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Hyperinsulinism of infancy: Novel ABCC8 and KCNJ11 mutations and evidence for additional locus heterogeneity
Year:
2004
Authors :
Shatz, Olga
;
.
Volume :
89
Co-Authors:
Tornovsky, S., Endocrinology and Metabolism Service, Internal Medicine Department, Hadassah-Hebrew Univ. Med. School, Jerusalem 91120, Israel
Crane, A., Dept. of Med. Cell. and Molec. Biol., Baylor College of Medicine, Houston, TX 77030, United States
Cosgrove, K.E., School of Biological Science, University of Manchester, Manchester M13 9PT, United Kingdom
Hussain, K., London Ctr. Childhood Pancreatic D., Gt. Ormond St. Hospital for Children, National Health Service Trust, London WC1N 3JH, United Kingdom, Institute of Child Health, London WC1N 3JH, United Kingdom
Lavie, J., Endocrinology and Metabolism Service, Internal Medicine Department, Hadassah-Hebrew Univ. Med. School, Jerusalem 91120, Israel
Heyman, M., Endocrinology and Metabolism Service, Internal Medicine Department, Hadassah-Hebrew Univ. Med. School, Jerusalem 91120, Israel
Nesher, Y., Endocrinology and Metabolism Service, Internal Medicine Department, Hadassah-Hebrew Univ. Med. School, Jerusalem 91120, Israel
Kuchinski, N., Endocrinology and Metabolism Service, Internal Medicine Department, Hadassah-Hebrew Univ. Med. School, Jerusalem 91120, Israel
Ben-Shushan, E., Endocrinology and Metabolism Service, Internal Medicine Department, Hadassah-Hebrew Univ. Med. School, Jerusalem 91120, Israel
Shatz, O., Endocrinology and Metabolism Service, Internal Medicine Department, Hadassah-Hebrew Univ. Med. School, Jerusalem 91120, Israel
Nahari, E., Endocrinology and Metabolism Service, Internal Medicine Department, Hadassah-Hebrew Univ. Med. School, Jerusalem 91120, Israel
Potikha, T., Endocrinology and Metabolism Service, Internal Medicine Department, Hadassah-Hebrew Univ. Med. School, Jerusalem 91120, Israel
Zangen, D., Department of Pediatrics, Hadassah-Hebrew University, Medical School, Jerusalem 91120, Israel
Tenenbaum-Rakover, Y., Pediatric Endocrine Unit, Ha' Emek Medical Center, Afula 18101, Israel
De Vries, L., Inst. for Endocrinology and Diabetes, Natl. Center for Childhood Diabetes, Schneider Children's Med. Ctr. I., Petah Tikva 49202, Israel, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel
Argente, J., Hosp. Inf. Univ. Nino Jesus, E-28009 Madrid, Spain
Gracia, R., Hosp. Infantil Universitario La Paz, E-28034 Madrid, Spain
Landau, H., Department of Pediatrics, Hadassah-Hebrew University, Medical School, Jerusalem 91120, Israel
Eliakim, A., Pediatric Endocrinology Clinic, Pediatric Department, Meir General Hospital, Kfar-Saba, Israel, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel
Lindley, K., London Ctr. Childhood Pancreatic D., Gt. Ormond St. Hospital for Children, National Health Service Trust, London WC1N 3JH, United Kingdom, Institute of Child Health, London WC1N 3JH, United Kingdom
Dunne, M.J., School of Biological Science, University of Manchester, Manchester M13 9PT, United Kingdom
Aguilar-Bryan, L., Dept. of Med. Cell. and Molec. Biol., Baylor College of Medicine, Houston, TX 77030, United States
Glaser, B., Endocrinology and Metabolism Service, Internal Medicine Department, Hadassah-Hebrew Univ. Med. School, Jerusalem 91120, Israel, Endocrinology and Metabolism Service, Hadassah-Hebrew University, Medical Center, Jerusalem 91120, Israel
Facilitators :
From page:
6224
To page:
6234
(
Total pages:
11
)
Abstract:
