Loss-of-Function Mutations in the Cardiac Calcium Channel Underlie a New Clinical Entity Characterized by ST-Segment Elevation, Short QT Intervals, and Sudden Cardiac Death

@article{Antzelevitch2007LossofFunctionMI,
  title={Loss-of-Function Mutations in the Cardiac Calcium Channel Underlie a New Clinical Entity Characterized by ST-Segment Elevation, Short QT Intervals, and Sudden Cardiac Death},
  author={C. Antzelevitch and G. Pollevick and J. Cordeiro and O. Casis and M. Sanguinetti and Y. Aizawa and A. Guerchicoff and Ryan Pfeiffer and A. Oliva and B. Wollnik and P. Gelber and Elias P. Bonaros and Elena Burashnikov and Y. Wu and John D Sargent and S. Schickel and R. Oberheiden and A. Bhatia and L. Hsu and M. Ha{\"i}ssaguerre and R. Schimpf and M. Borggrefe and C. Wolpert},
  journal={Circulation},
  year={2007},
  volume={115},
  pages={442-449}
}
Background— Cardiac ion channelopathies are responsible for an ever-increasing number and diversity of familial cardiac arrhythmia syndromes. We describe a new clinical entity that consists of an ST-segment elevation in the right precordial ECG leads, a shorter-than-normal QT interval, and a history of sudden cardiac death. Methods and Results— Eighty-two consecutive probands with Brugada syndrome were screened for ion channel gene mutations with direct sequencing. Site-directed mutagenesis was… Expand
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Short QT syndrome.
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References

SHOWING 1-10 OF 47 REFERENCES
Sudden Death Associated With Short-QT Syndrome Linked to Mutations in HERG
TLDR
The genetic basis for a new clinical entity characterized by sudden death and short-QT intervals in the ECG is described and a novel genetic and biophysical mechanism responsible for sudden death in infants, children, and young adults caused by mutations in KCNH2 is demonstrated. Expand
Mutation in the KCNQ1 Gene Leading to the Short QT-Interval Syndrome
TLDR
It is demonstrated that the electrocardiographic short QT-interval syndrome is genetically heterogeneous and can also be caused by mutation in the KCNQ1 gene, which is linked to gain-of-function mutation in KCNH2. Expand
Severe arrhythmia disorder caused by cardiac L-type calcium channel mutations.
TLDR
Computer modeling showed prolongation of cardiomyocyte action potentials and delayed afterdepolarizations, factors that increase risk of arrhythmia, and data indicate that gain-of-function mutations of CaV1.2 exons 8 and 8A cause distinct forms of TS. Expand
A Novel Form of Short QT Syndrome (SQT3) Is Caused by a Mutation in the KCNJ2 Gene
TLDR
Computer simulations predict a steeper steady-state restitution curve for the D172N and WT/D172N mutation, compared with WT or to HERG or KvLQT1 mutations, which may predispose SQT3 patients to a greater risk of reentrant arrhythmias. Expand
Sodium channel gene (SCN5A) mutations in 44 index patients with Brugada syndrome: Different incidences in familial and sporadic disease
TLDR
Genetic testing of SCN5A is especially useful in familial disease to identify individuals at cardiac risk and in sporadic cases, however, a genetic basis and the value of mutation screening has to be further determined. Expand
Amplified Transmural Dispersion of Repolarization as the Basis for Arrhythmogenesis in a Canine Ventricular-Wedge Model of Short-QT Syndrome
TLDR
The data suggest that heterogeneous abbreviation of the action potential duration among different cell types spanning the ventricular wall creates the substrate for the genesis of VT under conditions associated with short QT intervals. Expand
CaV1.2 Calcium Channel Dysfunction Causes a Multisystem Disorder Including Arrhythmia and Autism
TLDR
Functional expression reveals that G406R produces maintained inward Ca(2+) currents by causing nearly complete loss of voltage-dependent channel inactivation, which likely induces intracellular Ca( 2+) overload in multiple cell types. Expand
A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome
To identify genes involved in cardiac arrhythmia, we investigated patients with long QT syndrome (LQT), an inherited disorder causing sudden death from a ventricular tachyarrythmia, torsade deExpand
Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias
Genetic factors contribute to the risk of sudden death from cardiac arrhythmias. Here, positional cloning methods establish KVLQT1 as the chromosome 11-linked LQT1 gene responsible for the mostExpand
Acquired forms of the Brugada syndrome.
  • W. Shimizu
  • Medicine
  • Journal of electrocardiology
  • 2005
TLDR
Any intervention that increases outward currents or decreases inward currents at the end of phase 1 of the AP can accentuate or unmask ST-segment elevation, similar to that found in the Brugada syndrome, thus producing acquired forms of the Bragada syndrome. Expand
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