Congenital Hyperinsulinism (CHI) is a rare heterogeneous disease characterized by unregulated insulin secretion. Dominant mutations in ABCC8 causing medically unresponsive CHI have been reported; however, the molecular mechanisms are not clear. The molecular basis of medically unresponsive CHI due to dominant ABCC8 mutations has been studied in 10 patients, who were medically unresponsive to diazoxide (DZX), and nine of whom required a near-total pancreatectomy, and one partial pancreatectomy. DNA sequencing revealed seven dominant inactivating heterozygous missense mutations in ABCC8, including one novel and six previously reported but uncharacterized mutations. Two groups of mutations with different cellular mechanisms were characterized. Mutations in the transmembrane domain (TMD) were more responsive to channel activators such as DZX, MgADP and metabolic inhibition. The trafficking analysis has shown that nucleotide-binding domain two (NBD2) mutations are not retained in the endoplasmic reticulum (ER) and are present on the membrane. However, the TMD mutations were retained in the ER. D1506E was the most severe SUR1-NBD2 mutation. Homologous expression of D1506E revealed a near absence of KATP currents in the presence of DZX and intracellular MgADP. Heterozygous expression of D1506E showed a strong dominant-negative effect on SUR1\Kir6.2 currents. Overall, we define two groups of mutation with different cellular mechanisms. In the first group, channel complexes with mutations in NBD2 of SUR1 traffic normally but are unable to be activated by MgADP. In the second group, channels mutations in the TMD of SUR1 are retained in the ER and have variable functional impairment.
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- Cell Line
- Congenital Hyperinsulinism/diagnosis
- Gene Expression
- Genes, Dominant
- Genetic Association Studies
- Infant, Newborn
- Intracellular Space/metabolism
- Patch-Clamp Techniques
- Potassium Channels/genetics
- Potassium Channels, Inwardly Rectifying/metabolism
- Protein Transport
- Sulfonylurea Receptors/chemistry