treatments including N-carbamoyl-L-glutamate (NCG), pharmacological chaperones, and gene therapy to treat hyperammonemia.Expert opinion: Probably, the f...
Nicola Longo - One of the best experts on this subject based on the ideXlab platform.
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long term safety and efficacy of glycerol phenylbutyrate for the management of Urea Cycle Disorder patients
Molecular Genetics and Metabolism, 2019Co-Authors: George A Diaz, Nicola Longo, William J Rhead, Annette Feigenbaum, William E Berquist, Renata C Gallagher, Andreas Schulze, Derek Wong, Lawrence J Merritt, Dennis BartholomewAbstract:Abstract Introduction Glycerol phenylbutyrate (GPB) is currently approved for use in the US and Europe for patients of all ages with Urea Cycle Disorders (UCD) who cannot be managed with protein restriction and/or amino acid supplementation alone. Currently available data on GPB is limited to 12 months exposure. Here, we present long-term experience with GPB. Methods This was an open-label, long-term safety study of GPB conducted in the US (17 sites) and Canada (1 site) monitoring the use of GPB in UCD patients who had previously completed 12 months of treatment in the previous safety extension studies. Ninety patients completed the previous studies with 88 of these continuing into the long-term evaluation. The duration of therapy was open ended until GPB was commercially available. The primary endpoint was the rate of adverse events (AEs). Secondary endpoints were venous ammonia levels, number and causes of hyperammonemic crises (HACs) and neuropsychological testing. Results A total of 45 pediatric patients between the ages of 1 to 17 years (median 7 years) and 43 adult patients between the ages of 19 and 61 years (median 30 years) were enrolled. The treatment emergent adverse events (TEAE) reported in ≥10% of adult or pediatric patients were consistent with the TEAEs reported in the previous safety extension studies with no increase in the overall incidence of TEAEs and no new TEAEs that indicated a new safety signal. Mean ammonia levels remained stable and below the adult upper limit of normal ( Conclusion Following the completion of 12-month follow-up studies with GPB treatment, UCD patients were followed for an additional median of 1.85 (range 0 to 5.86) years in the present study with continued maintenance of ammonia control, similar rates of adverse events, and no new adverse events identified.
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Glycerol phenylbutyrate for the maintenance treatment of patients with deficiencies in enzymes of the Urea Cycle
Expert Opinion on Orphan Drugs, 2017Co-Authors: Nicola Longo, Robert J. HoltAbstract:ABSTRACTIntroduction: Urea Cycle Disorders are rare inborn errors of metabolism resulting in the accumulation of ammonia. Over the last 3 decades, the use of alternative nitrogen excretion pathways has been exploited to improve survival and outcomes for Urea Cycle Disorder patients.Areas covered: Early discovered nitrogen scavengers (sodium benzoate, phenylacetate, and phenylbutyrate) are effective in lowering ammonia. However, they have side effects and administration issues that can reduce compliance to therapy and limit optimal outcomes. Glycerol phenylbutyrate, a pro-drug of phenylbutyrate, was developed to improve therapy for patients with Urea Cycle Disorders. Research with glycerol phenylbutyrate has produced the largest body of controlled study data in Urea Cycle Disorder patients to date.Expert opinion: Glycerol phenylbutyrate is better tolerated than sodium phenylbutyrate and enables patients with Urea Cycle Disorders to reach ammonia and glutamine targets. Maintenance of target ammonia levels a...
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protein and calorie intakes in adult and pediatric subjects with Urea Cycle Disorders participating in clinical trials of glycerol phenylbutyrate
Molecular genetics and metabolism reports, 2016Co-Authors: Debra Hook, Nicola Longo, Brendan Lee, George A Diaz, James Bartley, William E Berquist, Cynthia Le Mons, Ingrid Rudolphangelich, Marty Porter, Bruce F ScharschmidtAbstract:Background Little prospectively collected data are available comparing the dietary intake of Urea Cycle Disorder (UCD) patients to UCD treatment guidelines or to healthy individuals.
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blood ammonia and glutamine as predictors of hyperammonemic crises in patients with Urea Cycle Disorder
Genetics in Medicine, 2015Co-Authors: Brendan Lee, George A Diaz, William J Rhead, Uta Lichterkonecki, Annette Feigenbaum, Susan A Berry, Cindy Le Mons, James Bartley, Nicola LongoAbstract:The aim of this study was to examine predictors of ammonia exposure and hyperammonemic crises in patients with Urea Cycle Disorders. The relationships between fasting ammonia, daily ammonia exposure, and hyperammonemic crises were analyzed in >100 patients with Urea Cycle Disorders. Fasting ammonia correlated strongly with daily ammonia exposure (r = 0.764; P 200% (P < 0.0001), respectively. The relationship between ammonia and hyperammonemic crisis risk seemed to be independent of treatment, age, Urea Cycle Disorder subtype, dietary protein intake, or blood Urea nitrogen. Fasting glutamine correlated weakly with daily ammonia exposure assessed as 24-hour area under the curve and was not a significant predictor of hyperammonemic crisis. Fasting ammonia correlates strongly and positively with daily ammonia exposure and with the risk and rate of hyperammonemic crises, suggesting that patients with Urea Cycle Disorder may benefit from tight ammonia control. Genet Med 17 7, 561–568.
