Exome Sequencing and Systems Biology Converge to Identify Novel Mutations in the L-Type Calcium Channel, CACNA1C, Linked to Autosomal Dominant Long QT.

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Exome Sequencing and Systems Biology Converge to Identify Novel Mutations in the L-Type Calcium Channel, CACNA1C, Linked to Autosomal Dominant Long QT SyndromeClinical Perspective by Nicole J. Boczek, Jabe M. Best, David J. Tester, John R. Giudicessi, Sumit Middha, Jared M. Evans, Timothy J. Kamp, and Michael J. Ackerman Circ Genom Precis Med Volume 6(3):279-289 June 18, 2013 Copyright © American Heart Association, Inc. All rights reserved.

Whole-exome sequencing and familial genomic triangulation for the elucidation of a novel genetic substrate for long QT syndrome (LQTS). Whole-exome sequencing and familial genomic triangulation for the elucidation of a novel genetic substrate for long QT syndrome (LQTS). A, Black circles/squares are affected, gray are borderline, and white are unaffected with LQTS. Arrow identifies the proband. Asterisks represent those who were whole-exome sequenced. Numbers in each circle/square represent QTc values (milliseconds) when available. Plus signs represent Pro857Arg-CACNA1C mutation–positive family members. Minus signs represent mutation-negative family members. NA denotes where DNA samples were not available. B, Lead II of the ECG for the index case (III.2). The full ECG is available in Figure IA in the online-only Data Supplement. C, Schematic representation of our sequencing strategy. D, DNA sequencing chromatogram showing the Pro857Arg mutation. SNVs indicates single-nucleotide variants. Nicole J. Boczek et al. Circ Cardiovasc Genet. 2013;6:279-289 Copyright © American Heart Association, Inc. All rights reserved.

Functional analysis of Pro857Arg-Cav1 Functional analysis of Pro857Arg-Cav1.2 mutation using whole-cell patch clamp technique. Functional analysis of Pro857Arg-Cav1.2 mutation using whole-cell patch clamp technique. A, Representative ICa,L traces recorded from HEK293 cells expressing WT- or Pro857Arg-Cav1.2 along with auxiliary β2cN4 and α2δ1 subunits. B, Current–voltage (I–V) relations constructed from wild type (WT)-Cav1.2 (squares; n=10) or Pro857Arg-Cav1.2 expressing cells (circles; n=10). Data were compared using Students unpaired t test and *P<0.05 when WT-Cav1.2 was compared with Pro857Arg-Cav1.2. Nicole J. Boczek et al. Circ Cardiovasc Genet. 2013;6:279-289 Copyright © American Heart Association, Inc. All rights reserved.

Increased surface membrane density of Cav1.2 Pro857Arg channels. Increased surface membrane density of Cav1.2 Pro857Arg channels. HEK293 cells expressing either yellow fluorescent protein-tagged Cav1.2 wild type (WT) or Cav1.2-Pro857Arg along with auxiliary β2cN4 and α2δ1 subunits were cell-surface biotinylated at 4°C. A, NeutrAvidin (nAv)-captured surface membrane proteins (left) and whole-cell lysates (WCL; right) were analyzed by SDS-PAGE and Western blotting. Densitometric analysis of surface membrane Cav1.2 signal (B) or total cellular Cav1.2 (C) was performed to summarize the results of 9 independent experiments. In both cases, normalization of Cav1.2 signal was achieved using the corresponding signal of the endogenous surface membrane protein transferrin receptor (Tfn-R). Solid red lines through distributions indicate population means. Data were compared using Student unpaired t test and *P≤0.05 when WT-Cav1.2 was compared with Pro857Arg-Cav1.2. Nicole J. Boczek et al. Circ Cardiovasc Genet. 2013;6:279-289 Copyright © American Heart Association, Inc. All rights reserved.

Topology diagram of the CACNA1C channel α-subunit. Topology diagram of the CACNA1C channel α-subunit. Each variant is represented as a black circle followed by the amino acid position and change. Asterisk represents the mutation identified by whole-exome sequencing in the pedigree (Figure 1). Patient history is displayed for each variant. The PEST domain sequence is highlighted showing the position of the 3 variants residing within this domain as well as the species conservation. Stromal interaction molecule 1 (STIM1) binding region 1806 to 1905 is shown in the C-terminal tail of CACNA1C. STIM1 interacts with the LTCC to normally suppress channel function.39,40 LQTS indicates long QT syndrome; QTc, heart rate–correct QT interval; and SCA, sudden cardiac arrest. Nicole J. Boczek et al. Circ Cardiovasc Genet. 2013;6:279-289 Copyright © American Heart Association, Inc. All rights reserved.