caa a22 4500 397573235 CHVBK 20180308164847.0 cr unu---uuuuu 161202e199609 xx s 000 0 eng 10.1093/hmg/5.9.1319 doi (NATIONALLICENCE)oxford-10.1093/hmg/5.9.1319 KVLQT1 Mutations in Three Families with Familial or Sporadic Long QT Syndrome [Elektronische Daten] [Mark W. Russell, Macdonald Dick, Francis S. Collins, Lawrence C. Brody] Congenital long QT syndrome (LQTS) is a heterogeneous group of heritable disorders characterized by prolongation of the QT interval on the electrocardiogram, ventricular arrhythmias and sudden death. At least four genes can, when mutated, produce this phe-notype. Of these genes, the recently identified KVLQT1 potassium channel is thought to be the one most commonly responsible. In this study, we used single strand conformational polymorphism (SSCP) analysis to screen two large and nine small LQTS families for mutations of the KVLQT1 potassium channel gene. We identified a novel missense mutation in two unrelated families which substitutes a serine for a conserved glycine in the putative pore region of the KVLQT1 channel. In a third family, a new alanine to valine mutation at a CpG dinucleotide resulted in the spontaneous occurrence of the long QT syndrome in monozygotic twin offspring of unaffected parents. Mutations at this same nucleotide have been observed in eight of the 19 LQTS families determined to have KVLQT1 mutations, suggesting this is a mutational hot spot. Both of these mutations alter the amino acid sequence in, or adjacent to, the pore of the channel and may diminish the channel's ability to conduct a repolarizing potassium current. To date, all KVLQT1 mutations determined to cause the LQTS are missense mutations. These data confirm the role of KVLQT1 in the LQTS and suggest that mutant KVLQT1 proteins may exert a dominant negative effect on repolarizing potassium currents by forming multimers with normal potassium channel protein subunits, dramatically reducing the number of fully-functional KVLQT1 channels. © 1996 Oxford University Press Russell Mark W. Division of Pediatric Cardiology, University of Michigan, C.S. Mott Children's Hospital, MCHC F1310/ Box 0204, 1500 E. Medical Ctr. Dr., Ann Arbor, MI 48109-0204, USA aut Dick Macdonald Division of Pediatric Cardiology, University of Michigan, C.S. Mott Children's Hospital, MCHC F1310/ Box 0204, 1500 E. Medical Ctr. Dr., Ann Arbor, MI 48109-0204, USA aut Collins Francis S. Division of Pediatric Cardiology, University of Michigan, C.S. Mott Children's Hospital, MCHC F1310/ Box 0204, 1500 E. Medical Ctr. Dr., Ann Arbor, MI 48109-0204, USA aut Brody Lawrence C. Division of Pediatric Cardiology, University of Michigan, C.S. Mott Children's Hospital, MCHC F1310/ Box 0204, 1500 E. Medical Ctr. Dr., Ann Arbor, MI 48109-0204, USA aut Human Molecular Genetics Oxford University Press 5/9(1996-09), 1319-1324 0964-6906 5:9<1319 1996 5 hmg https://doi.org/10.1093/hmg/5.9.1319 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1093/hmg/5.9.1319 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Russell Mark W. Division of Pediatric Cardiology, University of Michigan, C.S. Mott Children's Hospital, MCHC F1310/ Box 0204, 1500 E. Medical Ctr. Dr., Ann Arbor, MI 48109-0204, USA aut NATIONALLICENCE 700 1- Dick Macdonald Division of Pediatric Cardiology, University of Michigan, C.S. Mott Children's Hospital, MCHC F1310/ Box 0204, 1500 E. Medical Ctr. Dr., Ann Arbor, MI 48109-0204, USA aut NATIONALLICENCE 700 1- Collins Francis S. Division of Pediatric Cardiology, University of Michigan, C.S. Mott Children's Hospital, MCHC F1310/ Box 0204, 1500 E. Medical Ctr. Dr., Ann Arbor, MI 48109-0204, USA aut NATIONALLICENCE 700 1- Brody Lawrence C. Division of Pediatric Cardiology, University of Michigan, C.S. Mott Children's Hospital, MCHC F1310/ Box 0204, 1500 E. Medical Ctr. Dr., Ann Arbor, MI 48109-0204, USA aut NATIONALLICENCE 773 0- Human Molecular Genetics Oxford University Press 5/9(1996-09), 1319-1324 0964-6906 5:9<1319 1996 5 hmg Metadata rights reserved CC BY-NC-4.0 http://creativecommons.org/licenses/by-nc/4.0 nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-oxford