F Schliess

Summary

Affiliation: Heinrich Heine University
Country: Germany

Publications

  1. ncbi request reprint Mitogen-activated protein kinases mediate the stimulation of bile acid secretion by tauroursodeoxycholate in rat liver
    F Schliess
    Heinrich Heine Universitat, Klinik fur Gastroenterologie, Hepatologie, und Infektiologie, Dusseldorf, Germany
    Gastroenterology 113:1306-14. 1997
  2. ncbi request reprint Involvement of integrins and Src in insulin signaling toward autophagic proteolysis in rat liver
    Freimut Schliess
    Division of Gastroenterology, Hepatology, and Infectious Diseases, Heinrich Heine University, Moorenstrasse 5, D 40225 Dusseldorf, Germany
    J Biol Chem 279:21294-301. 2004
  3. ncbi request reprint Hypoosmotic swelling increases protein tyrosine nitration in cultured rat astrocytes
    Freimut Schliess
    Clinic for Gastroenterology, Hepatology and Infectiology, Heinrich Heine University, Dusseldorf, Germany
    Glia 47:21-9. 2004
  4. ncbi request reprint Cell hydration and insulin signalling
    F Schliess
    Department of Internal Medicine, Heinrich Heine Universitat, Dusseldorf, Germany
    Cell Physiol Biochem 10:403-8. 2000
  5. ncbi request reprint Glucagon-induced expression of the MAP kinase phosphatase MKP-1 in rat hepatocytes
    F Schliess
    Klinik für Gastroenterologie und Infektiologie, Medizinische Einrichtungen der Heinrich Heine Universitat, Dusseldorf, Germany
    Gastroenterology 118:929-36. 2000
  6. ncbi request reprint Hyperosmotic induction of the mitogen-activated protein kinase phosphatase MKP-1 in H4IIE rat hepatoma cells
    F Schliess
    Clinic for Gastroenterology, Hepatology, and Infectiology, Heinrich Heine Universitat, Dusseldorf, Germany
    Arch Biochem Biophys 351:35-40. 1998
  7. ncbi request reprint Role of p38(MAPK) in cell volume regulation of perfused rat liver
    S Vom Dahl
    Div of Gastroenterology, Hepatology and Infectious Diseases, Heinrich Heine Universitat, Dusseldorf, Germany
    Cell Physiol Biochem 11:285-94. 2001
  8. ncbi request reprint Insulin resistance induced by loop diuretics and hyperosmolarity in perfused rat liver
    F Schliess
    Clinic for Gastroenterology, Hepatology and Infectiology, Heinrich-Heine-University, , Germany
    Biol Chem 382:1063-9. 2001
  9. ncbi request reprint Osmotic regulation of the heat shock response in H4IIE rat hepatoma cells
    F Schliess
    Clinic for Gastroenterology, Hepatology and Infectiology, Heinrich Heine Universitat, Dusseldorf, Germany
    FASEB J 13:1557-64. 1999
  10. ncbi request reprint Cell hydration and mTOR-dependent signalling
    F Schliess
    Clinic for Gastroenterology, Hepatology and Infectiology, Heinrich Heine University, Dusseldorf, and San Francisco Hospital, Department for Internal Medicine, Cologne, Germany
    Acta Physiol (Oxf) 187:223-9. 2006

Collaborators

Detail Information

Publications49

  1. ncbi request reprint Mitogen-activated protein kinases mediate the stimulation of bile acid secretion by tauroursodeoxycholate in rat liver
    F Schliess
    Heinrich Heine Universitat, Klinik fur Gastroenterologie, Hepatologie, und Infektiologie, Dusseldorf, Germany
    Gastroenterology 113:1306-14. 1997
    ..Tauroursodeoxycholate (TUDCA) is widely used in the treatment of cholestatic liver disease. The purpose of this study was to elucidate molecular mechanisms underlying its beneficial effect...
  2. ncbi request reprint Involvement of integrins and Src in insulin signaling toward autophagic proteolysis in rat liver
    Freimut Schliess
    Division of Gastroenterology, Hepatology, and Infectious Diseases, Heinrich Heine University, Moorenstrasse 5, D 40225 Dusseldorf, Germany
    J Biol Chem 279:21294-301. 2004
    ..The data suggest that sensing of cell swelling by integrins essentially contributes to insulin signaling, thereby defining a novel way of integrin involvement in growth factor signaling...
