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

Andrew P. Landstrom, Nicole J. Boczek, Dan Ye, Christina Y. Miyake, Caridad M. De la Uz, Hugh D. Allen, Michael John Ackerman, Jeffrey J. Kim

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)290-298
Number of pages9
JournalInternational Journal of Cardiology
Volume220
DOIs
StatePublished - Oct 1 2016

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Long QT Syndrome
L-Type Calcium Channels
Missense Mutation
Mutation
Atrioventricular Block
Genotype
Syndactyly
Exome
Sudden Death
Timothy syndrome

Keywords

  • CACNA1C
  • L-type calcium channel
  • Long QT syndrome
  • Mutation
  • Timothy syndrome

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

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. / Landstrom, Andrew P.; Boczek, Nicole J.; Ye, Dan; Miyake, Christina Y.; De la Uz, Caridad M.; Allen, Hugh D.; Ackerman, Michael John; Kim, Jeffrey J.

In: International Journal of Cardiology, Vol. 220, 01.10.2016, p. 290-298.

Research output: Contribution to journalArticle

Landstrom, Andrew P. ; Boczek, Nicole J. ; Ye, Dan ; Miyake, Christina Y. ; De la Uz, Caridad M. ; Allen, Hugh D. ; Ackerman, Michael John ; Kim, Jeffrey J. / 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. In: International Journal of Cardiology. 2016 ; Vol. 220. pp. 290-298.
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abstract = "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.",
keywords = "CACNA1C, L-type calcium channel, Long QT syndrome, Mutation, Timothy syndrome",
author = "Landstrom, {Andrew P.} and Boczek, {Nicole J.} and Dan Ye and Miyake, {Christina Y.} and {De la Uz}, {Caridad M.} and Allen, {Hugh D.} and Ackerman, {Michael John} and Kim, {Jeffrey J.}",
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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 John

AU - Kim, Jeffrey J.

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.

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KW - L-type calcium channel

KW - Long QT syndrome

KW - Mutation

KW - Timothy syndrome

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