A novel mutation inKCNK16causing a gain-of-function in the TALK-1 potassium channel: a new cause of maturity onset diabetes of the young

ABSTRACT Background Maturity-onset diabetes of the young (MODY) is a heterogeneous group of monogenic disorders of impaired glucose-stimulated insulin secretion (GSIS). Mechanisms include β-cell KATPchannel dysfunction (e.g.,KCNJ11(MODY13) orABCC8(MODY12) mutations); however, no other β-cell channelopathies have been identified in MODY.Methods A four-generation family with autosomal dominant non-obese, non-ketotic antibody-negative diabetes, without mutations in known MODY genes, underwent exome sequencing. Whole-cell and single-channel K+currents, Ca2+handling, and GSIS were determined in cells expressing either mutated or wild-type (WT) protein.Results We identified a novel non-synonymous genetic mutation inKCNK16(NM_001135105: c.341T>C, p.Leu114Pro) segregating with MODY.KCNK16is the most abundant and β-cell-restricted K+channel transcript and encodes the two-pore-domain K+channel TALK-1. Whole-cell K+currents in transfected HEK293 cells demonstrated drastic (312-fold increase) gain-of-function with TALK-1 Leu144Pro vs. WT, due to greater single channel activity. Glucose-stimulated cytosolic Ca2+influx was inhibited in mouse islets expressing TALK-1 Leu114Pro (area under the curve [AUC] at 20mM glucose: Leu114Pro 60.1 vs. WT 89.1;P=0.030) and less endoplasmic reticulum calcium storage (cyclopiazonic acid-induced release AUC: Leu114Pro 17.5 vs. WT 46.8;P=0.008). TALK-1 Leu114Pro significantly blunted GSIS compared to TALK-1 WT in both mouse (52% decrease,P=0.039) and human (38% decrease,P=0.019) islets.Conclusions Our data identify a novel MODY-associated gene,KCNK16; with a gain-of-function mutation limiting Ca2+influx and GSIS. A gain-of-function common polymorphism inKCNK16is associated with type 2 diabetes (T2DM); thus, our findings have therapeutic implications not only forKCNK16-associated MODY but also for T2DM..

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Electronic Article

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bioRxiv.org - (2021) vom: 26. Feb.




Graff, Sarah M [Author]
Johnson, Stephanie R [Author]
Leo, Paul J [Author]
Dadi, Prasanna K [Author]
Nakhe, Arya Y [Author]
McInerney-Leo, Aideen M [Author]
Marshall, Mhairi [Author]
Brown, Matthew A [Author]
Jacobson, David A [Author]
Duncan, Emma L [Author]


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