A KCNK16 mutation causing TALK-1 gain of function is associated with maturity-onset diabetes of the young
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:6 |
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| Enthalten in: |
JCI insight - 6(2021), 13 vom: 08. Juli |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Graff, Sarah M [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 11.02.2022 Date Revised 28.01.2024 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1172/jci.insight.138057 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM325818134 |
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| 100 | 1 | |a Graff, Sarah M |e verfasserin |4 aut | |
| 245 | 1 | 2 | |a A KCNK16 mutation causing TALK-1 gain of function is associated with maturity-onset diabetes of the young |
| 264 | 1 | |c 2021 | |
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| 500 | |a Date Revised 28.01.2024 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Calcium signaling | |
| 650 | 4 | |a Diabetes | |
| 650 | 4 | |a Endocrinology | |
| 650 | 4 | |a Genetics | |
| 650 | 4 | |a Ion channels | |
| 650 | 7 | |a Blood Glucose |2 NLM | |
| 650 | 7 | |a KCNK16 protein, human |2 NLM | |
| 650 | 7 | |a Kcnk16 protein, mouse |2 NLM | |
| 650 | 7 | |a Potassium Channels, Tandem Pore Domain |2 NLM | |
| 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 Dickerson, Matthew T |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 Zaborska, Karolina E |e verfasserin |4 aut | |
| 700 | 1 | |a Schaub, Charles M |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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