ABCC9 p.Ala478Val
| ClinVar: |
c.1433C>T
,
p.Ala478Val
D
, Pathogenic
|
| Predicted by SNAP2: | C: N (66%), D: N (61%), E: N (82%), F: N (53%), G: N (87%), H: N (82%), I: N (82%), K: N (93%), L: N (72%), M: N (66%), N: N (87%), P: N (53%), Q: N (87%), R: N (82%), S: N (97%), T: N (93%), V: N (78%), W: D (71%), Y: D (59%), |
| Predicted by PROVEAN: | C: N, D: N, E: N, F: D, G: N, H: D, I: D, K: N, L: D, M: D, N: N, P: D, Q: N, R: D, S: N, T: N, V: D, W: D, Y: D, |
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[hide] Cantu syndrome is caused by mutations in ABCC9. Am J Hum Genet. 2012 Jun 8;90(6):1094-101. doi: 10.1016/j.ajhg.2012.04.014. Epub 2012 May 17. van Bon BW, Gilissen C, Grange DK, Hennekam RC, Kayserili H, Engels H, Reutter H, Ostergaard JR, Morava E, Tsiakas K, Isidor B, Le Merrer M, Eser M, Wieskamp N, de Vries P, Steehouwer M, Veltman JA, Robertson SP, Brunner HG, de Vries BB, Hoischen A
Cantu syndrome is caused by mutations in ABCC9.
Am J Hum Genet. 2012 Jun 8;90(6):1094-101. doi: 10.1016/j.ajhg.2012.04.014. Epub 2012 May 17., [PMID:22608503]
Abstract [show]
Cantu syndrome is a rare disorder characterized by congenital hypertrichosis, neonatal macrosomia, a distinct osteochondrodysplasia, and cardiomegaly. Using an exome-sequencing approach applied to one proband-parent trio and three unrelated single cases, we identified heterozygous mutations in ABCC9 in all probands. With the inclusion of the remaining cohort of ten individuals with Cantu syndrome, a total of eleven mutations in ABCC9 were found. The de novo occurrence in all six simplex cases in our cohort substantiates the presence of a dominant disease mechanism. All mutations were missense, and several mutations affect Arg1154. This mutation hot spot lies within the second type 1 transmembrane region of this ATP-binding cassette transporter protein, which may suggest an activating mutation. ABCC9 encodes the sulfonylurea receptor (SUR) that forms ATP-sensitive potassium channels (K(ATP) channels) originally shown in cardiac, skeletal, and smooth muscle. Previously, loss-of-function mutations in this gene have been associated with idiopathic dilated cardiomyopathy type 10 (CMD10). These findings identify the genetic basis of Cantu syndrome and suggest that this is a new member of the potassium channelopathies.
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No. Sentence Comment
33 All other mutations (c.3128G>A [p.Cys1043Tyr] and c.1433C>T [p.Ala478Val]) also affected either TMD1 or TMD2.
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ABCC9 p.Ala478Val 22608503:33:63
status: NEW[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
17 Here, we have focused on determining the functional consequences of three documented human CS-associated ABCC9 mutations: human P432L, A478V, and C1043Y.
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ABCC9 p.Ala478Val 26621776:17:135
status: NEW57 ABCC9 mutagenesis and heterologous expression of KATP channels The Quick Change II Site-Directed Mutagenesis kit (Agilent Technologies) was used to engineer P429L, A475V, and C1039Y mutations (equivalent to CS-associated P432L, A478V, and C1043Y mutations in human SUR2; Harakalova et al., 2012; van Bon et al., 2012) into rat SUR2A-pCMV6.
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ABCC9 p.Ala478Val 26621776:57:228
status: NEW98 For the present study, we focused on two previously unexamined mutations (human A478V and C1043Y corresponding to rat A475V and Figure 7.ߓ P429L and A475V show enhanced MgADP activation.
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ABCC9 p.Ala478Val 26621776:98:80
status: NEW