Genomic Organization of the KCNQ1 K ⁺ Channel Gene and Identification of C-Terminal Mutations in the Long-QT Syndrome

Abstract

Abstract-The voltage-gated Kϩ channel KVLQT1 is essential for the repolarization phase of the cardiac action potential and for K ϩ homeostasis in the inner ear. Mutations in the human KCNQ1 gene encoding the ␣ subunit of the KVLQT1 channel cause the long-QT syndrome (LQTS). The autosomal dominant form of this cardiac disease, the Romano-Ward syndrome, is characterized by a prolongation of the QT interval, ventricular arrhythmias, and sudden death. The autosomal recessive form, the Jervell and Lange-Nielsen syndrome, also includes bilateral deafness. In the present study, we report the entire genomic structure of KCNQ1, which consists of 19 exons spanning 400 kb on chromosome 11p15.5. We describe the sequences of exon-intron boundaries and oligonucleotide primers that allow polymerase chain reaction (PCR) amplification of exons from genomic DNA. Two new (CA) n repeat microsatellites were found in introns 10 and 14. The present study provides helpful tools for the linkage analysis and mutation screening of the complete KCNQ1 gene. By use of these tools, five novel mutations were identified in LQTS patients by PCR-single-strand conformational polymorphism (SSCP) analysis in the C-terminal part of KCNQ1: two missense mutations, a 20-bp and 1-bp deletions, and a 1-bp insertion. Such mutations in the C-terminal domain of the gene may be more frequent than previously expected, because this region has not been analyzed so far. This could explain the low percentage of mutations found in large LQTS cohorts. (Circ Res. 1999;84:290-297.)

Basolateral localisation of KCNQ1 potassium channels in MDCK cells: molecular identification of an N-terminal targeting motif

“…8). The sKvLQT1 sequence is 95 residues shorter than wt-KCNQ1, indicated by ∆95, and the first 11 amino acids is non-homologous to wt-KCNQ1 (Neyroud et al, 1999). transition mutants, 2xL-A-KCNQ1, Y51A-KCNQ1, Y111A-KCNQ1 and Y111C-KCNQ1, were analysed in both MDCK cells and Xenopus oocytes.…”

A maternal deletion upstream of the imprint control region 2 in 11p15 causes loss of methylation and familial Beckwith–Wiedemann syndrome

“…The green star indicates the location of the MLPA probe (L02903) within exon 1b of KCNQ1. Exon numbering according to Cerrato et al 17 and Neyroud et al 18 Not drawn to scale. …”

“…In addition, the deletion includes the 5′ region of the imprinted gene KCNQ1 but not the ICR2, which is aberrantly methylated in both twins (telomeric to centromeric orientation; Figure 5a). The deletion abolishes the start exons of both transcript variants of KCNQ1 and a large part of intron 1 (exon 1 of NM_000218.2 and CCDS7736.1 and the alternative exon 1 of NM_181798.1; equals exons 1a and 1b according to the numbering by Cerrato et al 17 and Neyroud et al; 18 Figure 5b). Furthermore, none of the putative enhancer regions for CDKN1C are affected by the deletion (Figure 5b).…”

Evolution of the Beckwith-Wiedemann syndrome region in vertebrates

“…AJ006345, Neyroud et al 1999). Kcnq1 exons in other species were identified by BLAST comparison (http:// www.ncbi.nlm.nih.gov/BLAST/) of the human KCNQ1 protein sequence to the translated genomic DNA sequence of the species of interest.…”