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ammonia control and neurocognitive outcome among Urea Cycle Disorder patients treated with glycerol phenylbutyrate
Hepatology, 2013Co-Authors: George A Diaz, Nicola Longo, William J Rhead, Annette Feigenbaum, Susan A Berry, James Bartley, William E Berquist, Lauren S Krivitzky, Masoud Mokhtarani, Renata C GallagherAbstract:Urea Cycle Disorders (UCD) are rare inborn errors of metabolism which result from mutations in the genes encoding for one of six enzymes or two transporters necessary for normal function of the Urea Cycle and are characterized by hyperammonemia and life-threatening hyperammonemic crises1,2. Hyperammonemia-related neurologic injury ranges from lethal cerebral edema to mild or subclinical cognitive impairment among individuals with milder genetic defects3. Abnormalities in executive function, manifested by difficulty in goal setting, planning, monitoring progress and purposeful problem solving significantly impair day-to-day function among children with UCDs, even those with milder disease who present beyond the neonatal period4. Management of UCD patients typically involves dietary protein restriction, dietary supplements and, when dietary management alone is insufficient, sodium phenylbutyrate (NaPBA), which is the only approved drug (Ucyclyd Pharma, US trade name: BUPHENYL®, EU: AMMONAPS®) for treatment of UCDs2,5. Glycerol phenylbutyrate is an investigational agent being developed for UCDs 6,7,8. Like NaPBA, it contains phenylbutyric acid (PBA), a pro-drug that is converted via β-oxidation to the active moiety, phenylacetic acid (PAA), which conjugates with glutamine to form phenylacetylglutamine (PAGN). PAGN is excreted in the urine and mediates waste nitrogen excretion. Unlike NaPBA, glycerol phenylbutyrate consists of three molecules of PBA joined to glycerol in ester linkage that is hydrolyzed in the small intestine by pancreatic lipases to release PBA, contains no sodium, has minimal taste and no odor, and 17.4 mL contains the same amount of PBA as 40 tablets of NaPBA, the maximal approved daily dose 6,7,8. The development of glycerol phenylbutyrate for UCD, rare Disorders with fewer than 500 patients in the US currently estimated to be treated with NaPBA, has involved a cooperative effort among investigators of the NIH-funded UCD Consortium, the National Urea Cycle Disorders Foundation and Hyperion Therapeutics 2,9,10. This report describes the results of the pivotal phase 3 study of glycerol phenylbutyrate for UCD, as well as short and long-term ammonia control and neurocognitive outcomes among a total of 91 UCD patients participating in four clinical trials.
Liyan Hu - One of the best experts on this subject based on the ideXlab platform.
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Unstable argininosuccinate lyase in variant forms of the Urea Cycle Disorder argininosuccinic aciduria
Journal of Inherited Metabolic Disease, 2015Co-Authors: Liyan Hu, Cécile Balmer, Sandra Eggimann, Veronique Rufenacht, Jean-marc Nuoffer, Amit V. Pandey, Johannes HäberleAbstract:Loss of function of the Urea Cycle enzyme argininosuccinate lyase (ASL) is caused by mutations in the ASL gene leading to ASL deficiency (ASLD). ASLD has a broad clinical spectrum ranging from life-threatening severe neonatal to asymptomatic forms. Different levels of residual ASL activity probably contribute to the phenotypic variability but reliable expression systems allowing clinically useful conclusions are not yet available. In order to define the molecular characteristics underlying the phenotypic variability, we investigated all ASL mutations that were hitherto identified in patients with late onset or mild clinical and biochemical courses by ASL expression in human embryonic kidney 293 T cells. We found residual activities >3 % of ASL wild type (WT) in nine of 11 ASL mutations. Six ASL mutations (p.Arg95Cys, p.Ile100Thr, p.Val178Met, p.Glu189Gly, p.Val335Leu, and p.Arg379Cys) with residual activities ≥16 % of ASL WT showed no significant or less than twofold reduced Km values, but displayed thermal instability. Computational structural analysis supported the biochemical findings by revealing multiple effects including protein instability, disruption of ionic interactions and hydrogen bonds between residues in the monomeric form of the protein, and disruption of contacts between adjacent monomeric units in the ASL tetramer. These findings suggest that the clinical and biochemical course in variant forms of ASLD is associated with relevant residual levels of ASL activity as well as instability of mutant ASL proteins. Since about 30 % of known ASLD genotypes are affected by mutations studied here, ASLD should be considered as a candidate for chaperone treatment to improve mutant protein stability.
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understanding the role of argininosuccinate lyase transcript variants in the clinical and biochemical variability of the Urea Cycle Disorder argininosuccinic aciduria
Journal of Biological Chemistry, 2013Co-Authors: Liyan Hu, Sandra Eggimann, Veronique Rufenacht, Jean-marc Nuoffer, Amit V. Pandey, Dorothea Moslinger, Johannes HäberleAbstract:Argininosuccinic aciduria (ASA) is an autosomal recessive Urea Cycle Disorder caused by deficiency of argininosuccinate lyase (ASL) with a wide clinical spectrum from asymptomatic to severe hyperammonemic neonatal onset life-threatening courses. We investigated the role of ASL transcript variants in the clinical and biochemical variability of ASA. Recombinant proteins for ASL wild type, mutant p.E189G, and the frequently occurring transcript variants with exon 2 or 7 deletions were (co-)expressed in human embryonic kidney 293T cells. We found that exon 2-deleted ASL forms a stable truncated protein with no relevant activity but a dose-dependent dominant negative effect on enzymatic activity after co-expression with wild type or mutant ASL, whereas exon 7-deleted ASL is unstable but seems to have, nevertheless, a dominant negative effect on mutant ASL. These findings were supported by structural modeling predictions for ASL heterotetramer/homotetramer formation. Illustrating the physiological relevance, the predominant occurrence of exon 7-deleted ASL was found in two patients who were both heterozygous for the ASL mutant p.E189G. Our results suggest that ASL transcripts can contribute to the highly variable phenotype in ASA patients if expressed at high levels. Especially, the exon 2-deleted ASL variant may form a heterotetramer with wild type or mutant ASL, causing markedly reduced ASL activity.
