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Horm Res Paediatr. 2013;80(1):18-27. doi: 10.1159/000351943. Epub 2013 Jul 13.

Dominant form of congenital hyperinsulinism maps to HK1 region on 10q.

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  • 1Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia, Pa. 19104, USA.

Abstract

BACKGROUND/AIMS:

In a family with congenital hyperinsulinism (HI), first described in the 1950s by McQuarrie, we examined the genetic locus and clinical phenotype of a novel form of dominant HI.

METHODS:

We surveyed 25 affected individuals, 7 of whom participated in tests of insulin dysregulation (24-hour fasting, oral glucose and protein tolerance tests). To identify the disease locus and potential disease-associated mutations we performed linkage analysis, whole transcriptome sequencing, whole genome sequencing, gene capture, and next generation sequencing.

RESULTS:

Most affecteds were diagnosed with HI before age one and 40% presented with a seizure. All affecteds responded well to diazoxide. Affecteds failed to adequately suppress insulin secretion following oral glucose tolerance test or prolonged fasting; none had protein-sensitive hypoglycemia. Linkage analysis mapped the HI locus to Chr10q21-22, a region containing 48 genes. Three novel noncoding variants were found in hexokinase 1 (HK1) and one missense variant in the coding region of DNA2.

CONCLUSION:

Dominant, diazoxide-responsive HI in this family maps to a novel locus on Chr10q21-22. HK1 is the more attractive disease gene candidate since a mutation interfering with the normal suppression of HK1 expression in beta-cells could readily explain the hypoglycemia phenotype of this pedigree.

Copyright © 2013 S. Karger AG, Basel.

PMID:
23859901
[PubMed - indexed for MEDLINE]
PMCID:
PMC3876732
Free PMC Article
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