ABCMdb

PMID: 22610116

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., [PubMed]

Sentences

No. Mutations Sentence Comment

31 ABCC9 p.Arg1154Gln 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 40 ABCC9 p.Pro432Leu The p.Pro432Leu alteration would render hinge-bending motion more difficult, thereby inhibiting conformational changes. Login to comment 59 ABCC9 p.Arg1154Gln ABCC9 p.Arg1154Trp ABCC9 p.Pro432Leu ABCC9 p.Gly380Cys ABCC9 p.Arg1116Cys ABCC9 p.Asp207Glu ABCC9 p.Ser1020Pro ABCC9 p.Phe1039Ser ABCC9 p.Ser1054Tyr ABCC9 p.His60Tyr ABCC9 p.Arg1116His 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 ABCC9 p.Arg1154Gln ABCC9 p.Arg1154Gln ABCC9 p.Arg1154Gln ABCC9 p.Arg1154Trp ABCC9 p.Pro432Leu ABCC9 p.Gly380Cys ABCC9 p.Arg1116Cys ABCC9 p.Asp207Glu ABCC9 p.Ser1020Pro ABCC9 p.Phe1039Ser ABCC9 p.Ser1054Tyr ABCC9 p.His60Tyr ABCC9 p.Arg1116His 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 ABCC9 p.Arg1154Gln ABCC9 p.Pro432Leu 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 ABCC9 p.Arg1154Gln ABCC9 p.Arg1154Gln ABCC9 p.Arg1154Gln ABCC9 p.Pro432Leu ABCC9 p.Pro432Leu ABCC9 p.Pro432Leu ABCC9 p.Arg1116His ABCC9 p.Arg1116His ABCC9 p.Arg1116His 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 ABCC9 p.Arg1154Gln ABCC9 p.Pro432Leu ABCC9 p.Arg1116His Wild-type ABCC9, n = 8; ABCC9 p.Arg1154Gln, n = 7; ABCC9 p.Pro432Leu, n = 6; ABCC9 p.Arg1116His, n = 5. Login to comment 227 ABCC9 p.Arg1154Gln ABCC9 p.Pro432Leu ABCC9 p.Arg1116His 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