Hyperinsulinism of infancy: Novel ABCC8 and KCNJ11 mutations and evidence for additional locus heterogeneity

Sharona Tornovsky, Ana Crane, Karen E. Cosgrove, Khalid Hussain, Judith Lavie, Ma'ayan Heyman, Yaron Nesher, Na'ama Kuchinski, Etti Ben-Shushan, Olga Shatz, Efrat Nahari, Tamara Potikha, David Zangen, Yardena Tenenbaum-Rakover, Liat De Vries, Jesús Argente, Ricardo Gracia, Heddy Landau, Alon Eliakim, Keith LindleyMark J. Dunne, Lydia Aguilar-Bryan, Benjamin Glaser*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

75 Scopus citations

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.

Original languageAmerican English
Pages (from-to)6224-6234
Number of pages11
JournalJournal of Clinical Endocrinology and Metabolism
Volume89
Issue number12
DOIs
StatePublished - Dec 2004

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