ABCMdb

ABCC9 p.Arg1154Gln

ClinVar:	c.3461G>A , p.Arg1154Gln D , Pathogenic c.3460C>T , p.Arg1154Trp D , Pathogenic
Predicted by SNAP2:	A: D (63%), C: D (75%), D: D (91%), E: D (80%), F: D (66%), G: D (63%), H: D (85%), I: N (57%), K: D (59%), L: N (66%), M: N (57%), N: D (63%), P: D (85%), Q: D (53%), S: D (53%), T: N (53%), V: N (57%), W: D (91%), Y: D (85%),
Predicted by PROVEAN:	A: N, C: D, D: D, E: N, F: D, G: D, H: N, I: N, K: N, L: N, M: N, N: N, P: D, Q: N, S: N, T: N, V: N, 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
19 Phenotype of Individuals with Cantu &#b4; Syndrome Clinical Features Affected Individuals 1 2a 2b 2c 3 4 5 6 7 8a 8b 9a 9b 10 Gender M F F F M F M F M F M M F M Mutation (cDNA) 3460C>T 3461G>A 3461G>A 3461G>A 3461G>A 3460C>T 3460C>T 3128G>A 3461G>T 1433C>T 1433C>T - - - Alteration (protein) Arg1154Trp Arg1154Gln Arg1154Gln Arg1154Gln Arg1154Gln Arg1154Trp Arg1154Trp Cys1043Tyr Arg1154Gln Ala478Val Ala478Val - - - Inherited de novo inherited inherited de novo de novo de novo de novo de novo inherited Consanguinity &#fe; - - - - - &#fe; - - - &#fe; &#fe; &#fe; - Age at evaluation 4 m 16 yrs 10 yrs 39 yrs 8 yrs 21 yrs 3.5 m 4.5 yrs 9.8 yrs 4 m 32 yrs 6 yrs 4 yrs 3 m Alive - &#fe; &#fe; &#fe; &#fe; &#fe; &#fe; &#fe; &#fe; &#fe; &#fe; &#fe; - &#fe; Congenital hypertrichosis &#fe; &#fe; &#fe; &#fe; &#fe; &#fe; &#fe; &#fe; &#fe; &#fe; &#fe; &#fe; &#fe; &#fe; Macrosomia at birth &#fe; - &#fe; &#fe; - &#fe; - &#fe; - &#fe; &#fe; - - &#fe; Macrocephaly &#fe; &#fe; &#fe; &#fe; &#fe; - &#fe; &#fe; &#fe; &#fe; &#fe; &#fe; &#fe; &#fe; ID* and/or developmental delay - - - - &#fe; - &#fe; - - &#fe; - &#fe; &#fe; &#fe; Facial Features Coarse face &#fe; &#fe; &#fe; &#fe; &#fe; &#fe; &#fe; &#fe; &#fe; &#fe; &#fe; &#fe; &#fe; &#fe; Epicanthal folds &#fe; &#fe; &#fe; &#fe; &#fe; &#fe; &#fe; &#fe; &#fe; &#fe; &#fe; &#fe; &#fe; - Abundant and/or curly eyelashes &#fe; &#fe; &#fe; - &#fe; - &#fe; &#fe; &#fe; &#fe; - &#fe; &#fe; &#fe; Broad and/or flat nasal bridge &#fe; &#fe; &#fe; &#fe; &#fe; - &#fe; &#fe; &#fe; &#fe; &#fe; &#fe; &#fe; &#fe; Small nose and/or anteverted nostrils &#fe; &#fe; &#fe; &#fe; &#fe; &#fe; &#fe; &#fe; &#fe; &#fe; - - - &#fe; Prominent mouth and/or thick lips &#fe; &#fe; &#fe; &#fe; &#fe; &#fe; &#fe; &#fe; &#fe; &#fe; &#fe; &#fe; &#fe; &#fe; Long philtrum &#fe; &#fe; &#fe; &#fe; &#fe; &#fe; &#fe; &#fe; &#fe; &#fe; &#fe; &#fe; &#fe; &#fe; High and/or narrow palate &#fe; &#fe; &#fe; &#fe; - &#fe; &#fe; - - - &#fe; &#fe; &#fe; - Macroglossy &#fe; &#fe; &#fe; &#fe; - &#fe; &#fe; - - - &#fe; - - - Anterior open bite - &#fe; &#fe; - - &#fe; - - - - - - - Gingival hyperplasia &#fe; &#fe; &#fe; &#fe; - &#fe; &#fe; - - &#fe; - - - - Short neck - - - &#fe; &#fe; - &#fe; &#fe; &#fe; - - &#fe; &#fe; &#fe; (Continued on next page) Table 1. Login to comment

[hide] Dominant missense mutations in ABCC9 cause Cantu s... Nat Genet. 2012 May 18;44(7):793-6. doi: 10.1038/ng.2324. Harakalova M, van Harssel JJ, Terhal PA, van Lieshout S, Duran K, Renkens I, Amor DJ, Wilson LC, Kirk EP, Turner CL, Shears D, Garcia-Minaur S, Lees MM, Ross A, Venselaar H, Vriend G, Takanari H, Rook MB, van der Heyden MA, Asselbergs FW, Breur HM, Swinkels ME, Scurr IJ, Smithson SF, Knoers NV, van der Smagt JJ, Nijman IJ, Kloosterman WP, van Haelst MM, van Haaften G, Cuppen E
Dominant missense mutations in ABCC9 cause Cantu syndrome.
Nat Genet. 2012 May 18;44(7):793-6. doi: 10.1038/ng.2324., [PMID:22610116]