  3. ncbi request reprint Hypoosmotic swelling increases protein tyrosine nitration in cultured rat astrocytes
    Freimut Schliess
    Clinic for Gastroenterology, Hepatology and Infectiology, Heinrich Heine University, Dusseldorf, Germany
    Glia 47:21-9. 2004
    ....
  4. ncbi request reprint Cell hydration and insulin signalling
    F Schliess
    Department of Internal Medicine, Heinrich Heine Universitat, Dusseldorf, Germany
    Cell Physiol Biochem 10:403-8. 2000
    ..Blockage of the cell volume response to insulin may be the common denominator in dehydration-induced insulin resistance found in clinical settings such as sepsis, burn injury and diabetes mellitus...
  5. ncbi request reprint Glucagon-induced expression of the MAP kinase phosphatase MKP-1 in rat hepatocytes
    F Schliess
    Klinik für Gastroenterologie und Infektiologie, Medizinische Einrichtungen der Heinrich Heine Universitat, Dusseldorf, Germany
    Gastroenterology 118:929-36. 2000
    ..Glucagon exerts pleiotropic effects on liver function, but the underlying signal transduction is incompletely understood. We investigated the effect of glucagon on the mitogen-activated protein (MAP) kinase phosphatase MKP-1 expression...
  6. ncbi request reprint Hyperosmotic induction of the mitogen-activated protein kinase phosphatase MKP-1 in H4IIE rat hepatoma cells
    F Schliess
    Clinic for Gastroenterology, Hepatology, and Infectiology, Heinrich Heine Universitat, Dusseldorf, Germany
    Arch Biochem Biophys 351:35-40. 1998
    ....
  7. ncbi request reprint Role of p38(MAPK) in cell volume regulation of perfused rat liver
    S Vom Dahl
    Div of Gastroenterology, Hepatology and Infectious Diseases, Heinrich Heine Universitat, Dusseldorf, Germany
    Cell Physiol Biochem 11:285-94. 2001
    ..The findings suggest that swelling-induced activation of p38(MAPK), but not of Erks and PI-3-kinase, is involved in RVD in liver, whereas p38(MAPK) is apparently not involved in the net K(+) release induced by oxidative stress...
  8. ncbi request reprint Insulin resistance induced by loop diuretics and hyperosmolarity in perfused rat liver
    F Schliess
    Clinic for Gastroenterology, Hepatology and Infectiology, Heinrich-Heine-University, , Germany
    Biol Chem 382:1063-9. 2001
    ..The perturbation of insulin-induced cell swelling may be of pathophysiological relevance for the development of insulin resistance in clinical situations associated with hyperosmotic dehydration and loop diuretic treatment...
  9. ncbi request reprint Osmotic regulation of the heat shock response in H4IIE rat hepatoma cells
    F Schliess
    Clinic for Gastroenterology, Hepatology and Infectiology, Heinrich Heine Universitat, Dusseldorf, Germany
    FASEB J 13:1557-64. 1999
    ..The osmodependence of the H4IIE cell response to heat differs from that recently found in primary rat hepatocytes. The data are discussed in terms of cellular adaption mechanisms and their physiological relevance...
  10. ncbi request reprint Cell hydration and mTOR-dependent signalling
    F Schliess
    Clinic for Gastroenterology, Hepatology and Infectiology, Heinrich Heine University, Dusseldorf, and San Francisco Hospital, Department for Internal Medicine, Cologne, Germany
    Acta Physiol (Oxf) 187:223-9. 2006
    ....
  11. ncbi request reprint Hypoosmolarity influences the activity of transcription factor NF-kappaB in rat H4IIE hepatoma cells
    M Michalke
    Department of Gastroenterology, Hepatology and Infectiology, Heinrich Heine University, Moorenstr 5, D 40225, D usseldorf, Germany
    FEBS Lett 465:64-8. 2000
    ..Transforming growth factor beta-induced apoptosis was diminished by hypoosmolarity. However, this anti-apoptotic effect was probably not related to NF-kappaB activation...
