Functional characterization of inactivating ABCC8 variants causing congenital hyperinsulinism

Abstract Congenital hyperinsulinism (CHI; OMIM: 256450) is characterized by persistent insulin secretion despite severe hypoglycemia. The most common causes are variants in the ATP‐binding cassette subfamily C member 8( ABCC8 ) and potassium inwardly‐rectifying channel subfamily J member 11( KCNJ11 ) genes. These encode ATP‐sensitive potassium (K ATP ) channel subunit sulfonylurea receptor 1 (SUR1) and inwardly rectifying potassium channel (Kir6.2) proteins. A 7‐day‐old male infant presented with frequent hypoglycemic episodes and was clinically diagnosed with CHI, underwent trio‐whole‐exome sequencing, revealing compound heterozygous ABCC8 variants (c.307C>T, p.His103Tyr; and c.3313_3315del, p.Ile1105del) were identified. In human embryonic kidney 293 (HEK293) and rat insulinoma cells (INS‐1) transfected with wild‐type and variant plasmids, K ATP channels formed by p.His103Tyr were delivered to the plasma membrane, whereas p.Ile1105del or double variants (p.His103Tyr coupled with p.Ile1105del) failed to be transported to the plasma membrane. Compared to wild‐type channels, the channels formed by the variants (p.His103Tyr; p.Ile1105del) had elevated basal [Ca 2+ ] i , but did not respond to stimulation by glucose. Our results provide evidence that the two ABCC8 variants may be related to CHI owing to defective trafficking and dysfunction of K ATP channels.