Hyperinsulinism of infancy is a genetically heterogeneous disease characterized by dysregulation of insulin secretion resulting in severe hypoglycemia. To date, mutations in five different genes, the sulfonylurea receptor (SUR1, ABCC8), the inward rectifying potassium channel (K IR6.2, KCNJ11), glucokinase (GCK), glutamate dehydrogenase (GLUD1), and short-chain 3-hydroxyacyl-coenzyme A dehydrogenase (SCHAD), have been implicated. Previous reports suggest that, in 40% of patients, no mutation can be identified in any of these genes, suggesting additional locus heterogeneity. However, previous studies did not screen all five genes using direct sequencing, the most sensitive technique available for mutation detection. We selected 15 hyperinsulinism of infancy patients and systematically sequenced the promoter and all coding exons and intron/exon boundaries of ABCC8 and KCNJ11. If no mutation was identified, the coding sequence and intron/exon boundaries of GCK, GLUD1, and SCHAD were sequenced. Seven novel mutations were found in the ABCC8 coding region, one mutation was found in the KCNJ11 coding region, and one novel mutation was found in each of the two promoter regions screened. Functional studies on β-cells from six patients showed abnormal ATP-sensitive K + channel function in five of the patients; the sixth had normal channel activity, and no mutations were found. Photolabeling studies using a reconstituted system showed that all missense mutations altered intracellular trafficking. Each of the promoter mutations decreased expression of a reporter gene by about 60% in a heterologous expression system. In four patients (27%), no mutations were identified. Thus, further genetic heterogeneity is suggested in this disorder. These patients represent a cohort that can be used for searching for mutations in other candidate genes.
Note:
Related Files :
adenosine triphosphate
chromosome mapping
gene expression
mutation
Mutation, Missense
Show More
Related Content
More details
DOI :
10.1210/jc.2004-1233
Article number:
Affiliations:
Database:
Scopus
Publication Type:
article
;
.
Language:
English
Editors' remarks:
ID:
22766
Last updated date:
02/03/2022 17:27
Creation date:
16/04/2018 23:54
Scientific Publication
Hyperinsulinism of infancy: Novel ABCC8 and KCNJ11 mutations and evidence for additional locus heterogeneity
89
Tornovsky, S., Endocrinology and Metabolism Service, Internal Medicine Department, Hadassah-Hebrew Univ. Med. School, Jerusalem 91120, Israel
Crane, A., Dept. of Med. Cell. and Molec. Biol., Baylor College of Medicine, Houston, TX 77030, United States
Cosgrove, K.E., School of Biological Science, University of Manchester, Manchester M13 9PT, United Kingdom
Hussain, K., London Ctr. Childhood Pancreatic D., Gt. Ormond St. Hospital for Children, National Health Service Trust, London WC1N 3JH, United Kingdom, Institute of Child Health, London WC1N 3JH, United Kingdom
Lavie, J., Endocrinology and Metabolism Service, Internal Medicine Department, Hadassah-Hebrew Univ. Med. School, Jerusalem 91120, Israel
Heyman, M., Endocrinology and Metabolism Service, Internal Medicine Department, Hadassah-Hebrew Univ. Med. School, Jerusalem 91120, Israel
Nesher, Y., Endocrinology and Metabolism Service, Internal Medicine Department, Hadassah-Hebrew Univ. Med. School, Jerusalem 91120, Israel
Kuchinski, N., Endocrinology and Metabolism Service, Internal Medicine Department, Hadassah-Hebrew Univ. Med. School, Jerusalem 91120, Israel
Ben-Shushan, E., Endocrinology and Metabolism Service, Internal Medicine Department, Hadassah-Hebrew Univ. Med. School, Jerusalem 91120, Israel
Shatz, O., Endocrinology and Metabolism Service, Internal Medicine Department, Hadassah-Hebrew Univ. Med. School, Jerusalem 91120, Israel
Nahari, E., Endocrinology and Metabolism Service, Internal Medicine Department, Hadassah-Hebrew Univ. Med. School, Jerusalem 91120, Israel
