Abstrakt
Background: Congenital hyperinsulinism (CHI) is frequently caused by mutations in one of the K-ATP channel subunits encoded by the genes ABCC8 and KCNJ11. The effect of simultaneous mutations in both of these genes on the pancreatic beta-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 beta-cell dysfunction presenting as CHI. Methods: 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 beta-cells function were examined in an in vitro functional study using radioactive rubidium efflux assay. Results: We showed that the activation of the mutated K-ATP 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 beta-cell function leading to CHI although conclusive evidence is needed to be added. Conclusions: 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.