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The Journal of Clinical Endocrinology & Metabolism Vol. 86, No. 4 1782-1787
Copyright © 2001 by The Endocrine Society

Original Studies

Hyperinsulinism/Hyperammonemia Syndrome in Children with Regulatory Mutations in the Inhibitory Guanosine Triphosphate-Binding Domain of Glutamate Dehydrogenase1

Courtney MacMullen, Jie Fang, Betty Y. L. Hsu, Andrea Kelly, Pascale de Lonlay-Debeney, Jean-Marie Saudubray, Arupa Ganguly, Thomas J. Smith, Charles A. Stanley and The Hyperinsulinism/Hyperammonemia Contributing Investigators2

Division of Endocrinology, The Children’s Hospital of Philadelphia (C.M., J.F., B.Y.L.H., A.K., C.A.S.), and Departments of Pediatrics and Genetics (A.G.), University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104; Department of Pediatrics, Hopital des Enfants-Malades (P.d.L.-D., J.-M.S.), 75743 Paris CEDEX 15, France; and Department of Biological Sciences, Purdue University (T.A.S.), West Lafayette, Indiana 47907

Address all correspondence and requests for reprints to: Charles A. Stanley, M.D., Division of Endocrinology, The Children’s Hospital of Philadelphia, 3516 Civic Center Boulevard, Philadelphia, Pennsylvania 19104. E-mail: stanleyc{at}email.chop.edu


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The hyperinsulinism/hyperammonemia (HI/HA) syndrome is a form of congenital hyperinsulinism in which affected children have recurrent symptomatic hypoglycemia together with asymptomatic, persistent elevations of plasma ammonium levels. We have shown that the disorder is caused by dominant mutations of the mitochondrial enzyme, glutamate dehydrogenase (GDH), that impair sensitivity to the allosteric inhibitor, GTP. In 65 HI/HA probands screened for GDH mutations, we identified 19 (29%) who had mutations in a new domain, encoded by exons 6 and 7. Six new mutations were found: Ser217Cys, Arg221Cys, Arg265Thr, Tyr266Cys, Arg269Cys, and Arg269His. In all five mutations tested, lymphoblast GDH showed reduced sensitivity to allosteric inhibition by GTP (IC50, 60–250 vs. 20–50 nmol/L in normal subjects), consistent with a gain of enzyme function. Studies of ATP allosteric effects on GDH showed a triphasic response with a decrease in high affinity inhibition of enzyme activity in HI/HA lymphoblasts. All of the residues altered by exons 6 and 7 HI/HA mutations lie in the GTP-binding domain of the enzyme. These data confirm the importance of allosteric regulation of GDH as a control site for amino acid-stimulated insulin secretion and indicate that the GTP-binding site is essential for regulation of GDH activity by both GTP and ATP.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
CONGENITAL HYPERINSULINISM is the most common cause of hypoglycemia in infants and young children (1). Recently, mutations in four different genes have been identified as causes of congenital hyperinsulinism. These include recessive mutations of the SUR1 and Kir6.2 genes located on 11p14–15.1 that together form the ß-cell ATP-dependent potassium channel (2, 3, 4, 5, 6). In addition, autosomal dominant forms of congenital hyperinsulinism have been associated with mutations of islet glucokinase, located on chromosome 7, and with the mitochondrial matrix enzyme, glutamate dehydrogenase (GDH), located on chromosome 10 (7, 8, 9). The latter defect presents as an unusual hyperinsulinism/hyperammonemia (HI/HA) syndrome in which patients have recurrent episodes of symptomatic hypoglycemia in combination with asymptomatic, 2- to 5-fold elevations of plasma ammonium (10, 11, 12, 13).

GDH, a key enzyme involved in amino acid-stimulated insulin secretion, is allosterically activated by leucine to oxidize glutamate to {alpha}-ketoglutarate plus ammonia (14). We have previously shown that HI/HA syndrome patients have GDH mutations that impair its responsiveness to allosteric inhibition by GTP, resulting in a gain of enzyme function (15, 16). The increased GDH activity leads to inappropriate insulin secretion in pancreatic ß-cells as well as to excessive ammonia production and decreased urea synthesis in the liver (17). Affected patients appear to have milder hypoglycemia than infants with SUR1 and Kir6.2 forms of hyperinsulinism, but have protein-sensitive hypoglycemia and exaggerated insulin responses to leucine (18).

