J Pediatr Endocrinol Metab. 2017 Nov 27;30(12):1311-1315. doi: 10.1515/jpem-2017-0163.
Rozenkova K, Nessa A, Obermannova B, Elblova , Dusatkova P, Sumnik Z, Lebl J, Hussain K, Pruhova S.
Congenital hyperinsulinism (CHI) is frequently caused by mutations in one of the KATP channel subunits encoded by the genes ABCC8 and KCNJ11. The effect of simultaneous mutations in both of these genes on the pancreatic β-cell function is not known and patients with CHI carrying both ABCC8 and KCNJ11 mutations have not yet been reported. We questioned if a combination of heterozygous mutations in the ABCC8 and KCNJ11 genes could also lead to β-cell dysfunction presenting as CHI.
As a model, we used a patient with transient CHI that paternally inherited novel heterozygous mutations in ABCC8 (p.Tyr1293Asp) and KCNJ11 (p.Arg50Trp) genes. The pathogenic effects on the pancreatic β-cells function were examined in an in vitro functional study using radioactive rubidium efflux assay.
We showed that the activation of the mutated KATP channels by diazoxide was decreased by 60.9% in the channels with the heterozygous combination of both mutations compared to the wild type channels. This could indicate the pathogenic effect on the pancreatic β-cell function leading to CHI although conclusive evidence is needed to be added.
Our findings may widen the spectrum of genetic causes of CHI and suggest a novel pathogenic mechanism of CHI that must however, be further investigated.