title: Genetic analysis of hyperpolarization-activated cyclic nucleotide-gated cation channels in sudden unexpected death in epilepsy cases.
abstract: Sudden unexpected death in epilepsy (SUDEP) is the most common epilepsy-related cause of death, yet the cause is unknown. Our previous studies suggest a role for arrhythmia-related ion channel genes in the pathogenesis of SUDEP. Hyperpolarization-activated cyclic nucleotide-gated cation (HCN1-4) channels are ion channels involved in generating spontaneous rhythmic activity in cardiac pacemaker and neuronal cells. This study sought to determine the role of pathogenic DNA variants in the HCN1-4 genes in a large SUDEP cohort collected from 1993 to 2009. Post-mortem DNA samples were amplified and analyzed for each HCN exon. Genetic analysis in 48 SUDEP cases (age range 12-82 years) identified six novel and three previously reported nonsynonymous (amino acid changing) variants in HCN1 (n = 1), HCN2 (n = 2), HCN3 (n = 2) and HCN4 (n = 4). The Phe738Cys and Pro802Ser variants in HCN2, and Gly973Arg in HCN4 were absent in control alleles and affecting highly conserved residues in the carboxyl-cytoplasmic tail region. Our results support a pathogenic link between the heart and brain in SUDEP, mediated by the HCN neuro-cardiac ion channel genes.
authors: Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Newtown, Australia.
authors: Emily
authors: E
authors: Tu
authors: Louise
authors: L
authors: Waterhouse
authors: Johan
authors: J
authors: Duflou
authors: Richard D
authors: RD
authors: Bagnall
authors: Christopher
authors: C
authors: Semsarian
references: Annu Rev Physiol. 1996;58:299-327
references: 8815797
references: J Clin Invest. 2003 May;111(10):1537-45
references: 12750403
references: J Mol Cell Cardiol. 2007 Sep;43(3):337-43
references: 17655857
references: Neurology. 1998 Nov;51(5):1270-4
references: 9818844
references: Nature. 1991 May 9;351(6322):145-7
references: 1709448
references: J Neurosci. 2002 Jun 1;22(11):4591-9
references: 12040066
references: Epilepsia. 2010 Sep;51(9):1915-8
references: 20738378
references: EMBO J. 2003 Jan 15;22(2):216-24
references: 12514127
references: J Child Neurol. 2010 Jul;25(7):916-21
references: 20395638
references: EMBO J. 1999 May 4;18(9):2323-9
references: 10228147
references: J Neurosci. 2007 Nov 21;27(47):13012-21
references: 18032674
references: Ann Neurol. 2010 Apr;67(4):542-6
references: 20437590
references: Epilepsy Res. 2004 Mar;59(1):51-60
references: 15135167
references: Annu Rev Physiol. 1993;55:455-72
references: 7682045
references: J Neurosci. 2003 Jul 30;23(17):6826-36
references: 12890777
references: Nature. 1998 Jun 11;393(6685):587-91
references: 9634236
references: J Biol Chem. 1999 Apr 30;274(18):12835-9
references: 10212270
references: Proc Natl Acad Sci U S A. 1995 Dec 5;92(25):11716-20
references: 8524835
references: Nat Rev Neurol. 2009 Sep;5(9):492-504
references: 19668244
references: Eur J Neurosci. 2004 Jun;19(11):3048-58
references: 15182313
references: J Biol Chem. 2004 Jun 25;279(26):27194-8
references: 15123648
references: N Engl J Med. 2006 Jan 12;354(2):151-7
references: 16407510
references: Seizure. 2009 Mar;18(2):158-60
references: 18752973
references: Nat Med. 2001 Mar;7(3):331-7
references: 11231632
references: Proc Natl Acad Sci U S A. 1999 Aug 3;96(16):9391-6
references: 10430953
references: Lancet Neurol. 2008 Nov;7(11):1021-31
references: 18805738
references: Epilepsia. 1997 Nov;38(11 Suppl):S6-8
references: 19909329
references: Brain Pathol. 2011 Mar;21(2):201-8
references: 20875080
references: Cell. 1998 May 29;93(5):717-29
references: 9630217
references: Epilepsia. 2008 Oct;49(10):1686-95
references: 18397293
references: J Physiol. 1996 Apr 1;492 ( Pt 1):97-106
references: 8730586
references: Neurobiol Dis. 2008 Jan;29(1):59-70
references: 17931874
references: Circulation. 2007 Jul 31;116(5):463-70
references: 17646576
references: Neurology. 2001 Feb 27;56(4):519-25
references: 11222798
references: Epilepsia. 2000;41 Suppl 2:S7-12
references: 10885735
references: Proc Natl Acad Sci U S A. 2003 Dec 9;100(25):15235-40
references: 14657344
references: J Cardiovasc Electrophysiol. 2010 Dec;21(12):1365-72
references: 20662977