Endocrine Abstracts

Background: Congenital hyperinsulinism (CHI) is a disorder of unregulated insulin secretion causing persistent hypoglycaemia. In around 50% of the patients with CHI, the underlying molecular genetic etiology is unknown. Ca²⁺/calmodulin-dependent protein kinase 2 (CaMKK2) belongs to the Serine/Threonine protein kinase family. Alternative splicing results in multiple transcripts encoding distinct isoforms. We report, for the first time, CaMKK2 mutation as a novel genetic cause of CHI.

Patient and methods: A Caucasian child born to non-consanguineous parents at 33 weeks gestation presented with hypoglycaemic seizures at 7 months of age requiring intravenous glucose load up to 15 mg/kg per min. The investigations confirmed CHI (plasma insulin concentration of 37 pmol/l and supressed β-hydroxy butyrate (<100 mmol/l) during hypoglycaemia). No mutation was identified in ABCC8, KCNJ11 or GCK. The 18-Fluro-DOPA PET CT scan suggested diffuse CHI and the patient responded well to diazoxide. At the age of 5 years, the patient requires 10 mg/kg per day of diazoxide and has features of developmental and speech delay.

Results: Whole exome sequencing was performed on the genomic DNA of the patient and the biological parents. A de novo heterozygous frameshift mutation (p.G539fs*4) was found at the terminal exon (exon 16) of CaMKK2 (NM_001270486.1) (isoform-7). CaMKK2 isoform-7 (WT) and the pG539fs*4 mutant were expressed in COS7 cells and the pG539fs*4 mutant was noted to have significantly higher basal and Ca²⁺-CaM dependent kinase activity compared with WT isoform-7. Both isoform-7 and the pG539fs*4 mutant have elevated basal activity compared with isoform-1, the major CaMKK2 isoform expressed in most tissues.

Conclusion: We describe for the first time, a mutation in CaMKK2 as a novel genetic cause of persistent CHI. Calcium has a key role in mediating glucose stimulated insulin secretion via the action of multifunctional kinases (CaM-KI and CaM-KIV), activated by CaMKK2, an upstream kinase. We hypothesise that the increase in the Ca²⁺-CaM dependent kinase activity as a result of the mutation, to be increasing the insulin secretion, probably via the upregulated transcription of INS-1.