In previous studies GDH mutations producing the HI/HA syndrome were found to be located in a single domain encoded by exons 11 and 12. On x-ray crystallography, this region was shown to form an antenna projection that is presumed to play an important role in allosteric regulation of enzyme (15, 16, 19). The purpose of the present report is to describe the occurrence of HI/HA mutations in a second domain encoded by exons 6 and 7, which appears to form the inhibitory GTP binding site. Studies of the effects of these mutations on lymphoblast GDH suggest that this site is also responsible for the inhibitory effects of ATP on GDH activity.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Clinical materials

Peripheral blood samples were obtained on 65 children with clinical features of the HI/HA syndrome for isolation of DNA and establishment of cultured lymphoblasts. All subjects had clinical evidence of hyperinsulinism, including attacks of symptomatic hypoglycemia and elevated concentrations of plasma ammonium. The diagnosis of hyperinsulinism was established by clinical findings such as evidence of inappropriately elevated plasma insulin, suppressed concentrations of plasma free fatty acids and ketones, and glycemic response to glucagon at times of hypoglycemia (10). Contributing investigators provided clinical information on affected children and their families. These studies were reviewed and approved by the institutional review board, and written informed consent was obtained from subjects or their parents.

Mutation analysis

Genomic DNA was isolated from peripheral blood leukocytes or from cultured lymphoblasts and used for amplification of exons 5–13. The primers shown in Table 1Go were employed to amplify exons 5–10 and 13; primers for exon 11 and 12 have previously been reported (16). Conformation-sensitive gel electrophoresis was used to screen amplified exons for mutations (21) as previously described with the following modifications: an 0.8-mm thick gel was prepared with final concentrations of 40% acrylamide-bis(acryloyl) piperazine (99:1; Fluka, Buchs, Switzerland), 2 x TTE buffer (1 x TTE is 89 mmol/L Tris and 29 mmol/L taurine/0.5 mmol/L ethylenediamine tetraacetate, pH 9.0; U.S. Biochemical Corp., Cleveland, OH), 15% (wt/vol) formamide (Roche, Indianapolis, IN), and 10% (vol/vol) ethylene glycol (Fisher Scientific, Pittsburgh, PA).


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  		Table 1. Oligonucleotide sequences, annealing temperatures, and PCR fragment sizes of GDH exons 5–10 and 13

 
The gel was run for 18 h at 500 V in 0.5 x TTE buffer. PCR products showing aberrant band shifts were then sequenced to determine the mutation as previously described (16). Nucleotides in GDH complementary DNA were numbered according to the sequence reported by Nakatani (22). Amino acids were numbered according to the sequence of the mature peptide, omitting the 53-amino acid leader sequence.

Polymorphism analysis

Fifty unrelated normal control genomic DNA samples were amplified and run on conformation-sensitive gel electrophoresis for each exon in which there was a mutation or suspected polymorphism. The products that displayed band shifts were confirmed through sequencing or restriction enzyme digestion. The results were analyzed by the Fisher exact test using the InStat program (version 2.0; Dr. Harvey J. Motulsky, John R. Pilkington, and Paul Stannard) to determine whether the frequency of polymorphism in the patient population was significantly different from the frequency in the healthy control population.

Enzyme assay

Lymphoblast GDH enzyme activity and allosteric responsiveness were determined using the assay described by Wrzeszczynski and Colman (23) with modifications as previously described (16).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Clinical features of HI/HA patients with mutations in exons 6 and 7

