TY - JOUR
T1 - Novel long QT syndrome-associated missense mutation, L762F, in CACNA1C-encoded L-type calcium channel imparts a slower inactivation tau and increased sustained and window current
AU - Landstrom, Andrew P.
AU - Boczek, Nicole J.
AU - Ye, Dan
AU - Miyake, Christina Y.
AU - De la Uz, Caridad M.
AU - Allen, Hugh D.
AU - Ackerman, Michael J.
AU - Kim, Jeffrey J.
N1 - Funding Information:
To confirm absence of putatively pathogenic mutations in ostensibly healthy individuals, presence of the mutation was analyzed in 1360 reference alleles (N = 680 subjects). Control genomic DNA was obtained from the European Collection of Cell Cultures (HPA Culture Collections, UK), the Human Genetic Cell Repository sponsored by the National Institute of General Medical Sciences, and the Coriell Institute for Medical Research (Camden, NJ). Further, absence of the mutation in all publically-held databases including the 1000 Genome Project (N = 1094 subjects) comprised of 381 whites, 246 blacks, 286 Asians, and 181 Hispanics = 5379 subjects) comprise of 3510 whites and 1869 blacks = 12,000 subjects) = 60,706) [14] ; the National Heart, Lung, and Blood Institute GO Exome Sequencing Project (N [15] ; the 12,000 Exome Chip (N [15] ; and the ExAC database (N [16] . In total, putatively pathogenic variants were absent in approximately 99,006 subjects and 198,012 reference alleles.
Funding Information:
M.J.A. is a consultant for Boston Scientific, Gilead Sciences, Medtronic, and St. Jude Medical. M.J.A. and Mayo Clinic receive sales based royalties from Transgenomic with respect to their FAMILION-LQTS and FAMILION-CPVT genetic tests. No financial support was provided by any of these entities for this study.
Publisher Copyright:
© 2016 Elsevier Ireland Ltd
PY - 2016/10/1
Y1 - 2016/10/1
N2 - Background Mutations in the CACNA1C-encoded L-type calcium channel have been associated with Timothy syndrome (TS) with severe QT prolongation, syndactyly, facial dysmorphisms, developmental delay, and sudden death. Recently, patients hosting CACNA1C mutations with only long QT syndrome (LQTS) have been described. We sought to identify novel variants in CACNA1C associated with either TS or LQTS, and to determine the impact of the mutation on channel function. Methods/results Two probands were identified with mutations in CACNA1C, one with a TS-associated mutation, G406R, and a second with genotype-negative LQTS. Illumina HiSeq 2000 whole exome sequencing on the genotype-negative LQTS proband revealed a novel variant, CACNA1C-L762F, that co-segregated within a multi-generational family. The missense mutation localized to the DII/DIII intracellular interlinker segment of the channel in a highly conserved region in close proximity to the 6th transmembrane segment of domain II (DIIS6). Whole cell patch clamp of heterologously expressed CACNA1C-L762F in TSA201 cells demonstrated slower inactivation tau and increased sustained and window current. Comprehensive review and topological mapping of all described CACNA1C mutations revealed TS-specific hotspots localizing to the cytoplasmic aspect of 6th transmembrane segment of respective domains. Probands hosting TS mutations were associated with elevated QTc, higher prevalence of 2:1 AV block, and a younger age at presentation compared to LQTS. Conclusions The CACNA1C-L762F mutation is associated with development of LQTS through slower channel inactivation and increased sustained and window current. TS-associated mutations localize to specific areas of CACNA1C and are associated with a younger age at presentation, higher QTc, and 2:1 AV block than isolated LQTS-associated mutations.
AB - Background Mutations in the CACNA1C-encoded L-type calcium channel have been associated with Timothy syndrome (TS) with severe QT prolongation, syndactyly, facial dysmorphisms, developmental delay, and sudden death. Recently, patients hosting CACNA1C mutations with only long QT syndrome (LQTS) have been described. We sought to identify novel variants in CACNA1C associated with either TS or LQTS, and to determine the impact of the mutation on channel function. Methods/results Two probands were identified with mutations in CACNA1C, one with a TS-associated mutation, G406R, and a second with genotype-negative LQTS. Illumina HiSeq 2000 whole exome sequencing on the genotype-negative LQTS proband revealed a novel variant, CACNA1C-L762F, that co-segregated within a multi-generational family. The missense mutation localized to the DII/DIII intracellular interlinker segment of the channel in a highly conserved region in close proximity to the 6th transmembrane segment of domain II (DIIS6). Whole cell patch clamp of heterologously expressed CACNA1C-L762F in TSA201 cells demonstrated slower inactivation tau and increased sustained and window current. Comprehensive review and topological mapping of all described CACNA1C mutations revealed TS-specific hotspots localizing to the cytoplasmic aspect of 6th transmembrane segment of respective domains. Probands hosting TS mutations were associated with elevated QTc, higher prevalence of 2:1 AV block, and a younger age at presentation compared to LQTS. Conclusions The CACNA1C-L762F mutation is associated with development of LQTS through slower channel inactivation and increased sustained and window current. TS-associated mutations localize to specific areas of CACNA1C and are associated with a younger age at presentation, higher QTc, and 2:1 AV block than isolated LQTS-associated mutations.
KW - CACNA1C
KW - L-type calcium channel
KW - Long QT syndrome
KW - Mutation
KW - Timothy syndrome
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U2 - 10.1016/j.ijcard.2016.06.081
DO - 10.1016/j.ijcard.2016.06.081
M3 - Article
C2 - 27390944
AN - SCOPUS:84977599307
SN - 0167-5273
VL - 220
SP - 290
EP - 298
JO - International Journal of Cardiology
JF - International Journal of Cardiology
ER -