Short QT syndrome classification
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Sumanth Khadke, MD[2]
Overview
Five variants of short QT syndrome have been characterized based upon the underlying genetic mutation, the electrocardiographic phenotype, and the clinical manifestations of the variant. The different genes which are mutated are KCNH 2 gene for SQTS 1 which causes upregulation of Ikr channel, KCNQ 1 for SQT 2 which upregulates IKs, KCNJ 2 gene for SQTS 3 which causes upregulation of alpha subunit of IK1, CACNA1C for SQTS 4 which causes downregulation of ICa and CACNB2b, for SQTS 5 which also causes downregulation of Ica.
Classification
| Type | OMIM | Gene | Gene Location | Mutation | Protein | Notes | |
|---|---|---|---|---|---|---|---|
| 1 | SQTS 1[1][2] | 609620 | KCNH2
HERG[3] |
7q 36.1 | Mutation in the KCNH2 gene causing gain of function of α-subunit Ikr | Kv11.1 | |
| 2 | SQTS 2[1][4] | 609621 | KCNQ1,
KvLQT1[3] |
11p15.5-p15.4 | Mutation in KCNQ1 causing gain of function of α-subunit Iks | Kv7.1 | |
| 3 | SQTS 3[1][5] | 609622 | KCNJ2,
Kir2.1[3] |
17q24.3 | Mutation in KCNJ2 gene causing gain of function of α-subunit IK1 | Kir2.1 | |
| 4 | SQTS 4[1][6] | CACNA1C,
Cav1.2[3] |
12p13.3 | Mutation in CACNB2b causing loss of function of α-subunit ICa (L-channel) | Cav1.2 | ||
| 5 | SQTS 5[1][6] | CACNB2b,
Cavβ2b[3] |
10p12 | Mutation in CACNA1c causing loss of function of β2-subunit ICa (L-channel) | Cavβ2 |
Short QT syndrome type 1 (SQT1)
Type 1 SQTS is caused by a missense mutation in KCNH2 gene. It is the most common familial variety of SQTS occurring in autosomal dominant pattern. The KCNH2 gene is located on chromosome 7q 36.1. The KCNH2 gene is often referred as HERG gene. HERG stands for the human ether-a-go-go-related gene which expresses a protein Kv11.1. This protein forms the alpha subunit of potassium channel responsible for rapidly activating rectifier outwards current (Ikr) [7].The genetic analysis reveal missense mutation with cytosine to guanine substitution at nucleotide 1764 resulting in change in the amino acid (N588K) in KCNH2 gene. The N588K mutation appears to be the main reason for occurrence of SQTS syndrome[1]. The Bio-physical analysis reveal a gain of function mutation in IKr currents causing shortening of action potential duration and refractoriness making patients prone to re-entrant type of arrythmias [8]. The N588K mutations cause large outward currents in the ventricles sparing the Purkinje fiber system. There is a selective shortening of action potentials and shortening of the refractory periods in ventricles with sparing of the Purkinje fibers. This differential change promotes favorable factors for reentrant arrhythmia[9]. The functional studies reveal N588K mutation leads to loss of normal correction of IKr at the normal range of voltages. This causes a voltage-dependent inactivation of the channel by +90mV which explains the gain of function of the channel during the plateau phase of the action potential.
Short QT syndrome type 2 (SQT2)
Type 2 SQTS is caused by a mutation in the KCNQ1 gene which codes for Kv7.1 protein. This protein forms a part of slowly activating delayed outward potassium current (IKs). Bellocq and colleagues first identified this mutation where Valine was substituted by Leucine at position 307 (V307L). The biophysical analysis showed that KCNQ1 mutation produced physiological outward potassium current but caused a significant shift in the half-activation potential. The mutated channel now got activated at more negative potentials with accelerated activation kinetics. This led to the gain of function of the outward current. The functional studies reveal a shift of -20mV in the half-activation potential and caused enhanced activation or gain of function of IKs channel[9][10].
Short QT syndrome type 3 (SQT3)
Type 3 SQTS is caused by a mutation in the KCNJ2 gene which normally codes for protein Kir 2.1. This protein is believed to form a part of alpha subunit of the inward rectifier IK1 channel. The genetic studies revealed the substitution of aspartic acid by asparagine at position 172 (D172N). The net effect is the gain of function in outward potassium channel IK1 and shortening of the action potential[9][10].
