Background: Congenital hyperinsulinism (CHI) is a disorder characterised by dysregulation of insulin secretion that leads to severe hypoglycaemia in neonates and infants. The focal form of CHI is caused by an autosomal recessive mutation in the genes ABCC8 or KCNJ11 inherited from the father and a second somatic event in the affected islet of Langerhans.
Objective: We report molecular genetic examination of focal pancreatic lesions of patients receiving therapeutic surgery in order to discover the genetic mechanisms in focal form of CHI.
Method: Patients were selected from the German Registry for Congenital Hyperinsulinism with proven ABCC8 or KCNJ11 mutations. Loss of heterozygosity (LOH) and gene expression levels were analysed by PCR, RT-PCR and Sanger sequencing in 11 patients with focal form of CHI. Deletions, duplications and uniparental isodisomy (UPD) were tested by methylation-specific MLPA (MS-MLPA).
Results: Complete and partial LOH was found in 10/11 focal lesions and monoallellic expression of the mutant ABCC8/KCNJ11 alleles was observed in all lesions. In contrast, there was no LOH detected in surrounding pancreatic tissue or blood cells. This supports somatic mosaicism specific in pancreatic beta cells. Both, ABCC8 and KCNJ11, are located in proximity to the Beckwith-Wiedemann imprinting control region on chromosome 11p15 that is also known for UPD. By MS-MLPA paternal UPD at 11p15 was detected in all samples showing LOH, whereas no deletion or duplication was found of this region.
Conclusion: In focal form of CHI monoallelic expression of mutant ABCC8/KCNJ11 is mainly caused by somatic paternal UPD 11p15.
Funding: MicroDissect GmbH (Spende:Somatische Mosaike # 995040).
01 - 03 Oct 2015
European Society for Paediatric Endocrinology