Loss-of-activity-mutation in the cardiac chloride-bicarbonate exchanger AE3 causes short QT syndrome

Thorsen, Kasper; Dam, Vibeke Secher; Kjær-Sørensen, Kasper; Pedersen, Lisbeth Nørum; Skeberdis, Vytenis Arvydas; Jurevičius, Jonas; Treinys, Rimantas; Petersen, Ida M. B. S.; Nielsen, Morten Schak; Oxvig, Claus; Morth, J. Preben; Matchkov, Vladimir V.; Aalkjær, Christian; Bundgaard, Henning; Jensen, Henrik Kjærulf

doi:10.1038/s41467-017-01630-0

Cited by 93 publications

(67 citation statements)

References 39 publications

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“…abbreviated repolarisation in rabbit hearts [77] . Collectively, these observations suggest that intracellular alkalization and reduced [Cl -] i as a result of the R370H AE3 mutation contribute to accelerated repolarisation in this form of SQTS [77]. The processes affected by these changes to effect faster repolarisation remain to be elucidated.…”

Section: Sqt8mentioning

confidence: 99%

“…Candidate ion channel screening has resulted in positive genotyping in <30% of SQTS cases [9]. Exome or genome sequencing can thus be predicted to uncover novel, unexpected QT c shortening and also resulted in raised intracellular pH in zebrafish embryo hearts [77].…”

Section: Sqt8mentioning

confidence: 99%

“…The recent discovery of impaired AE3 function in SQT8 highlights a potential new target for treatment, at least in this variant of the SQTS [77]. However, there is no current pharmacological approach that could restore normal function of mutant AE3.…”

Section: Ae3 Activationmentioning

confidence: 99%

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Emerging therapeutic targets in the short QT syndrome

Hancox

Whittaker

Du³

et al. 2018

Expert Opinion on Therapeutic Targets

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Short QT Syndrome (SQTS) is a rare but dangerous condition characterised by abbreviated repolarisation, atrial and ventricular arrhythmias and risk of sudden death. Implantable cardioverter defibrillators (ICDs) are a first line protection against sudden death, but adjunct pharmacology is beneficial and desirable. Areas covered: The genetic basis for genotyped SQTS variants (SQT1-SQT8) and evidence for arrhythmia substrates from experimental and simulation studies are discussed. The main ion channel/transporter targets for antiarrhythmic pharmacology are considered in respect of potential genotype-specific and non-specific treatments for the syndrome. Expert opinion: Potassium channel blockade is valuable for restoring repolarisation and QT interval, though genotype-specific limitations exist in the use of some K channel inhibitors. A combination of K current inhibition during the action potential plateau, with sodium channel inhibition that collectively result in delaying repolarisation and post-repolarisation refractoriness is likely to be valuable in prolonging effective refractory period and wavelength for re-entry. Genotype-specific K channel inhibition is limited by a lack of targeted inhibitors in clinical use, though experimentally available selective inhibitors now exist. The relatively low proportion of successfully genotyped cases justifies an exome or genome sequencing approach, to reveal new mediators and targets, as demonstrated recently for SLC4A3 in SQT8.

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Section: Sqt8mentioning

confidence: 99%

Section: Sqt8mentioning

confidence: 99%

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Emerging therapeutic targets in the short QT syndrome

Hancox

Whittaker

Du³

et al. 2018

Expert Opinion on Therapeutic Targets

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“…Recently, a "loss of function" mutation in the SLC4A3 gene, which encodes the cardiac chloride-bicarbonate exchanger AE3, was reported by Thorsen et al to be associated with SQTS. This mutation was associated with an increase in intracellular pH, causing a potential shortening in QTc (29).…”

