ABCC8 p.Pro1198Leu
| Predicted by SNAP2: | A: D (59%), C: D (59%), D: D (71%), E: D (66%), F: D (66%), G: D (66%), H: D (63%), I: D (63%), K: D (63%), L: D (63%), M: D (59%), N: D (66%), Q: D (63%), R: D (66%), S: D (59%), T: D (63%), V: D (63%), W: D (66%), Y: D (59%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, Q: D, R: D, S: D, T: D, V: D, W: D, Y: D, |
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[hide] Differential mechanisms of Cantu syndrome-associat... J Gen Physiol. 2015 Dec;146(6):527-40. doi: 10.1085/jgp.201511495. Cooper PE, Sala-Rabanal M, Lee SJ, Nichols CG
Differential mechanisms of Cantu syndrome-associated gain of function mutations in the ABCC9 (SUR2) subunit of the KATP channel.
J Gen Physiol. 2015 Dec;146(6):527-40. doi: 10.1085/jgp.201511495., [PMID:26621776]
Abstract [show]
Cantu syndrome (CS) is a rare disease characterized by congenital hypertrichosis, distinct facial features, osteochondrodysplasia, and cardiac defects. Recent genetic analysis has revealed that the majority of CS patients carry a missense mutation in ABCC9, which codes for the sulfonylurea receptor SUR2. SUR2 subunits couple with Kir6.x, inwardly rectifying potassium pore-forming subunits, to form adenosine triphosphate (ATP)-sensitive potassium (KATP) channels, which link cell metabolism to membrane excitability in a variety of tissues including vascular smooth muscle, skeletal muscle, and the heart. The functional consequences of multiple uncharacterized CS mutations remain unclear. Here, we have focused on determining the functional consequences of three documented human CS-associated ABCC9 mutations: human P432L, A478V, and C1043Y. The mutations were engineered in the equivalent position in rat SUR2A (P429L, A475V, and C1039Y), and each was coexpressed with mouse Kir6.2. Using macroscopic rubidium ((86)Rb(+)) efflux assays, we show that KATP channels formed with P429L, A475V, or C1039Y mutants enhance KATP activity compared with wild-type (WT) channels. We used inside-out patch-clamp electrophysiology to measure channel sensitivity to ATP inhibition and to MgADP activation. For P429L and A475V mutants, sensitivity to ATP inhibition was comparable to WT channels, but activation by MgADP was significantly greater. C1039Y-dependent channels were significantly less sensitive to inhibition by ATP or by glibenclamide, but MgADP activation was comparable to WT. The results indicate that these three CS mutations all lead to overactive KATP channels, but at least two mechanisms underlie the observed gain of function: decreased ATP inhibition and enhanced MgADP activation.
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No. Sentence Comment
240 Science. 245:177-180. http://dx.doi.org/10.1126/science.2501869 Takagi, T., H. Furuta, M. Miyawaki, K. Nagashima, T. Shimada, A. Doi,S.Matsuno,D.Tanaka,M.Nishi,H.Sasaki,etal.2013.Clinical and functional characterization of the Pro1198Leu ABCC8 gene mutation associated with permanent neonatal diabetes mellitus.
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ABCC8 p.Pro1198Leu 26621776:240:227
status: NEW