KCNQ member 1 (KCNQ1, α subunit) co-assembles with KCNE accessory subunits (β subunit) to generate the KV7.1 channel. Kv channels and KATP channels interact with voltage-dependent Ca2+ channels to trigger and maintain glucose-stimulated insulin secretion of pancreatic β cells. Here, our collaborators (Prof. Dr. K. Raile and Dr. M Gong) reported a diabetes patient with the KCNQ1 homozygous point mutation who had intrauterine growth retardation with low birth weight and permanent neonatal diabetes. I generated the homozygous point mutation in hESCs_H1 imitating our neonatal diabetes patient by CRISPR-Cas9 homology-directed genome editing. The isogenic mutated hESCs_H1, wild type hESCs_H1, and unmodified control hESCs_H1 were converted into pancreatic islet-like organoids. The KCNQ1 homozygous point mutation β-like cells had a variational phenotype from higher insulin secretion turn into a lower level compared to controls. The KCNQ1 homozygous point mutation and the blockade of Kv7.1 channel increased the membrane action potential resulting in cytoplasmic Ca2+ accumulation. The increase of insulin secretion as a result of cytoplasmic Ca2+ accumulation negatively regulated the expression of metabolic genes of the cAMP pathway, FGFRs, HNF4α and PDX1. FGFR1 and PDX1 finally down-regulated GLUT1 and resulted in a decrease in insulin secretion. Nevertheless, the organoids from the late stage of mature β cells were pro-apoptotic, which could be accelerated by chronic exposure to high glucose resulting in loss of β-cell mass and further decreased β-cell function by lower insulin secretion. Our results expose the critical roles of KCNQ1 in functional β-Cell development.