Short QT syndrome type 4 (SQT4)
Type 4 SQTS is caused by a loss of function mutation in the CACNA1C gene. The L-type cardiac calcium channel is the association of α1, β, and α2δ subunits. The pore-forming Cav1.2 α1-subunit is encoded by CACNA1C and the β-subunit is encoded by CACNB2b (mutated in SQT5). CACNA1c codes for pore-forming protein Cav1.2. A missense mutation causing substitution of Alanine by valine at position 39 (A39V) or substitution of Glycine by arginine at position 490 (G490R) is seen in STQS4.
Short QT syndrome type 5 (SQT5)
Type 5 SQTS is caused by a loss of function mutation in CACNB2b which codes for protein Cavβ2 which is a part of pore-forming proteins. A missense mutation causing substitution of serine by leucine at position 481 (S481L) is seen in SQTS5.
Both STQS 4 and STQS 5 cause a loss of function of Ica.
References
- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 Hedley PL, Jørgensen P, Schlamowitz S, Wangari R, Moolman-Smook J, Brink PA; et al. (2009). "The genetic basis of long QT and short QT syndromes: a mutation update". Hum Mutat. 30 (11): 1486–511. doi:10.1002/humu.21106. PMID 19862833.
- ↑ Brugada R, Hong K, Dumaine R, Cordeiro J, Gaita F, Borggrefe M; et al. (2004). "Sudden death associated with short-QT syndrome linked to mutations in HERG". Circulation. 109 (1): 30–5. doi:10.1161/01.CIR.0000109482.92774.3A. PMID 14676148.
- ↑ 3.0 3.1 3.2 3.3 3.4 Schmoldt A, Benthe HF, Haberland G (1975). "Digitoxin metabolism by rat liver microsomes". Biochem Pharmacol. 24 (17): 1639–41. PMID https://doi.org/10.1161/CIRCEP.109.921056 Check
|pmid=value (help). - ↑ Bellocq C, van Ginneken AC, Bezzina CR, Alders M, Escande D, Mannens MM; et al. (2004). "Mutation in the KCNQ1 gene leading to the short QT-interval syndrome". Circulation. 109 (20): 2394–7. doi:10.1161/01.CIR.0000130409.72142.FE. PMID 15159330.
- ↑ Priori SG, Pandit SV, Rivolta I, Berenfeld O, Ronchetti E, Dhamoon A; et al. (2005). "A novel form of short QT syndrome (SQT3) is caused by a mutation in the KCNJ2 gene". Circ Res. 96 (7): 800–7. doi:10.1161/01.RES.0000162101.76263.8c. PMID 15761194.
- ↑ 6.0 6.1 Antzelevitch C, Pollevick GD, Cordeiro JM, Casis O, Sanguinetti MC, Aizawa Y; et al. (2007). "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". Circulation. 115 (4): 442–9. doi:10.1161/CIRCULATIONAHA.106.668392. PMC 1952683. PMID 17224476.
- ↑ Schimpf R, Borggrefe M, Wolpert C (2008). "Clinical and molecular genetics of the short QT syndrome". Curr Opin Cardiol. 23 (3): 192–8. doi:10.1097/HCO.0b013e3282fbf756. PMID 18382206.
- ↑ Hong K, Bjerregaard P, Gussak I, Brugada R (2005). "Short QT syndrome and atrial fibrillation caused by mutation in KCNH2". J Cardiovasc Electrophysiol. 16 (4): 394–6. doi:10.1046/j.1540-8167.2005.40621.x. PMID 15828882.
- ↑ 9.0 9.1 9.2 Brugada R, Hong K, Cordeiro JM, Dumaine R (2005). "Short QT syndrome". CMAJ. 173 (11): 1349–54. doi:10.1503/cmaj.050596. PMC 1283503. PMID 16301704.
- ↑ 10.0 10.1 Patel C, Yan GX, Antzelevitch C (2010). "Short QT syndrome: from bench to bedside". Circ Arrhythm Electrophysiol. 3 (4): 401–8. doi:10.1161/CIRCEP.109.921056. PMC 2933105. PMID 20716721.