Abstract [show]
Cantu syndrome is characterized by congenital hypertrichosis, distinctive facial features, osteochondrodysplasia and cardiac defects. By using family-based exome sequencing, we identified a de novo mutation in ABCC9. Subsequently, we discovered novel dominant missense mutations in ABCC9 in 14 of the 16 individuals with Cantu syndrome examined. The ABCC9 protein is part of an ATP-dependent potassium (K(ATP)) channel that couples the metabolic state of a cell with its electrical activity. All mutations altered amino acids in or close to the transmembrane domains of ABCC9. Using electrophysiological measurements, we show that mutations in ABCC9 reduce the ATP-mediated potassium channel inhibition, resulting in channel opening. Moreover, similarities between the phenotype of individuals with Cantu syndrome and side effects from the K(ATP) channel agonist minoxidil indicate that the mutations in ABCC9 result in channel opening. Given the availability of ABCC9 antagonists, our findings may have direct implications for the treatment of individuals with Cantu syndrome.

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Sentences [show]
No. Sentence Comment
31 The encoded p.Arg1154Gln variant is most likely damaging (predicted to be probably damaging, deleterious and deleterious by Polyphen-2, Condel and SIFT, respectively, using the Variant Effect Predictor tool (ENSEMBL version 67)) and highly conserved (Genomic Evolutionary Rate Profiling (GERP) scores of 4.33 (35 way)). Login to comment
59 The nucleotide-binding Table 1 Summary of detected heterozygous missense mutations in ABCC9 Subject Chr. Genomic alterationa cDNA alteration Protein alteration 9 12 g.22086822C>T c.178C>T p.His60Tyr 7 12 g.22068797C>A c.621C>A p.Asp207Glu 10 12 g.22063786G>T c.1138G>T p.Gly380Cys 5 12 g.22063116C>T c.1295C>T p.Pro432Leu 12 12 g.21998575T>C c.3058T>C p.Ser1020Pro 16 12 g.21997830T>C c.3116>C p.Phe1039Ser 15 12 g.21997785C>A c.3161>A p.Ser1054Tyr 2,3 (child and mother) 12 g.21995374G>A c.3347G>A p.Arg1116His 14 12 g.21995375C>T c.3346C>T p.Arg1116Cys 4 12 g.21995261C>T c.3460C>T p.Arg1154Trp 1,6,8 12 g.21995260G>A c.3461G>A p.Arg1154Gln Chr., chromosome. Login to comment
62 a b NBD2 NBD1 TMD2 TMD1 TMD0 p.His60Tyr p.Asp207Glu p.Gly380Cys p.Pro432Leu p.Ser1020Pro p.Phe1039Ser p.Ser1054Tyr p.Arg1116Cys p.Arg1116His p.Arg1116His* p.Arg1154Gln p.Arg1154Gln p.Arg1154Gln p.Arg1154Trp Figure 1 Clinical presentation of subjects with Cant&#fa; syndrome and mutations in ABCC9. Login to comment
81 In contrast, ABCC9 p.Arg1154Gln (0.88 &#b1; 0.19 and 0.76 &#b1; 0.12 mM for inward and outward components, respectively), ABCC9 p.Pro432Leu (1.18 &#b1; 0.18 and 1.25 &#b1; 0.16 mM) and ABCC9 p.Arg1116His(0.28&#b1;0.05and0.24&#b1;0.04mM)mutantchannelsshowed reduced ATP sensitivity. Login to comment
88 The similarities between the phenotypic characteristics of individuals with Cant&#fa; -2,000 -1,500 -1,000 -500 0 500 1,000 1,500 -2,000 -1,500 -1,000 -500 0 500 1,000 1,500 -2,000 -1,500 -1,000 -500 0 500 1,000 1,500 -2,000 -1,500 -1,000 -500 0 500 1,000 1,500 WT p.Pro432Leu p.Arg1116His p.Arg1154Gln C 0.1 1.0 10 C, 0.1 1.0 10 C 0.1 1.0 10 C 0.1 1.0 10 0.0 0.01 0.1 1 10 ATP (mM) 0 20 40 60 80 100 Remaining current (%) Inward 0.0 0.01 0.1 1 10 ATP (mM) Outward 0 20 40 60 80 100 Remaining current (%) WT p.Arg1154Gln IC 50 0.88 &#b1; 0.19* p.Pro432Leu IC 50 1.18 &#b1; 0.18** p.Arg1116His IC 50 0.28 &#b1; 0.05*** WT IC 50 0.07 &#b1; 0.01 p.Arg1154Gln IC 50 0.76 &#b1; 0.12* p.Pro432Leu IC 50 1.25 &#b1; 0.16** p.Arg1116His IC 50 0.24 &#b1; 0.04*** Asp207 Arg1154 Pro432 Ser1020 Phe1039 Arg1116 Ser1054 Gly380 Current (pA) Current (pA) Current (pA) Current (pA) -100 100 0 Membrane potential (mV) IC 50 0.07 &#b1; 0.01 a b c Figure 2 Topology and biophysical effect of ABCC9 mutations. Login to comment
98 Wild-type ABCC9, n = 8; ABCC9 p.Arg1154Gln, n = 7; ABCC9 p.Pro432Leu, n = 6; ABCC9 p.Arg1116His, n = 5. Login to comment
227 Nucleotide changes encoding the p.Arg1154Gln, p.Pro432Leu and p.Arg1116His alterations were engineered into the ABCC9 expression construct using the QuikChange II XL Site-Directed Mutagenesis Kit (Stratagene) and custom-designed mutagenesis primers. Login to comment