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      Loss of Imprinted Genes and Paternal SUR1 Mutations Lead to Focal Form of Congenital Hyperinsulinism

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          Abstract

          Persistent hyperinsulinaemic hypoglycaemia of infancy (PHHI) is a heterogeneous disorder characterized by profound hypoglycaemia due to inappropriate hypersecretion of insulin. An important diagnostic goal is to distinguish patients with a focal hyperplasia of islet cells of the pancreas (FoPHHI) from those with a diffuse abnormality of islets (DiPHHI), because the management differs significantly. The intriguing similarity between islet cell hyperplasia and tumourigenesis prompted us to investigate whether the imprinted genes in the 11p15 region are involved. Results showed that diffuse forms are caused by constitutional homozygous or compound heterozygous mutations of the SUR1 gene. In contrast, focal forms are caused by loss of the maternally inherited 11p15 region, resulting in both loss of the maternally expressed tumour suppressor genes accounting for hyperplasia and somatic reduction to hemizygosity or homozygosity of the paternally inherited SUR1, limited to the lesion. Thus, this somatic disorder, which leads both to β-cell proliferation and to hyperinsulinism, can be considered the somatic equivalent, restricted to a microscopic focal lesion, of constitutional uniparental disomy associated with unmasking of a heterozygous parental mutation.

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          Most cited references 5

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          Tumour-suppressor activity of H19 RNA.

          Loss of heterozygosity in certain human embryonal tumours implicates a tumour-suppressor gene at chromosome 11p15.5 and selective loss of maternal alleles suggests that this gene is paternally imprinted. The human H19 gene maps to 11p15.5, is expressed in differentiating fetal cells and is paternally imprinted. We report here that two embryonal tumour cell lines, RD and G401, showed growth retardation and morphological changes when transfected with an H19 expression construct. More importantly, clonogenicity in soft agar and tumorigenicity in nude mice were abrogated in the G401-H19 transfectants. In addition to demonstrating its tumour-suppressor potential, this transfection system should help structural and functional studies of the enigmatic H19 gene.
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            Hyperinsulinism and hyperammonemia in infants with regulatory mutations of the glutamate dehydrogenase gene.

            A new form of congenital hyperinsulinism characterized by hypoglycemia and hyperammonemia was described recently. We hypothesized that this syndrome of hyperinsulinism and hyperammonemia was caused by excessive activity of glutamate dehydrogenase, which oxidizes glutamate to alpha-ketoglutarate and which is a potential regulator of insulin secretion in pancreatic beta cells and of ureagenesis in the liver. We measured glutamate dehydrogenase activity in lymphoblasts from eight unrelated children with the hyperinsulinism-hyperammonemia syndrome: six with sporadic cases and two with familial cases. We identified mutations in the glutamate dehydrogenase gene by sequencing glutamate dehydrogenase complementary DNA prepared from lymphoblast messenger RNA. Site-directed mutagenesis was used to express the mutations in COS-7 cells. The sensitivity of glutamate dehydrogenase to inhibition by guanosine 5'-triphosphate was a quarter of the normal level in the patients with sporadic hyperinsulinism-hyperammonemia syndrome and half the normal level in patients with familial cases and their affected relatives, findings consistent with overactivity of the enzyme. These differences in enzyme insensitivity correlated with differences in the severity of hypoglycemia in the two groups. All eight children were heterozygous for the wild-type allele and had a mutation in the proposed allosteric domain of the enzyme. Four different mutations were identified in the six patients with sporadic cases; the two patients with familial cases shared a fifth mutation. In two clones of COS-7 cells transfected with the mutant sequence from one patient, the sensitivity of the enzyme to guanosine 5'-triphosphate was reduced, findings similar to those in the child's lymphoblasts. The hyperinsulinism-hyperammonemia syndrome is caused by mutations in the glutamate dehydrogenase gene that impair the control of enzyme activity.
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              Familial hyperinsulinism caused by an activating glucokinase mutation.

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                Author and article information

                Journal
                HRE
                Horm Res Paediatr
                10.1159/issn.1663-2818
                Hormone Research in Paediatrics
                S. Karger AG
                978-3-8055-7097-8
                978-3-318-00598-1
                1663-2818
                1663-2826
                2000
                July 2000
                17 November 2004
                : 53
                : Suppl 1
                : 2-6
                Affiliations
                aINSERM UR 383 Hôpital Necker-Enfants Malades, Clinique Maurice-Lamy, Paris, and Departments of bPathology, cPediatrics, dRadiology and eSurgery, Hôpital Necker-Enfants Malades, Paris, France; fDepartment of Pathology, University Hospital St-Luc of Louvain, Brussels, Belgium
                Article
                53197 Horm Res 2000;53(suppl 1):2–6
                10.1159/000053197
                10895035
                © 2000 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                References: 33, Pages: 5
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