ABCMdb

PMID: 16563363

Minoretti P, Falcone C, Aldeghi A, Olivieri V, Mori F, Emanuele E, Calcagnino M, Geroldi D
A novel Val734Ile variant in the ABCC9 gene associated with myocardial infarction.
Clin Chim Acta. 2006 Aug;370(1-2):124-8. Epub 2006 Mar 6., [PubMed]

Sentences

No. Mutations Sentence Comment

0 ABCC9 p.Val734Ile A novel Val734Ile variant in the ABCC9 gene associated with myocardial infarction Piercarlo Minoretti a,b , Colomba Falcone b,c , Alessia Aldeghi b , Valentina Olivieri b , Francesca Mori c , Enzo Emanuele b , Margherita Calcagnino c , Diego Geroldi b,⁎ a Department of Cardiology, Alessandro Manzoni Hospital of Lecco, Lecco, Italy b Interdepartmental Center for Research in Molecular Medicine (CIRMC), University of Pavia, Viale Taramelli 24, I-27100, Pavia, Italy c Department of Cardiology, IRCCS San Matteo Hospital, University of Pavia, Pavia, Italy Received 11 January 2006; received in revised form 1 February 2006; accepted 1 February 2006 Available online 6 March 2006 Abstract Background: Alterations in coronary vasomotor tone are deemed to play an important role in myocardial infarction (MI), and the ATP-binding cassette transporter C9-ABCC9-may be involved in the regulation of coronary artery vasomotility. Login to comment 3 ABCC9 p.Val734Ile Results: A novel missense mutation, Val734Ile in exon 17, was detected in one MI patient. Login to comment 55 ABCC9 p.Val734Ile Genotyping of the missense variant Val734Ile by TspRI digestion PCR for ABCC9 exon 17 was performed with the upstream primer 5'-CCTGACGTGTATGCACATTG-3', and the downstream primer 5'-TCAGAGTAAGCAAAATGAGAT- TAAAGA-3', in a final volume of 50μL. PCR conditions were as follows: 95 °C for 90 s, 35 cycles of a 94 °C denaturing step for 30 s, a 58 °C annealing step for 45 s, and a 72 °C extension for 60 s, followed by a final extension at 72 °C for 5 min, resulting in a 197 bp fragment. Login to comment 83 ABCC9 p.Val734Ile Additionally, together with a 11bp deletion in the 5'UTR of exon 6, our analysis revealed three previously unidentified genetic variants: IVS21+44C>A, IVS26+8G>A, and a heterozygous missense mutation in exon 17, Val734Ile (Fig. 1). Login to comment 86 ABCC9 p.Val734Ile Of the detected genetic variants, we selected the missense Val734Ile mutation for subsequent genetic studies because of its potential functional relevance. Login to comment 88 ABCC9 p.Val734Ile ABCC9 p.Val734Ile Analysis of the Val734Ile variant The Val734Ile variant was typed in the large case-control cohort by using a PCR-RFLPs approach. Login to comment 92 ABCC9 p.Val734Ile Sequencing chromatogram of ABCC9 exon 17 (GenBank Accession: AF061304) showing a heterozygous G>A substitution (arrow) resulting in the missense Val734Ile mutation. Login to comment 101 ABCC9 p.Val734Ile Discussion In our initial screening of the entire coding region of the ABCC9 gene, we found a novel missense Val734Ile mutation in exon 17 from a patient with precocious myocardial infarction. Login to comment 106 ABCC9 p.Val734Ile In the next future, it would be important to know the functional significance of the missense Val734Ile variant in the ABCC9 gene. Login to comment 108 ABCC9 p.Val734Ile Given the high degree of conservation of the Val734 residue across different species, and the reduction in ATP sensitivity that results with the removal of exon 17 from ABCC9 [12], it would be tempting to speculate that the Val734Ile mutation would affect the risk of myocardial infarction by altering nucleotide responsiveness of ABCC9-containing KATP channels. Login to comment 112 ABCC9 p.Val734Ile Alternatively, another potential explanation for the association between the Val734Ile variant and MI may involve the role played by KATP channels against ischemia/reperfusion injury. Login to comment 116 ABCC9 p.Val734Ile Firstly, we are aware that the chief limitation of our study is the lack of a functional characterization of the Val734Ile mutation. Login to comment 124 ABCC9 p.Val734Ile Hence, because the Val734Ile mutation was found to be associated with precocious MI but not with arterial hypertension, it remains to be addressed whether alterations of vascular tone could actually represent the real pathophysiological link behind the identified association between the 734Ile allele and ischemic heart disease. Login to comment 125 ABCC9 p.Val734Ile Although the precise functional link between the Val734Ile mutation in ABCC9 and MI has yet to be elucidated, we believe that our present data provide novel important evidences that genetic defects in KATP channels could be associated with life-threatening cardiac diseases, possibly resulting from the inability of the channel complex to optimally fulfill their physiological role [17,18]. Login to comment 126 ABCC9 p.Val734Ile Table 2 Genotype and allele distribution of the Val734Ile variant of the ABCC9 gene in precocious MI patients and healthy comparison subjects Subject group n Genotype (%) Allele frequency (%) Val/Val Val/Ile Ile/Ile P Val Ile P Precocious MI 584 573 (98.1%) 11 (1.9%) 0 (0%) 0.0074 1157 (99.0%) 11 (1.0%) 0.0075 Control subjects 873 870 (99.7%) 3 (0.3%) 0 (0%) 1743 (99.8%) 3 (0.2%) P values are calculated by means of χ2 tests. Login to comment