Identification and characterisation of a novel KCNQ1 mutation in a family with Romano−Ward syndrome

Romano−Ward syndromenext term (RWS), the autosomal dominant form of the congenital long QT previous termsyndrome,next term is characterised by prolongation of the cardiac repolarisation process associated with ventricular tachyarrhythmias of the torsades de pointes type. Genetic studies have identified previous termmutations innext term six ion channel genes, previous termKCNQ1,next term KCNH2, SCN5A, KCNE1 and KCNE2 and the accessory protein Ankyrin−B gene, to be responsible for this disorder. Single−strand conformation polymorphism (SSCP) analysis and subsequent DNA sequence analysis have identified previous terma KCNQ1 mutation in a familynext term that were clinically conspicuous due to several syncopes and prolonged QTc intervals previous terminnext term the ECG. The mutant subunit was expressed and functionally characterised previous terminnext term the Xenopus oocyte expression system. previous termA novelnext term heterozygous missense previous termmutation with anext term C to T transition at the first position of codon 343 (CCA) of the previous termKCNQ1next term gene was identified previous terminnext term three concerned previous termfamilynext term members (QTc intervals: 500, 510 and 530 ms, respectively). As previous termanext term result, proline 343 localised within the highly conserved transmembrane segment S6 of the previous termKCNQ1next term channel is replaced by previous termanext term serine. Co−expression of mutant (previous termKCNQ1next term−P343S) and wild−type (previous termKCNQ1)next term cRNA previous terminnext term Xenopus oocytes produced potassium currents reduced by ≈92%, while IKs reconstitution experiments with previous termanext term combination of previous termKCNQ1next term mutant, wild−type and KCNE1 subunits yielded currents reduced by ≈60%. previous termA novel mutationnext term (P343S) identified previous termin the KCNQ1next term subunit gene of three members of previous termanext term RWS previous termfamilynext term showed previous termanext term dominant−negative effect on native IKs currents leading to prolongation of the heart repolarisation and possibly increases the risk of malign arrhythmias with sudden cardiac death