Section: Pathophysiologymentioning

confidence: 99%

Rare but lethal short QT syndrome: most recent understanding of the disease

et al. 2019

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Short QT syndrome (SQTS) is a rare genetic channelopathy that affects the repolarization of cardiac cells and is associated with cardiac arrhythmia and sudden cardiac death (SCD). "Abbreviated repolarization" is the hallmark of the disease, which is secondary to genetic defects; mutations in several genes that encode different cardiac ion channels have been identified in individuals with the disease. Presentations of the disease include syncope, atrial or ventricular arrhythmia and SCD. SQTS is diagnosed with a corrected-QT (QTc) interval of <340 milliseconds (ms) or a QTc of 340-360 ms and either personal or family history of SCD, family history of SQTS or an identified genetic mutation. Implantable cardioverter-defibrillator (ICD) is the main treatment used in the secondary prevention of SCD in patients with the disease who have experienced previous major arrhythmic events. Pharmacological treatment with quinidine is used as an adjuvant therapy to ICD in the setting of recurrent shocks or as an alternative treatment when ICD is not feasible. The goal of this review article is to describe this rare and under-studied condition, highlight steps to diagnosis and describe treatment modalities, particularly in South America where there is a lack of studies and understanding of this disease.

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“…Since describing this rare arrhythmic disorder (Gussak et al, 2000) different SQTS types have been proposed such as SQTS 1 -3 with a gain of potassium channels, SQTS 4 -6 with a loss of calcium channels and a new SQTS with a cardiac Cl/HCO3 exchanger AE3 (Thorsen et al, 2017). However, the most frequent described type is SQTS 1.…”

Section: Introductionmentioning

confidence: 99%

Differences in Short QT Syndrome Subtypes: A Systematic Literature Review and Pooled Analysis

El‐Battrawy

Schlentrich

et al. 2020

Front. Genet.

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Background: Short QT syndrome (SQTS) is a rare syndrome and affects different types of genes. However, data on differences of clinical profile and outcome of different SQTS types are sparse. Methods: We conducted a pooled analysis of 110 SQTS patients. Patients have been diagnosed between 2000 and 2017 at our institution (n = 12) and revealed using a literature review (n = 98). 29 studies were identified by analysing systematic data bases (PubMed, Web of Science, Cochrane Libary, Cinahl). Results: 67 patients with genotype positive SQTS origin and 43 patients with genotype negative origin were found. A significant difference is documented between the sex with a higher predominance of male in genotype negative SQTS patients and predominance of females in genotype positive SQTS patients (male 52% versus 84%, female 45% versus 14%; p = 0.0016). No relevant difference of their median age (genotype positive 27 ± 19 versus genotype negative 29 ± 15; p = 0.48) was found. Asymptomatic patients and patients reporting symptoms such as syncope, sudden cardiac death, atrial flutter and ventricular fibrillation documented in both groups were similar except atrial fibrillation (genotype positive 19% versus genotype negative 0%; p = 0.0055). The QTc interval was not significantly different in both groups (genotype positive 315 ± 32 versus genotype negative 320 ± 19; p = 0.30). The treatments (medical treatment and ICD implantation) in both groups were comparable. Electrophysiology studies were not significantly higher documented in patients with genotype positive and negative origin (24% versus 9%; p = 0.075). Events at follow up such as VT, VF, and SCD were not higher presented in patients with genotype positive (13% versus 9%) (p = 0.25). 54% of genotype positive SQTS patients showed SQTS 1 followed by STQS 2 (21%) and SQTS 3 (10%). Conclusions: The long-term risk of a malignant arrhythmic event is not higher in patients with genotype positive. However, patients with genotype positive present themselves more often with AF with a female predominance. Also, other events at follow up such as syncope, atrial flutter and palpitation were not significantly higher (9% versus 0%; p = 0.079).

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Loss-of-activity-mutation in the cardiac chloride-bicarbonate exchanger AE3 causes short QT syndrome

Cited by 93 publications

References 39 publications

Emerging therapeutic targets in the short QT syndrome

Emerging therapeutic targets in the short QT syndrome

Rare but lethal short QT syndrome: most recent understanding of the disease

Differences in Short QT Syndrome Subtypes: A Systematic Literature Review and Pooled Analysis

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