A total of 65 probands with clinical features of the HI/HA syndrome were screened for mutations in GDH. As previously reported, 31 (48%) of these patients had mutations in exons 11 and 12, encoding the antenna region of the enzyme. Nineteen (29%) of the total had mutations in exons 6 and 7, as described below. The clinical phenotypes of these children (Table 2Go) were similar to those previously described in HI/HA children with exon 11 and 12 mutations. Birth weights were not large for gestational age, except for 1 infant of a diabetic mother. The median age of apparent onset of symptomatic hypoglycemia was late in the first year of life and not during the neonatal period. Plasma ammonium concentrations were persistently elevated between 49 and 150 µmol/L (normal, <35 µmol/L), but the hyperammonemia was not considered to be symptomatic in any patient. Eleven of 19 were treated with diazoxide and achieved good control of hypoglycemia; 8 were treated successfully with diet alone. One case had persistent hypoglycemia after 95% pancreatectomy and has insulin-dependent diabetes since a second surgery. Half of the cases reached developmental milestones at appropriate ages, whereas the other half were reported to have developmental delays or mental retardation related to episodes of hypoglycemia.


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  		Table 2. Clinical manifestations in HI/HA children with GDH exon 6 or 7 mutations

 
HI/HA GDH disease mutations

Table 3Go shows the disease-causing mutations found in the 19 HI/HA probands with mutations in exons 6 and 7 of GDH. All were single nucleotide missense mutations that occurred between amino acid residues 217–269 of the mature GDH protein. In each case the patients were heterozygous, possessing both a mutated and a normal allele, consistent with dominant expression. Three of the mutations occurred in multiple, unrelated probands: 8 for the Arg269His mutation, 6 for the Arg221Cys mutation, and 2 for the Arg265 Thr mutation. Both the Arg269 and the Arg221 are CpG mutation hot spot sites (24). In 3 of the 4 probands with affected family members, at least 3 generations were affected. The other 15 probands were sporadic cases with de novo mutations.


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  		Table 3. GDH exon 6 and 7 mutations in HI/HA patients

 
Nondisease-causing GDH polymorphisms

Genomic DNA screening of GDH exons 5–13 revealed three polymorphisms in the entire group of 65 patients. Fifty normal controls were examined to determine whether these mutations were true polymorphisms. Table 3Go shows the frequency of the polymorphisms in the HI/HA patients and normal controls. By Fisher sxact test, there was no difference in the frequency of the polymorphisms between patients and controls.

GDH enzyme analysis

Table 4Go shows the enzyme activities and allosteric constants of lymphoblast GDH from patients with mutations in exons 6 and 7. All five showed reduced sensitivity to inhibition by the allosteric effector, GTP, with IC50 values ranging from 1.2–5 times normal. These reductions in sensitivity to GTP inhibition of lymphoblast GDH activity were similar to those previously reported in HI/HA patients with mutations of exons 11 and 12 (15, 16).


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  		Table 4. Activity and allosteric responses of lymphoblast GDH with exon 6 and 7 mutations (mean ± SD)

 
Other minor changes were seen with many of the mutations, including reduced maximal activity when stimulated with ADP or leucine, reduced basal enzyme activity, decreased responsiveness to palmitoyl-coenzyme A inhibition, or increased responsiveness to diethylstilbestrol inhibition. The latter alterations in enzyme properties did not correlate to the loss of sensitivity to GTP inhibition.

Figure 1Go compares the allosteric effects of ATP on lymphoblast GDH enzyme activity in two HI/HA patients and a normal control. In contrast to other allosteric effectors, ATP produced a triphasic response, with initial inhibition followed by stimulation and, finally, inhibition of activity. The initial inhibitory phase was blunted in the two mutants, and the ATP trough concentration was lower than that in the normal control. The results of additional studies of lymphoblast GDH responses to ATP in five exon 6 and 7 mutations and in three previously reported exon 11 and 12 mutations are shown in Table 5Go. In most cases, the maximal ATP-stimulated activity was similar to that in the control, but there was impairment of the first phase suppression by ATP. With all of these mutations, similar to the patterns shown in Fig. 1Go, the stimulatory second and the inhibitory third phases of response to ATP did not appear to be affected.



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  		Figure 1. Allosteric effects of ATP on HI/HA lymphoblast GDH activity. Shown are the activities of lymphoblast GDH from patients with Arg221Cys ({blacktriangleup}) and Arg269Cys (•) mutations compared with a normal control ({circ}) with ATP added at concentrations from 0–5000 µmol/L.