  12. doi request reprint Pathogenetic mechanisms of hepatic encephalopathy
    D Haussinger
    Clinic for Gastroenterology, Hepatology, and Infectiology, Heinrich Heine University Dusseldorf, Dusseldorf, Germany
    Gut 57:1156-65. 2008
    ..The potential of therapies targeting downstream pathophysiological events in HE has not yet been explored, but offers novel potential sites of therapeutic intervention...
  13. ncbi request reprint The hepatocyte integrin system and cell volume sensing
    D Haussinger
    Clinic for Gastroenterology, Hepatology and Infectiology, Heinrich Heine University, Dusseldorf, Germany
    Acta Physiol (Oxf) 187:249-55. 2006
    ....
  14. ncbi request reprint Modulation of the heme oxygenase HO-1 expression by hyperosmolarity and betaine in primary rat hepatocytes
    M R Lordnejad
    Clinic for Gastroenterology, Hepatology and Infectiology, , , Germany
    Arch Biochem Biophys 388:285-92. 2001
    ..Thus, stabilizing HO-1 expression may contribute to hepatocyte protection against hyperosmotic stress by organic osmolytes...
  15. ncbi request reprint Ammonia-induced heme oxygenase-1 expression in cultured rat astrocytes and rat brain in vivo
    Ulrich Warskulat
    Clinic for Gastroenterology, Hepatology and Infectiology, Heinrich Heine University, Dusseldorf, Germany
    Glia 40:324-36. 2002
    ..It is concluded that ammonia-induced HO-1 expression may contribute to cerebral hyperemia in hyperammonic states...
  16. ncbi request reprint Protein tyrosine nitration in hyperammonemia and hepatic encephalopathy
    Dieter Haussinger
    Clinic for Gastroenterology, Hepatology and Infectiology, Heinrich Heine University Dusseldorf, D 40225, Dusseldorf, Germany
    Metab Brain Dis 20:285-94. 2005
    ..The pathobiochemical relevance of astrocytic PTN for the development of HE symptoms remains to be established...
  17. ncbi request reprint Inflammatory cytokines induce protein tyrosine nitration in rat astrocytes
    Boris Gorg
    Clinic for Gastroenterology, Hepatology and Infectiology, Heinrich Heine University, Dusseldorf, Germany
    Arch Biochem Biophys 449:104-14. 2006
    ..This may be relevant for the pathogenesis of HE and other conditions involving cytokine exposure the brain...
  18. ncbi request reprint Ammonia induces MK-801-sensitive nitration and phosphorylation of protein tyrosine residues in rat astrocytes
    Freimut Schliess
    Clinic for Gastroenterology, Hepatology and Infectiology, Heinrich Heine University, Dusseldorf, Germany
    FASEB J 16:739-41. 2002
    ..The production of reactive nitrogen intermediates and protein tyrosine nitration may alter astrocyte function and contribute to ammonia neurotoxicity...
  19. ncbi request reprint Inborn error of amino acid synthesis: human glutamine synthetase deficiency
    Johannes Haberle
    Klinik und Poliklinik für Kinder und Jugendmedizin, Universitatsklinikum Munster, Albert Schweitzer Str 33, 48129, Munster, Germany
    J Inherit Metab Dis 29:352-8. 2006
    ..Deficiency of GS has to be added to the list of inherited metabolic disorders as a rare example of a defect in the biosynthesis of an amino acid...
  20. ncbi request reprint Pathogenetic interplay between osmotic and oxidative stress: the hepatic encephalopathy paradigm
    Freimut Schliess
    Clinic for Gastroenterology, Hepatology and Infectiology, Heinrich Heine University, D 40225 Dusseldorf, Germany
    Biol Chem 387:1363-70. 2006
    ....
  21. ncbi request reprint Glutamine metabolism and signaling in the liver
    Dieter Haussinger
    Heinrich Heine University Dusseldorf, Clinic for Gastroenterology, Hepatology and Infectiology, Moorenstrasse 5, 40225 Dusseldorf, Germany
    Front Biosci 12:371-91. 2007
    ..This review summarizes recent progress in the understanding of glutamine metabolism and signal transduction, which provides further rationale for the use of glutamine as a therapeutic tool...
  22. ncbi request reprint Reversible inhibition of mammalian glutamine synthetase by tyrosine nitration
    Boris Gorg
    Clinic for Gastroenterology, Hepatology and Infectiology, Heinrich Heine University Dusseldorf, Moorenstrasse 5, D 40225 Dusseldorf, Germany
    FEBS Lett 581:84-90. 2007
    ..The data point to a potential regulation of GS activity by a reversible tyrosine nitration. High levels of oxidative stress may irreversibly damage and predispose the enzyme to proteasomal degradation...
