4600/208 N. Matsuda et al.: EGF receptor and osteoblastic differentiationJ Hum Genet (2002) 47:208212 Jpn Soc Hum Genet and Springer-Verlag 2002
Hiroyasu Iwasa Masahiko Kurabayashi Ryozo NagaiYusuke Nakamura Toshihiro Tanaka
Twenty single-nucleotide polymorphisms in four genes encoding cardiacion channels
Received: January 7, 2002 / Accepted: January 29, 2002
Since mutations in any of these five genes can be detectedin nearly 40% of LQTS families, this syndrome in the re-maining families is likely to be caused by other unknowngenes.
Voltage-gated ion channels play important roles in theexcitement of cardiomyocytes, and all the genes responsiblefor LQTS identified so far belong to this group. Althoughmany channel proteins have been identified at present, onlya few have been reported to be involved in cardiac excite-ment. For example, in mice, decreased expression of Kv1.5,encoded by KCNA5, prolongs QT-intervals of ECGs(London et al. 1998), and hKv1.3, encoded by alternativesplicing of KCNAB1, is expressed in human ventricle andalters the functional properties of hKv1.5 (England et al.1995). A novel class of auxiliary proteins for Kv4 subunits,K-channel interacting proteins (KChIPs), modulates thetransient inward potassium current (Ito) (An et al. 2000).KChIP2, encoded by KCNIP2, is expressed with a steepgradient across the human ventricle and might be involvedin the transmural gradient of Ito in the free ventricular wall(Rosati et al. 2001), and KChIP2/ mice are susceptible tocardiac arrhythmias (Kuo et al. 2001). An inward calciumion current generated by an L-type voltage-dependent cal-cium ion channel, encoded by CACNA1C, is implicated inearly afterdepolarizations (January and Riddle 1989), oscil-lations in cell membrane voltage thought to initiatearrhythmias caused by long-QT syndrome.
Here we report single-nucleotide polymorphisms (SNPs)and other genetic variations found in four genes encodingcardiac ion channels along with their allelic frequenciesamong normal and LQTS-affected Japanese subjects.
Subjects and methods
In the course of a search for mutations in these candidategenes in 73 unrelated Japanese LQTS patients, we identi-fied genetic variations. Our screening method was describedpreviously (Itoh et al. 1998). In brief, we prepared genomicDNA from blood samples according to standard protocols,
Abstract We here report 20 novel single-nucleotide poly-morphisms in four genes that are potentially involved in theexcitement of cardiomyocytes: 1 in KCNA5 (encodingKv1.5), 5 in KCNAB1 (encoding Kv1.3), 5 in KCNIP2(encoding KChIP2), and 9 in CACNA1C (encoding acardiac L-type voltage-dependent calcium ion channel,dihydropyridine receptor). We also examined their allelicfrequencies in Japanese individuals. These data will be use-ful for genetic association studies designed to investigatesecondary long QT syndrome or other circulatory disorders.
Key words Long QT syndrome Single-nucleotide poly-morphism Japanese population Voltage-gated potassiumion channel KChIP L-type voltage-dependent calcium ionchannel
Long QT syndrome (LQTS), an arrhythmogenic disordercharacterized by prolongation of the QT interval on electro-cardiograms (ECGs), often causes syncope or sudden car-diac death as a result of recurrent and lethal arrhythmia.Five genes in which inherited mutations are responsible forthis syndrome have been identified to date: KCNA9(KVLQT1, KCNQ1), KCNH2 (HERG), KCNE1, KCNE2,and SCN5A (Bennett et al. 1995; Curran et al. 1995; Wanget al. 1996a, b; Splawski et al. 1997; Abbott et al. 1999).
H. Iwasa Y. Nakamura T. Tanaka (*)Laboratory of Molecular Medicine, Human Genome Center,Institute of Medical Science, University of Tokyo, 4-6-1Shirokanedai, Minato-ku, Tokyo 108-8639, JapanTel. 81-3-5449-5375; Fax 81-3-5449-5406e-mail: email@example.com
H. Iwasa M. KurabayashiSecond Department of Internal Medicine, Gunma University Schoolof Medicine, Gunma, Japan
R. NagaiDepartment of Cardiovascular Medicine, Graduate School ofMedicine, University of Tokyo, Tokyo, Japan