| Molecular basis and characterization of the hyperinsulinism/hyperammonemia syndrome: predominance of mutations in exons 11 and 12 of the glutamate dehydrogenase gene. HI/HA Contributing Investigators. | |
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MedLine Citation:
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PMID: 10871207 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Glutamate dehydrogenase (GDH) is allosterically activated by the amino acid leucine to mediate protein stimulation of insulin secretion. Children with the hyperinsulinism/hyperammonemia (HI/HA) syndrome have symptomatic hypoglycemia plus persistent elevations of plasma ammonium. We have reported that HI/HA may be caused by dominant mutations of GDH that lie in a unique allosteric domain that is encoded within GDH exons 11 and 12. To examine the frequency of mutations in this domain, we screened genomic DNA from 48 unrelated cases with the HI/HA syndrome for exon 11 and 12 mutations in GDH. Twenty-five (52%) had mutations in these exons; 74% of the mutations were sporadic. Clinical manifestations included normal birth weight, late onset of hypoglycemia, diazoxide responsiveness, and protein-sensitive hypoglycemia. Enzymatic studies of lymphoblast GDH in seven of the mutations showed that all had reduced sensitivity to inhibition with GTP, consistent with an increase in enzyme activity. Mutations had little or no effect on enzyme responses to positive allosteric effectors, such as ADP or leucine. Based on the three-dimensional structure of GDH, the mutations may function by impairing the binding of an inhibitory GTP to a domain responsible for the allosteric and cooperativity properties of GDH. |
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Authors:
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C A Stanley; J Fang; K Kutyna; B Y Hsu; J E Ming; B Glaser; M Poncz |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: Diabetes Volume: 49 ISSN: 0012-1797 ISO Abbreviation: Diabetes Publication Date: 2000 Apr |
Date Detail:
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Created Date: 2000-07-06 Completed Date: 2000-07-06 Revised Date: 2007-11-14 |
Medline Journal Info:
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Nlm Unique ID: 0372763 Medline TA: Diabetes Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: 667-73 Citation Subset: AIM; IM |
Affiliation:
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The Children's Hospital of Philadelphia, Department of Pediatrics, University of Pennsylvania School of Medicine, 19104, USA. stanleyc@email.chop.edu |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Adenosine Diphosphate
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pharmacology Allosteric Site Amino Acid Sequence Ammonia / blood* Enzyme Activation / drug effects Exons* Female Glutamate Dehydrogenase / blood, chemistry, genetics* Guanosine Triphosphate / pharmacology Humans Hyperinsulinism / genetics* Infant Infant, Newborn Lymphocytes / enzymology Male Models, Molecular Molecular Sequence Data Mutation* Syndrome |
| Grant Support | |
ID/Acronym/Agency:
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MO1 RR 00240/RR/NCRR NIH HHS; R01 DK 53012/DK/NIDDK NIH HHS |
| Chemical | |
Reg. No./Substance:
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58-64-0/Adenosine Diphosphate; 7664-41-7/Ammonia; 86-01-1/Guanosine Triphosphate; EC 1.4.1.2/Glutamate Dehydrogenase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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