  23. ncbi request reprint Osmotic regulation of betaine homocysteine-S-methyltransferase expression in H4IIE rat hepatoma cells
    Christine Schafer
    Clinic for Gastroenterology, Hepatology, and Infectiology, Dusseldorf, Germany
    Am J Physiol Gastrointest Liver Physiol 292:G1089-98. 2007
    ..The osmotic regulation of BHMT may be part of a cell volume-regulatory response and additionally lead to metabolic alterations that depend on the availability of betaine-derived methyl groups...
  24. ncbi request reprint Benzodiazepine-induced protein tyrosine nitration in rat astrocytes
    Boris Gorg
    Clinic for Gastroenterology, Hepatology and Infectiology, Heinrich Heine University, Dusseldorf, Germany
    Hepatology 37:334-42. 2003
    ..In conclusion, production of ROIs and increased PTN by benzodiazepines may alter astrocyte function and thereby contribute to the precipitation of HE episodes...
  25. ncbi request reprint Osmosensing by integrins in rat liver
    Freimut Schliess
    Clinic for Gastroenterology, Hepatology, and Infectiology, Heinrich Heine University, Dusseldorf, Germany
    Methods Enzymol 428:129-44. 2007
    ..These findings define a novel role of integrins in insulin and glutamine signaling and set an example for mechanotransduction as an integral part of overall growth factor and nutrient signaling...
  26. ncbi request reprint Osmosensing and signaling in the regulation of mammalian cell function
    Freimut Schliess
    Clinic for Gastroenterology, Hepatology and Infectiology, Heinrich Heine University, Dusseldorf, Germany
    FEBS J 274:5799-803. 2007
    ..This minireview summarizes recent progress in the understanding of how osmosensing and osmosignaling integrate into the overall context of growth factor signaling and the execution of apoptotic programs...
  27. doi request reprint Taurolithocholic acid-3 sulfate impairs insulin signaling in cultured rat hepatocytes and perfused rat liver
    Gudrun Mannack
    Clinic for Gastroenterology, Hepatology and Infectiology, Heinrich Heine University Dusseldorf, Dusseldorf, Germany
    Cell Physiol Biochem 21:137-50. 2008
    ..The role of bile acids for insulin resistance in cholestatic liver disease is unknown...
  28. doi request reprint Ammonia induces RNA oxidation in cultured astrocytes and brain in vivo
    Boris Gorg
    Clinic for Gastroenterology, Hepatology and Infectiology, Heinrich Heine University, Dusseldorf, Germany
    Hepatology 48:567-79. 2008
    ..RNA oxidation may affect gene expression and local protein synthesis and thereby provide another link between reactive oxygen species (ROS)/reactive nitrogen oxide species (RNOS) production and ammonia toxicity...
  29. ncbi request reprint Hypoosmotic swelling and ammonia increase oxidative stress by NADPH oxidase in cultured astrocytes and vital brain slices
    Roland Reinehr
    Clinic for Gastroenterology, Hepatology and Infectiology, Heinrich Heine University, Moorenstrasse 5, D 40225 Dusseldorf, Germany
    Glia 55:758-71. 2007
    ..The findings further support a close interrelation between osmotic and oxidative stress in astrocytes, which may be relevant to different brain pathologies including hepatic encephalopathy...
  30. ncbi request reprint LPS-induced tyrosine nitration of hepatic glutamine synthetase
    Boris Gorg
    Hepatology 42:499. 2005
  31. ncbi request reprint Involvement of integrins and Src in tauroursodeoxycholate-induced and swelling-induced choleresis
    Dieter Haussinger
    Department of Gastroenterology, Hepatology and Infectology, Universitatsklinikum Dusseldorf, Germany
    Gastroenterology 124:1476-87. 2003
    ..This study investigates the sensing and upstream signaling events of TUDC-induced choleresis...
  32. ncbi request reprint Call volume and insulin signaling
    Freimut Schliess
    Clinic for Gastroenterology, Hepatology and Infectiology, Heinrich Heine University, Dusseldorf, Germany
    Int Rev Cytol 225:187-228. 2003
    ....