Potikha, T., Endocrinology and Metabolism Service, Internal Medicine Department, Hadassah-Hebrew Univ. Med. School, Jerusalem 91120, Israel
Zangen, D., Department of Pediatrics, Hadassah-Hebrew University, Medical School, Jerusalem 91120, Israel
Tenenbaum-Rakover, Y., Pediatric Endocrine Unit, Ha' Emek Medical Center, Afula 18101, Israel
De Vries, L., Inst. for Endocrinology and Diabetes, Natl. Center for Childhood Diabetes, Schneider Children's Med. Ctr. I., Petah Tikva 49202, Israel, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel
Argente, J., Hosp. Inf. Univ. Nino Jesus, E-28009 Madrid, Spain
Gracia, R., Hosp. Infantil Universitario La Paz, E-28034 Madrid, Spain
Landau, H., Department of Pediatrics, Hadassah-Hebrew University, Medical School, Jerusalem 91120, Israel
Eliakim, A., Pediatric Endocrinology Clinic, Pediatric Department, Meir General Hospital, Kfar-Saba, Israel, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel
Lindley, K., London Ctr. Childhood Pancreatic D., Gt. Ormond St. Hospital for Children, National Health Service Trust, London WC1N 3JH, United Kingdom, Institute of Child Health, London WC1N 3JH, United Kingdom
Dunne, M.J., School of Biological Science, University of Manchester, Manchester M13 9PT, United Kingdom
Aguilar-Bryan, L., Dept. of Med. Cell. and Molec. Biol., Baylor College of Medicine, Houston, TX 77030, United States
Glaser, B., Endocrinology and Metabolism Service, Internal Medicine Department, Hadassah-Hebrew Univ. Med. School, Jerusalem 91120, Israel, Endocrinology and Metabolism Service, Hadassah-Hebrew University, Medical Center, Jerusalem 91120, Israel
Hyperinsulinism of infancy: Novel ABCC8 and KCNJ11 mutations and evidence for additional locus heterogeneity
Hyperinsulinism of infancy is a genetically heterogeneous disease characterized by dysregulation of insulin secretion resulting in severe hypoglycemia. To date, mutations in five different genes, the sulfonylurea receptor (SUR1, ABCC8), the inward rectifying potassium channel (K IR6.2, KCNJ11), glucokinase (GCK), glutamate dehydrogenase (GLUD1), and short-chain 3-hydroxyacyl-coenzyme A dehydrogenase (SCHAD), have been implicated. Previous reports suggest that, in 40% of patients, no mutation can be identified in any of these genes, suggesting additional locus heterogeneity. However, previous studies did not screen all five genes using direct sequencing, the most sensitive technique available for mutation detection. We selected 15 hyperinsulinism of infancy patients and systematically sequenced the promoter and all coding exons and intron/exon boundaries of ABCC8 and KCNJ11. If no mutation was identified, the coding sequence and intron/exon boundaries of GCK, GLUD1, and SCHAD were sequenced. Seven novel mutations were found in the ABCC8 coding region, one mutation was found in the KCNJ11 coding region, and one novel mutation was found in each of the two promoter regions screened. Functional studies on β-cells from six patients showed abnormal ATP-sensitive K + channel function in five of the patients; the sixth had normal channel activity, and no mutations were found. Photolabeling studies using a reconstituted system showed that all missense mutations altered intracellular trafficking. Each of the promoter mutations decreased expression of a reporter gene by about 60% in a heterologous expression system. In four patients (27%), no mutations were identified. Thus, further genetic heterogeneity is suggested in this disorder. These patients represent a cohort that can be used for searching for mutations in other candidate genes.
Scientific Publication
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