 

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  		Table 5. Lymphoblast GDH allosteric responses to ATP in HI/HA patients

 
To test whether there were differences in clinical as well as enzymatic phenotypes among the different HI/HA GDH mutations, we examined the relationship between plasma ammonium concentrations and the IC50 for GTP inhibition of lymphoblast GDH. The points shown in Fig. 2Go represent the mean GTP IC50 for each mutation and the mean serum ammonium values reported for each of the patients with the corresponding mutation. Included are data from patients with mutations in both the exon 6–7 and exon 11–12 regions. Linear correlation analysis showed a significant, positive relationship between mean plasma ammonium and GTP IC50.



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  		Figure 2. Relationship between plasma ammonium and lymphoblast GDH sensitivity to GTP inhibition in HI/HA patients. Shown are the mean plasma ammonium concentrations and the mean IC50 for GTP inhibition for 14 different HI/HA mutations of GDH: S217C, R221C, R265T, Y266C, R269C, and R269H ({blacksquare}) and F440L, Q441R, S445L, G446R, G446D, S448P, K450E, and H454Y ({square}; r2 = 0.41; P = 0.0025).

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The results of these studies identify the exon 6- and 7- coding domain of GLUD1 as a second site of mutation that causes the HI/HA syndrome. Nineteen of 65 HI/HA patients (29%) had mutations in this region compared with the 48% (31 of 65) who had mutations in exons 11 and 12. The clinical features of patients with exon 6 and 7 mutations were similar to those previously reported with exon 11 and 12 mutations (15, 16). This phenotype includes relatively mild hypoglycemia that was often unrecognized until the end of the first year of life or later. The hypoglycemia usually responded well to treatment with diazoxide. Hyperammonemia in the patients with exon 6 and 7 mutations was similar to that found with exon 11 and 12 mutations. Studies of lymphoblast GDH showed impairment of sensitivity to GTP inhibition that was also similar to that in patients possessing exon 11 and 12 mutations.

The HI/HA syndrome is the first genetic disorder identified that is caused by a gain of function in an enzyme of intermediary metabolism. Other gain of function disorders previously described have usually involved mutations in plasma membrane hormone receptor signaling pathways. These diseases include oncogenic mutations as well as several endocrine disorders, such as familial male limited precocious puberty, familial hypocalcemia, and McCune- Albright syndrome (25, 26). These gain of function disorders have several features in common: the mutated genes are key regulatory steps in the signaling pathways, the defects arise due to a loss of inhibitory control, and the disorders are dominantly expressed. The HI/HA syndrome shares all of these features, emphasizing the importance of GDH allosteric regulation and the possibility that GDH may be a site for defects that cause diabetes.

We have previously suggested that the mechanism of both the hyperinsulinism and the hyperammonemia in patients with GDH mutations is an increased rate of oxidative deamination of glutamate to {alpha}-ketoglutarate and ammonia. This suggestion is consistent with in vitro data showing an increase in labeled glutamate oxidation during leucine-stimulated insulin secretion in isolated islets (14, 18). Although this mechanism assumes that flux through GDH is always in the direction of oxidation, controversy about the direction of the reaction has recently arisen (27). Wollheim and colleagues have proposed that GDH flux in the direction of glutamate synthesis plays a central role in glucose-stimulated insulin secretion (28). In either case, loss of inhibitory control of GDH activity would be expected to increase insulin secretion, consistent with the hypothesis that the HI/HA syndrome is caused by excessive GDH activity.

The x-ray crystal structure of bovine GDH, which is 95% identical to that of human GDH, has recently been reported (19). As shown in Fig. 3Go, the mutations in exons 6 and 7 all lie in a pocket that forms one of two GTP-binding sites. This region is adjacent to the location of the exon 11 and 12 HI/HA mutations that lie along the antenna region (16). Together, these observations support the conclusion that the region in Fig. 3Go, previously termed the GTP1 site, is indeed the major GTP inhibitory allosteric binding site. The second GTP binding site, GTP2, (not shown) has been suggested to be the site for ADP allosteric activation of GDH activities.



