Allelic Complexity in Long QT Syndrome: A Family-Case Study
Abstract
:1. Introduction
2. Results
2.1. Clinical Phenotypes
2.2. Identification of the KCNQ1, KCNH2 and KCNE1 Variants
2.3. Functional Consequences of the KCNQ1-p.R583H and KCNH2-p.C108Y Variants
2.3.1. Functional Effects of KCNQ1-p.R583H
2.3.2. KCNH2-p.C108Y Exhibits a Dominant-Negative Loss-of-Function
3. Discussion
4. Materials and Methods
4.1. Clinical Investigations
4.2. Molecular Genetics
4.3. Mutagenesis
4.4. Cell Culture and Heterologous Expression
4.5. Cellular Electrophysiology
4.6. Cell Culture and Immunocytochemistry
4.7. Data Analysis and Statistics
5. Conclusions
Acknowledgments
Author Contributions
Conflicts of Interest
Abbreviations
Cm | Cell membrane capacitance |
ECG | Electrocardiogram |
HR | Heart rate |
IHERG | Potassium current conducted by HERG channel |
IKCNQ1 | Potassium current conducted by KCNQ1 channel |
IKs | Slow delayed rectifier potassium current |
IKr | Rapid delayed rectifier potassium current |
k | Slope factor |
LQTS | Long QT syndrome |
MAF | Minor allele frequency |
mV | Millivolt |
ms | Millisecond |
MΩ | Megaohm |
pA | Picoampere |
pF | Picofarad |
QTc | QT interval corrected for heart rate |
s | Seconds |
SEM | Standard error of the mean |
V1/2 | Half-maximal activation voltage |
yrs | Years |
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Subjects * | II-1 | II-2 | II-3 | |
---|---|---|---|---|
Age at diagnosis | 12 years | 9 years | 6 years | |
QTc † | at diagnosis | 560 | 530 | 470 |
after therapy | 470 | 470–490 | 420 | |
HR | after therapy | 56 | 58 | 80 # |
Syncope | Aged 10 years | Aged nine years | Aged 10 years, after 4 s sinus pause | |
Aged 11 years | ||||
Sinus pauses | No pause | No pause | Aged 9 years | |
Aged 10 years | ||||
Therapy | Propanolol | Propanolol | Propanolol | |
DDD-pacemaker | ||||
Other clinical information | None | None | Down syndrome |
Gene | Nucleotide Variation | Amino Acid Variation | MAF | Bioinformatic Tools | |
---|---|---|---|---|---|
Polyphen | SIFT | ||||
KCNE1 | G112A | G38S | 0.352 | Benign | Tolerated |
KCNH2 | G323A | C108Y | N.D. | Probably damaging | Damaging |
KCNH2 | A2690C | K897T | 0.187 | Benign | Not tolerated |
KCNQ1 | G1748A | R583H | 0.000016 | Benign | Not tolerated |
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Share and Cite
Zullo, A.; Frisso, G.; Detta, N.; Sarubbi, B.; Romeo, E.; Cordella, A.; Vanoye, C.G.; Calabrò, R.; George, A.L., Jr.; Salvatore, F. Allelic Complexity in Long QT Syndrome: A Family-Case Study. Int. J. Mol. Sci. 2017, 18, 1633. https://doi.org/10.3390/ijms18081633
Zullo A, Frisso G, Detta N, Sarubbi B, Romeo E, Cordella A, Vanoye CG, Calabrò R, George AL Jr., Salvatore F. Allelic Complexity in Long QT Syndrome: A Family-Case Study. International Journal of Molecular Sciences. 2017; 18(8):1633. https://doi.org/10.3390/ijms18081633
Chicago/Turabian StyleZullo, Alberto, Giulia Frisso, Nicola Detta, Berardo Sarubbi, Emanuele Romeo, Angela Cordella, Carlos G. Vanoye, Raffaele Calabrò, Alfred L. George, Jr., and Francesco Salvatore. 2017. "Allelic Complexity in Long QT Syndrome: A Family-Case Study" International Journal of Molecular Sciences 18, no. 8: 1633. https://doi.org/10.3390/ijms18081633