title: Cardiac potassium channel dysfunction in sudden infant death syndrome.
abstract: Life-threatening arrhythmias have been suspected as one cause of the sudden infant death syndrome (SIDS), and this hypothesis is supported by the observation that mutations in arrhythmia susceptibility genes occur in 5-10% of cases. However, the functional consequences of cardiac potassium channel gene mutations associated with SIDS and how these alleles might mechanistically predispose to sudden death are unknown. To address these questions, we studied four missense KCNH2 (encoding HERG) variants, one compound KCNH2 genotype, and a missense KCNQ1 mutation all previously identified in Norwegian SIDS cases. Three of the six variants exhibited functional impairments while three were biophysically similar to wild-type channels (KCNH2 variants V279M, R885C, and S1040G). When co-expressed with WT-HERG, R273Q and K897T/R954C generated currents resembling the rapid component of the cardiac delayed rectifier current (I(Kr)) but with significantly diminished amplitude. Action potential modeling demonstrated that this level of functional impairment was sufficient to evoke increased action potential duration and pause-dependent early afterdepolarizations. By contrast, KCNQ1-I274V causes a gain-of-function in I(Ks) characterized by increased current density, faster activation, and slower deactivation leading to accumulation of instantaneous current upon repeated stimulation. Action potential simulations using a Markov model of heterozygous I274V-I(Ks) incorporated into the Luo-Rudy (LRd) ventricular cell model demonstrated marked rate-dependent shortening of action potential duration predicting a short QT phenotype. Our results indicate that certain potassium channel mutations associated with SIDS confer overt functional defects consistent with either LQTS or SQTS, and further emphasize the role of congenital arrhythmia susceptibility in this syndrome.
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, TN, USA.
authors.forename: Troy E
authors.initials: TE
authors.lastname: Rhodes
authors.forename: Robert L
authors.initials: RL
authors.lastname: Abraham
authors.forename: Richard C
authors.initials: RC
authors.lastname: Welch
authors.forename: Carlos G
authors.initials: CG
authors.lastname: Vanoye
authors.forename: Lia
authors.initials: L
authors.lastname: Crotti
authors.forename: Marianne
authors.initials: M
authors.lastname: Arnestad
authors.forename: Roberto
authors.initials: R
authors.lastname: Insolia
authors.forename: Matteo
authors.initials: M
authors.lastname: Pedrazzini
authors.forename: Chiara
authors.initials: C
authors.lastname: Ferrandi
authors.forename: Ashild
authors.initials: A
authors.lastname: Vege
authors.forename: Torleiv
authors.initials: T
authors.lastname: Rognum
authors.forename: Dan M
authors.initials: DM
authors.lastname: Roden
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Schwartz
authors.forename: Alfred L
authors.initials: AL
authors.lastname: George
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D000072237:ERG1 Potassium Channel; D004594:Electrophysiology; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics* / Q000502:physiology; D020022:Genetic Predisposition to Disease; D006801:Humans; D007231:Infant, Newborn; D008133:Long QT Syndrome / Q000235:genetics / Q000503:physiopathology; D008390:Markov Chains; D008564:Membrane Potentials; D020125:Mutation, Missense; D013398:Sudden Infant Death / Q000235:genetics*; D014162:Transfection
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human