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  		Figure 3. Location of exon 6 and 7 HI/HA mutations on x-ray crystal structure of GDH. Shown is one subunit of the bovine form of GDH. The exon 6 and 7 mutations (multicolored) all lie in the inhibitory GTP-binding site. Also pictured are the exon 11 and 12 mutations (purple) that compose the hinge and antenna regions of the enzyme.

 
The fact that mutations in exon 6 and 7 as well as in exons 11 and 12 impair sensitivity to the first phase inhibitory effect of ATP on GDH activity indicates that ATP can also bind to the GTP inhibitory site. The second, stimulatory phase of ATP response may represent binding to the ADP-positive allosteric site, and the third, inhibitory phase may represent binding to a third site, such as the inhibitory NADH domain located beneath the GDH structure shown in Fig. 3Go. These suggestions are consistent with the observations that HI/HA mutations did not appear to alter the second and third phases of GDH response to ATP.

The mutated exon 6 and 7 residues contain positively charged arginine or hydroxyl side-chains capable of binding strongly to the negatively charged triphosphate tail of GTP. Ser217 also has the capacity of binding to the ribose sugar of GTP, and Arg265 can bind to the guanosine ring of the molecule. One of the mutated residues, Tyr262, has been previously demonstrated to be important for GTP inhibition through chemical modification studies (29). Yorifuji et al. and Miki et al. recently described additional patients with the HI/HA syndrome who have GDH mutations in exons 10 and 7, respectively (30, 31). The reported patients with Glu296Ala and Arg265Lys had similar clinical manifestations of the HI/HA syndrome. Additional sites of mutation in GDH may be discovered in other patients with the HI/HA syndrome, which either bind directly to GTP or disrupt the structural conformation of the inhibited enzyme.

Initial reports suggested that serum ammonium concentrations in patients with the HI/HA syndrome were always markedly elevated, 5–10 times over the upper limits of normal. However, the present data indicate that ammonium levels as low as 49 µmol/L may be found. There appeared to be a significant genotype-phenotype correlation between serum ammonium concentration and sensitivity to GTP inhibition that is consistent with the concept that altered GDH activity in the liver is responsible for the abnormal ammonia metabolism. No such correlation was apparent for the hypoglycemia component of the HI/HA syndrome. Patients with mild mutations, such as Arg269Cys, appear to have as many problems with hypoglycemia as those with severe defects, such as Arg221Cys, although attempts to quantify the severity of hypoglycemia have not been made. Nevertheless, it is possible that patients with hyperinsulinism due to GDH mutations may be discovered who have serum ammonia levels indistinguishable from normal.

In summary, the HI/HA syndrome is a common cause of congenital hyperinsulinism. The importance of the inhibitory GTP-binding domain of GDH is highlighted by the identification of the exon 6 and 7 mutations in the present series. The possibility of the HI/HA syndrome should be considered in adults with newly diagnosed hyperinsulinism, because some affected individuals escape recognition in childhood. Measurement of the plasma ammonium concentration on a casual blood sample provides a simple screening test for the disorder.


   Acknowledgments
 
We thank the nursing staff of The Children’s Hospital of Philadelphia General Clinical Research Center for expert care of the children with hyperinsulinism and Karen Kutoloski for her help in preparing patient lymphoblast cultures.


   Footnotes
 
1 This work was supported in part by NIH Grants RO1-DK-53012, RO1-DK-56268, P30-DK-19525, and MO1-RR-00240 and a grant from the American Diabetes Association. Back

2 The HI/HA contributing investigators are: Rosalind Brown (Worcester, MA), Neil Buist (Portland, OR), Majed Dasouki (Kansas City, MO), Richard Fefferman (Los Angeles, CA), Dorothy Grange (St. Louis, MO), Lefkothea Karaviti (Houston, TX), Christina Luedke (Boston, MA), Barbara Marriage (Edmonton, Canada), Judith McLaughlin (Baltimore, MD), Kusiel Perlman (Toronto, Canada), Margretta Seashore (New Haven, CT), and Guy Van Vliet (Montréal, Canada). Back

Received October 16, 2000.

Revised December 5, 2000.

