Update of variants identified in the pancreatic β-cell KATP channel genes KCNJ11 and ABCC8 in individuals with congenital hyperinsulinism and diabetes.

Elisa De Franco,Bradley Harman,Henrik Thybo Christesen,Siri Atma W Greeley,Klaus Brusgaard,Cécile Saint‐Martin,Sian Ellard,Amy E Knight Johnson,Raúl Calzada‐León,Pamela Bowman,Elisa Nishimura‐Meguro,May Sanyoura,Sarah E Flanagan,Jean‐Baptiste Arnoux,Lydia Aguilar‐Bryan,Christine Bellanné‐Chantelot,Annette Rønholt Larsen,Thomas W Laver ,Daniela Del Gaudio ,Jayne Houghton

doi:10.1002/humu.23995

Abstract

The most common genetic cause of neonatal diabetes and hyperinsulinism is pathogenic variants in ABCC8 and KCNJ11. These genes encode the subunits of the β‐cell ATP‐sensitive potassium channel, a key component of the glucose‐stimulated insulin secretion pathway. Mutations in the two genes cause dysregulated insulin secretion; inactivating mutations cause an oversecretion of insulin, leading to congenital hyperinsulinism, whereas activating mutations cause the opposing phenotype, diabetes. This review focuses on variants identified in ABCC8 and KCNJ11, the phenotypic spectrum and the treatment implications for individuals with pathogenic variants.

Highlights

ATP‐sensitive potassium (KATP) channels were found to couple glucose metabolism to membrane electrical activity and insulin release over 30 years ago (Ashcroft, Harrison, & Ashcroft, 1984; Cook &Hales, 1984; Rorsman & Trube, 1985)
By combining published reports together with data from five international molecular genetic screening laboratories in the UK, Denmark, France, and the United States of America, we report 953 pathogenic ABCC8 and KCNJ11 variants (Tables S1–S6) and discuss the role of these genes in congenital hyperinsulinism (CHI) and monogenic diabetes
Current estimates suggest that approximately 0.4% of all diabetes has a monogenic cause (Shepherd et al, 2016; Shields et al, 2017)

Summary

| INTRODUCTION

ATP‐sensitive potassium (KATP) channels were found to couple glucose metabolism to membrane electrical activity and insulin release over 30 years ago A total of 748 ABCC8 and 205 KCNJ11 pathogenic or likely pathogenic variants have been identified in individuals with CHI or NDM (Table 1 and Table 3 and Tables S1 and S4) — please note that these tables are meant to direct to the appropriate references and laboratories They do not provide in‐depth clinical information and variants that had been previously reported as pathogenic with a GnomAD frequency compatible with the disease frequency (as calculated by http://cardiodb.org/allelefrequencyapp/ using a biallelic mode of inheritance, a prevalence of 1/50,000, an allelic heterogeneity of 0.1, genetic heterogeneity of 0.5, and penetrance of 0.5) were not re‐assessed. Implementation of noninvasive prenatal testing for maternally inherited mutations will be extremely important, as a previous study suggested that sulphonylurea can cross the placenta and influence fetal growth with implications for treatment of monogenic diabetes pregnancies (Myngheer et al, 2014; Shepherd, Brook, Chakera, & Hattersley, 2017)

| SUMMARY

Findings

1–39 Exon1 Exon 1 Exon 1 Exon 1