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

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

Sara E Pinney  1 , Karthik Ganapathy, Jonathan Bradfield, David Stokes, Ariella Sasson, Katarzyna Mackiewicz, Kara Boodhansingh, Nkecha Hughes, Susan Becker, Stephanie Givler, Courtney Macmullen, Dimitrios Monos, Arupa Ganguly, Hakon Hakonarson, Charles A Stanley
Affiliations

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

Sara E Pinney et al. Horm Res Paediatr. 2013.

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.

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Figures

Figure 1
Figure 1
Pedigree of family with autosomal dominant congenital hyperinsulinism. Generation is indicated by number and family members are denoted with a letter. Males depicted as squares, females as circles, deceased individuals by a slashed line. Filled symbols are individuals diagnosed with hypoglycemia (n=25); hatched symbols are obligate carriers (n=5). Diamonds indicate number of unaffected descendants. Dashed lines outline original pedigree reported by McQuarrie (1). Asterisks indicate family members described in Table 1.
Figure 2
Figure 2
(a) Linkage analysis showing LOD score of 6.82 at chromosome 10q21–22. Shaded bar indicates the 11.1 cM shared haplotype region spanning 8.2 Mb and containing 48 genes. (b) Location of 3 novel disease-associated variants in non-coding regions of HK1. The promoters of the three HK1 isoforms are identified: PT (testes specific), PE (erythrocyte specific), and PU (ubiquitous). Tissue specific exons are designated T1-T6 and E1. Exons 2–18 are shared by all 3 isoforms. Transcription start sites are indicated with arrows.
Figure 2
Figure 2
(a) Linkage analysis showing LOD score of 6.82 at chromosome 10q21–22. Shaded bar indicates the 11.1 cM shared haplotype region spanning 8.2 Mb and containing 48 genes. (b) Location of 3 novel disease-associated variants in non-coding regions of HK1. The promoters of the three HK1 isoforms are identified: PT (testes specific), PE (erythrocyte specific), and PU (ubiquitous). Tissue specific exons are designated T1-T6 and E1. Exons 2–18 are shared by all 3 isoforms. Transcription start sites are indicated with arrows.
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References

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