Accepted December 7, 2000.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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T. Anno, S. Uehara, H. Katagiri, Y. Ohta, K. Ueda, H. Mizuguchi, Y. Moriyama, Y. Oka, and Y. Tanizawa
Overexpression of constitutively activated glutamate dehydrogenase induces insulin secretion through enhanced glutamate oxidation
Am J Physiol Endocrinol Metab, February 1, 2004; 286(2): E280 - E285.
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 J. Clin. Endocrinol. Metab.Home page
C. A. Stanley, P. S. Thornton, A. Ganguly, C. MacMullen, P. Underwood, P. Bhatia, L. Steinkrauss, L. Wanner, R. Kaye, E. Ruchelli, et al.
Preoperative Evaluation of Infants with Focal or Diffuse Congenital Hyperinsulinism by Intravenous Acute Insulin Response Tests and Selective Pancreatic Arterial Calcium Stimulation
J. Clin. Endocrinol. Metab., January 1, 2004; 89(1): 288 - 296.
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 Physiol. Rev.Home page
M. J. DUNNE, K. E. COSGROVE, R. M. SHEPHERD, A. AYNSLEY-GREEN, and K. J. LINDLEY
Hyperinsulinism in Infancy: From Basic Science to Clinical Disease
Physiol Rev, January 1, 2004; 84(1): 239 - 275.
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 DiabetesHome page
P. S. Thornton, C. MacMullen, A. Ganguly, E. Ruchelli, L. Steinkrauss, A. Crane, L. Aguilar-Bryan, and C. A. Stanley
Clinical and Molecular Characterization of a Dominant Form of Congenital Hyperinsulinism Caused by a Mutation in the High-Affinity Sulfonylurea Receptor
Diabetes, September 1, 2003; 52(9): 2403 - 2410.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Endocrinol. Metab.Home page
K. Eto, T. Yamashita, K. Hirose, Y. Tsubamoto, E. K. Ainscow, G. A. Rutter, S. Kimura, M. Noda, M. Iino, and T. Kadowaki
Glucose metabolism and glutamate analog acutely alkalinize pH of insulin secretory vesicles of pancreatic {beta}-cells
Am J Physiol Endocrinol Metab, August 1, 2003; 285(2): E262 - E271.
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 J. Biol. Chem.Home page
C. Li, H. Najafi, Y. Daikhin, I. B. Nissim, H. W. Collins, M. Yudkoff, F. M. Matschinsky, and C. A. Stanley
Regulation of Leucine-stimulated Insulin Secretion and Glutamine Metabolism in Isolated Rat Islets
J. Biol. Chem., January 24, 2003; 278(5): 2853 - 2858.
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 DiabetesHome page
A. Kelly, C. Li, Z. Gao, C. A. Stanley, and F. M. Matschinsky
Glutaminolysis and Insulin Secretion: From Bedside to Bench and Back
Diabetes, December 1, 2002; 51(90003): S421 - 426.
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I. Zaganas and A. Plaitakis
Single Amino Acid Substitution (G456A) in the Vicinity of the GTP Binding Domain of Human Housekeeping Glutamate Dehydrogenase Markedly Attenuates GTP Inhibition and Abolishes the Cooperative Behavior of the Enzyme
J. Biol. Chem., July 12, 2002; 277(29): 26422 - 26428.
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Y. Tanizawa, K. Nakai, T. Sasaki, T. Anno, Y. Ohta, H. Inoue, K. Matsuo, M. Koga, S. Furukawa, and Y. Oka
Unregulated Elevation of Glutamate Dehydrogenase Activity Induces Glutamine-Stimulated Insulin Secretion: Identification and Characterization of a GLUD1 Gene Mutation and Insulin Secretion Studies With MIN6 Cells Overexpressing the Mutant Glutamate Dehydrogenase
Diabetes, March 1, 2002; 51(3): 712 - 717.
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 J. Clin. Endocrinol. Metab.Home page
A. Kelly, D. Ng, R. J. Ferry Jr., A. Grimberg, S. Koo-McCoy, P. S. Thornton, and C. A. Stanley
Acute Insulin Responses to Leucine in Children with the Hyperinsulinism/Hyperammonemia Syndrome
J. Clin. Endocrinol. Metab., August 1, 2001; 86(8): 3724 - 3728.
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