  33. ncbi request reprint Involvement of integrins in osmosensing and signaling toward autophagic proteolysis in rat liver
    Stephan vom Dahl
    Division of Gastroenterology, Hepatology and Infectious Diseases, Heinrich Heine University, Moorenstrasse 5, D 40225 Dusseldorf, Germany
    J Biol Chem 278:27088-95. 2003
    ..They further point to a role of integrins as osmo- and mechanosensors in the intact liver, which may provide a link between cell volume and cell function...
  34. ncbi request reprint Hyperosmolarity triggers CD95 membrane trafficking and sensitizes rat hepatocytes toward CD95L-induced apoptosis
    Roland Reinehr
    Clinic for Gastroenterology, Hepatology and Infectiology, Heinrich Heine University Dusseldorf, Dusseldorf, Germany
    Hepatology 36:602-14. 2002
    ..Hyperosmotic hepatocyte shrinkage induces CD95 trafficking to the plasma membrane, which involves JNK-, PKA-, and PKC-dependent mechanisms and sensitizes hepatocytes toward CD95L-mediated apoptosis...
  35. ncbi request reprint Expression and regulation of the Na(+)/K(+)/2Cl(-) cotransporter NKCC1 in rat liver and human HuH-7 hepatoma cells
    Freimut Schliess
    Clinic for Gastroenterology, Hepatology and Infectiology, Heinrich Heine University, D 40225 Dusseldorf, Germany
    Arch Biochem Biophys 401:187-97. 2002
    ..This was antagonized by the compatible organic osmolytes betaine or taurine. The data suggest a role of NKCC1 in stellate cell transformation, hepatic volume regulation, and long-term adaption to dehydrating conditions...
  36. pmc Osmotic regulation of insulin-induced mitogen-activated protein kinase phosphatase (MKP-1) expression in H4IIE rat hepatoma cells
    Mohammad Reza Lornejad-Schäfer
    Medizinische Einrichtungen der Heinrich Heine Universitat, Klinik fur Gastroenterologie, Hepatologie und Infektiologie, Moorenstrasse 5, D 40225 Dusseldorf, Germany
    Biochem J 371:609-19. 2003
    ..The suppression of MKP-1 may further contribute to insulin resistance under dehydrating conditions by allowing unbalanced MAP kinase activation...
  37. ncbi request reprint Activities of MAP-kinase pathways in normal uroepithelial cells and urothelial carcinoma cell lines
    Sandra Swiatkowski
    Urologische Klinik, Heinrich Heine Universitat, Dusseldorf, Germany
    Exp Cell Res 282:48-57. 2003
    ..However, autonomous proliferation of TCC lines--unexpectedly--appears much less dependent on MAPK activation and may rather be promoted by defects in cell cycle regulation...
  38. ncbi request reprint Molecular aspects of medicine: from experimental to clinical hepatology
    Dieter Haussinger
    Clinic for Gastroenterology, Hepatology and Infectiology, Medizinische Universitätsklinik Düsseldorf, Heinrich Heine University, Moorenstrasse 5, Dusseldorf 40225, Germany
    Mol Aspects Med 25:221-360. 2004
  39. ncbi request reprint Lipopolysaccharide-induced tyrosine nitration and inactivation of hepatic glutamine synthetase in the rat
    Boris Gorg
    Clinic for Gastroenterology, Hepatology, and Infectiology, Heinrich Heine University, Dusseldorf, Germany
    Hepatology 41:1065-73. 2005
    ..The resulting defect of perivenous scavenger cell function with regard to ammonia elimination may contribute to sepsis-induced development of hyperammonemia in patients who have cirrhosis...
  40. ncbi request reprint Astrocyte swelling and protein tyrosine nitration in hepatic encephalopathy
    Dieter Haussinger
    Clinic for Gastroenterology, Hepatology and Infectiology, Heinrich Heine University, Dusseldorf, Germany
    Neurochem Int 47:64-70. 2005
    ..This review focuses on the involvement of astrocyte swelling in protein tyrosine nitration and potential consequences in the setting of HE...
