Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, USA.
Department of Endocrinology, Queensland Children's Hospital, South Brisbane, Queensland, Australia.
JCI Insight. 2021 Jul 8;6(13):138057. doi: 10.1172/jci.insight.138057.
Maturity-onset diabetes of the young (MODY) is a heterogeneous group of monogenic disorders of impaired pancreatic β cell function. The mechanisms underlying MODY include β cell KATP channel dysfunction (e.g., KCNJ11 [MODY13] or ABCC8 [MODY12] mutations); however, no other β cell channelopathies have been associated with MODY to date. Here, we have identified a nonsynonymous coding variant in KCNK16 (NM_001135105: c.341T>C, p.Leu114Pro) segregating with MODY. KCNK16 is the most abundant and β cell-restricted K+ channel transcript, encoding the two-pore-domain K+ channel TALK-1. Whole-cell K+ currents demonstrated a large gain of function with TALK-1 Leu114Pro compared with TALK-1 WT, due to greater single-channel activity. Glucose-stimulated membrane potential depolarization and Ca2+ influx were inhibited in mouse islets expressing TALK-1 Leu114Pro with less endoplasmic reticulum Ca2+ storage. TALK-1 Leu114Pro significantly blunted glucose-stimulated insulin secretion compared with TALK-1 WT in mouse and human islets. These data suggest that KCNK16 is a previously unreported gene for MODY.
青少年发病的成年型糖尿病（MODY）是一组胰腺β细胞功能障碍的遗传异质性疾病。MODY 的发病机制包括β细胞 KATP 通道功能障碍（例如，KCNJ11[MODY13]或 ABCC8[MODY12]突变）；然而，迄今为止，尚未有其他β细胞通道病与 MODY 相关。在这里，我们鉴定了与 MODY 共分离的 KCNK16（NM_001135105：c.341T>C，p.Leu114Pro）中的非同义编码变异。KCNK16 是最丰富和β细胞特异性的 K+通道转录本，编码双孔域 K+通道 TALK-1。与 TALK-1 WT 相比，TALK-1 Leu114Pro 的全细胞 K+电流具有较大的功能获得，这是由于单通道活性增加。与表达 TALK-1 Leu114Pro 的小鼠胰岛相比，葡萄糖刺激的膜电位去极化和 Ca2+内流受到抑制，内质网 Ca2+储存减少。与 TALK-1 WT 相比，TALK-1 Leu114Pro 显著减弱了小鼠和人胰岛的葡萄糖刺激胰岛素分泌。这些数据表明 KCNK16 是以前未报道的 MODY 相关基因。
