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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Preprint| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
bioRxiv.org - (2021) vom: 26. Feb. Zur Gesamtaufnahme - year:2021 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Graff, Sarah M [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| doi: |
10.1101/2020.02.04.929430 |
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| PPN (Katalog-ID): |
XBI000723193 |
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| 100 | 1 | |a Graff, Sarah M |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a A novel mutation inKCNK16causing a gain-of-function in the TALK-1 potassium channel: a new cause of maturity onset diabetes of the young |
| 264 | 1 | |c 2021 | |
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| 520 | |a 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. | ||
| 700 | 1 | |a Johnson, Stephanie R |e verfasserin |4 aut | |
| 700 | 1 | |a Leo, Paul J |e verfasserin |4 aut | |
| 700 | 1 | |a Dadi, Prasanna K |e verfasserin |4 aut | |
| 700 | 1 | |a Nakhe, Arya Y |e verfasserin |4 aut | |
| 700 | 1 | |a McInerney-Leo, Aideen M |e verfasserin |4 aut | |
| 700 | 1 | |a Marshall, Mhairi |e verfasserin |4 aut | |
| 700 | 1 | |a Brown, Matthew A |e verfasserin |4 aut | |
| 700 | 1 | |a Jacobson, David A |e verfasserin |4 aut | |
| 700 | 1 | |a Duncan, Emma L |e verfasserin |4 aut | |
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