Abstract
Despite the enormous efforts to understand Congenital hyperinsulinism (CHI), up to 50% of the patients are genetically unexplained. We aimed to functionally characterize a novel candidate gene in CHI.
A 4-month-old boy presented severe hyperinsulinemic hypoglycemia. A routine CHI genetic panel was negative.
A trio-based whole-exome sequencing (WES) was performed. Gene knockout in the RIN-m cell line was established by CRISPR/Cas9. Gene expression was performed using real-time PCR.
Hyperinsulinemic hypoglycemia with diffuse beta-cell involvement was demonstrated in the patient, who was diazoxide-responsive. By WES, compound heterozygous variants were identified in the adenylyl cyclase 7,
gene p.(Asp439Glu) and p.(Gly1045Arg).
is calcium-sensitive, expressed in beta-cells and converts ATP to cAMP. The variants located in the cytoplasmic domains C1 and C2 in a highly conserved and functional amino acid region. RIN-m
cells showed a significant increase in insulin secretion reaching 54% at low, and 49% at high glucose concentrations, compared to wild-type. In genetic expression analysis
loss of function led to a 34.1-fold to 362.8-fold increase in mRNA levels of the insulin regulator genes
and
(
0.0002), as well as increased glucose uptake and sensing indicated by higher mRNA levels of
and
upregulation of
, and
leading to the activation of the glucose stimulated-insulin secretion (GSIS) pathway.
This study identified a novel candidate gene,
, to cause CHI
activation of the GSIS pathway.