ESPE Abstracts (2016) 86 HA1

KCNQ1 Mutations Cause Both Neonatal Diabetes and Hyperinsulinemic Hypoglycaemia of Infancy

Lei Lianga, Shiqi Jiab, Sebastian Frohlerb, Peter Kühnenc, Oliver Blankensteinc, Winfried Krilld, Semik Khodaverdid, Aidi Caoa, Oliver Hummelb, Nancy Elbarbarye, Khalid Hussainf, Jacob Voelklg, Wei Chenb, Maolian Gonga,b & Klemens Railea,h


aExperimental and Clinical Research Center, Charité, Berlin, Germany; bMax-Delbrück-Center for Molecular Medicine, Berlin, Germany; cInstitute for Experimental Paediatric Endocrinology, Charité, Berlin, Germany; dDepartment of Paediatrics, Klinikum Hanau, Hanau, Germany; ePaediatric Endocrinology and Diabetology, Ain Shams University, Cairo, Egypt; fDevelopmental Endocrinology Research Group, CMG Unit, UCL Institute of Child Health, Great Ormond Street Hospital, London, UK; gDepartment of Physiology, University of Tübingen, Tübingen, Germany; hDepartment of Pediatric endocrinology and Diabetology, Charité, Berlin, Germany


Background: Mutations in genes involved in insulin secretion or regulation of β cell identity cause both persistent neonatal diabetes (PND) and hyperinsulinemic hypoglycemia of infancy (HHI) pinpointing shared pathogenic mechanisms. KCNQ1 encodes a potassium channel protein, Kv7.1, which is a voltage-gated potassium channel expressed in cardiac tissue, pancreas, inner ear neurons, and other tissues. Variants in or nearby to KCNQ1 were linked to risk for both long QT syndrome (LQTS) and type 2 diabetes (T2D).

Patients and methods: We performed exome sequencing in one child with PND and his consanguineous parents and subsequent sanger sequencing of KCNQ1 in additional 90 children with diabetes or HHI of unknown origin. We detected overall three KCNQ1 gene mutations in the child with PND (R397W, homozygous) and two children with HHI (G292D and splice-site mutation with complete deletion of E13, both heterozygous). Overexpressing these variants, we analysed insulin secretion and gene expression in a glucose-sensitive mouse β cell line. Moreover, we characterized morphological changes and gene expression in pancreas and islets of Kcnq1 knock out versus wild type mice.

Results and discussion: Overexpression of the KCNQ1-PND variant R397W in β cells suppressed, while that of the G292D-HHI and E13Del-HHI variants increased basal and glucose-stimulated insulin secretion; findings consistent with respective human phenotypes. Following overexpression of R397W, high MafB and Pax6 expression points to loss of β cell identity. Dedifferentiation or transdifferentiation of affected β cells are possible molecular mechanisms for diabetes and defective insulin secretion. In contrast, induction of Pdx1 by both HHI mutations (G292D & E13 del) suggests increase of β cell mass and insulin secretion. In Kcnq1 KO mice, β cell mass was reduced by 35% and a consistent suppression of Pdx1, Foxa2, Arx1 and Irx1 indicates early disruption of both β and α cell differentiation.

Conclusion: This is the first report on KCNQ1 mutations causing monogenic PND and HHI. Further deep investigation is necessary for better understanding of the molecular pathways linking these KCNQ1 mutations to early-onset β cell dysfunction in humans.