  41. ncbi request reprint Pathogenesis of hepatic encephalopathy
    Dieter Haussinger
    Clinic for Gastroenterology, Hepatology und Infectiology, Heinrich Heine University Dusseldorf, Dusseldorf, Germany
    J Gastroenterol Hepatol 17:S256-9. 2002
    ..Several proteins, which are nitrated in response to ammonia, benzodiazepines, hypoosmotic astrocyte swelling or inflammatory cytokines have been identified, including glutamine synthetase and the peripheral type benzodiazepine receptor...
  42. ncbi request reprint Bilateral, vascular and perivascular glial upregulation of heat shock protein-27 after repeated epileptic seizures
    Hans J Bidmon
    C and O Vogt Institute for Brain Research, Heinrich Heine University, Universitatsstr 1, D 40225 Dusseldorf, Germany
    J Chem Neuroanat 30:1-16. 2005
    ..Therefore, this PTZ-model of repeated seizure activity exhibited a cortical pattern of HSP-27 expression which is most comparable to that known from patients with epilepsy...
  43. ncbi request reprint Hyperosmolarity and CD95L trigger CD95/EGF receptor association and tyrosine phosphorylation of CD95 as prerequisites for CD95 membrane trafficking and DISC formation
    Roland Reinehr
    Clinic for Gastroenterology, Hepatology and Infectiology, Heinrich Heine University Dusseldorf, Germany
    FASEB J 17:731-3. 2003
    ..This provides a signal for CD95 membrane trafficking and DISC formation...
  44. ncbi request reprint Modulation of gene expression profiles by hyperosmolarity and insulin
    Christine Schafer
    Heinrich Heine University, Clinic for Gastroenterology, Hepatology, and Infectiology, Dusseldorf, Germany
    Cell Physiol Biochem 20:369-86. 2007
    ..The data indicate that hyperosmolarity differentially modulates insulin sensitivity at the level of gene expression...
  45. ncbi request reprint Osmotic regulation of STAT3 stability in H4IIE rat hepatoma cells
    Mohammad Lornejad-Schafer
    Klinik fur Gastroenterologie, Hepatologie und Infektiologie, Universitätsklinikum der Heinrich Heine Universität, Dusseldorf, Germany
    FEBS Lett 579:5791-7. 2005
    ..Accordingly, STAT3 Tyr(705) phosphorylation, alpha(2)-macroglobulin promoter activity and gamma-FBG expression were osmosensitive. Modulation of STAT3 stability may contribute to a hydration dependence of acute phase protein expression...
  46. ncbi request reprint The cellular hydration state: a critical determinant for cell death and survival
    Freimut Schliess
    Clinic for Gastroenterology, Hepatology and Infectiology, Heinrich Heine University, Dusseldorf, Germany
    Biol Chem 383:577-83. 2002
    ..In addition, the close relationship between osmotic and oxidative stress and the contribution of isoosmotic shrinkage to apoptotic cell death are considered...
  47. ncbi request reprint Copper ions strongly activate the phosphoinositide-3-kinase/Akt pathway independent of the generation of reactive oxygen species
    Elena A Ostrakhovitch
    Klinik fur Gastroenterologie, Hepatologie, und Infektionsbiologie, Heinrich Heine Universitat Dusseldorf, Dusseldorf, Germany
    Arch Biochem Biophys 397:232-9. 2002
    ..Rather, both activation of Akt and generation of ROS are proposed to occur in parallel, regulating cell survival after a copper stress...
  48. ncbi request reprint Osmotic regulation of MG-132-induced MAP-kinase phosphatase MKP-1 expression in H4IIE rat hepatoma cells
    Mohammad Lornejad-Schafer
    Institute of Environmental Medical Research, Molecular Ageing Research Dusseldorf, Germany
    Cell Physiol Biochem 16:193-206. 2005
    ..The dual specificity MAP-kinase phosphatase MKP-1 plays a role in balancing signals mediating cell death or survival. Here the effect of cell hydration on MG-132-induced MKP-1 expression was investigated in H4IIE rat hepatoma cells...
  49. ncbi request reprint Congenital glutamine deficiency with glutamine synthetase mutations
    Johannes Haberle
    Universitatsklinikum Munster, Klinik und Poliklinik für Kinderheilkunde und Jugendmedizin, Munster, Germany
    N Engl J Med 353:1926-33. 2005
    ..Studies that used immortalized lymphocytes expressing R324C glutamine synthetase (R324C-GS) and COS7 cells expressing R341C-GS suggest that these mutations are associated with reduced glutamine synthetase activity...