Novel AKAP9 mutation and long QT syndrome in a patient with torsades des pointes

Bottigliero, Dario; Monaco, Ilenia; Santacroce, Rosa; Casavecchia, Grazia; Correale, Michele; Guastafierro, Francesca; Leccese, Angelica; Cordisco, Giorgia; Ieva, Riccardo; Trunzo, Roberta; Margaglione, Maurizio

doi:10.1007/s10840-019-00606-y

Cited by 7 publications

(7 citation statements)

References 2 publications

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“… 50 , 52 , 53 , 54 Mutations that disrupt I Ks –AKAP-9 interaction result in reduced protein kinase–dependent phosphorylation of I Ks subunit KCNQ1 and inhibition of the SNS stimulation of I Ks , which can lead to LQTS. Different AKAP-9 mutations have been associated with LQTS 55 , 56 classified as LQT11. In addition, AKAP-9 has been identified as a genetic modifier of LQT1 syndrome contributing to phenotypic variability in patients with the same primary-causing mutation.…”

Section: Molecular Underpinning Of Lqtsmentioning

confidence: 99%

Long QT syndrome – Bench to bedside

Ponce-Balbuena

Deschênes

2021

Heart Rhythm O2

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Long QT syndrome (LQTS) is a cardiovascular disorder characterized by an abnormality in cardiac repolarization leading to a prolonged QT interval and T-wave irregularities on the surface electrocardiogram. It is commonly associated with syncope, seizures, susceptibility to torsades de pointes, and risk for sudden death. LQTS is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. The availability of therapy for this lethal disease emphasizes the importance of early and accurate diagnosis. Additionally, understanding of the molecular mechanisms underlying LQTS could help to optimize genotype-specific treatments to prevent deaths in LQTS patients. In this review, we briefly summarize current knowledge regarding molecular underpinning of LQTS, in particular focusing on LQT1, LQT2, and LQT3, and discuss novel strategies to study ion channel dysfunction and drug-specific therapies in LQT1, LQT2, and LQT3 syndromes.

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Section: Molecular Underpinning Of Lqtsmentioning

confidence: 99%

Long QT syndrome – Bench to bedside

Ponce-Balbuena

Deschênes

2021

Heart Rhythm O2

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“…Recent studies have suggested that the protein encoded by the AKAP9 gene is protein kinase A-anchored protein 9 (Yotiao protein) and that its function is mainly to act as a scaffold protein necessary for the assembly of several protein kinases and phosphatases on the centrosome and Golgi apparatus ( 6 ). The Yotiao protein forms a macromolecular complex with the voltage-gated potassium channel alpha subunit, Kv7.1 (also known as KCNQ1 ), and its associated beta subunit, KCNE1, which is responsible for the slow activation of delayed rectifier K+ currents and is a modifier of the clinical phenotype of LQTS ( 7 , 8 ). The AKAP9 gene not only alters QTc duration but also affects the risk and severity of cardiac events.…”

Section: Discussionmentioning

confidence: 99%

Frequent torsades de pointes in a child with novel AKAP9 mutation: A case report and literature review

Wang

Zuo²,

Wang³

et al. 2023

Front. Pediatr.

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IntroductionThe aim of the present study is to report the diagnosis and treatment of a rare case of frequent torsades de pointes (Tdp) in a child with a novel AKAP9 mutation. A 13-year-old girl suffered from repeated syncope and frequent Tdp. An electrocardiogram (ECG) showed frequent multisource premature ventricular contractions with the R-ON-T phenomenon. The QTc ranged from 410 to 468 ms. The genetic test indicated a heterozygous mutation, namely, c.11714T > C (p.M3905T), in the AKAP9 gene, which is a controversial gene in long QT syndrome. After treatment with propranolol, recurrent syncope occurred, and the patient received an implantable cardioverter defibrillator (ICD). Due to frequent electrical storms at home, the child was additionally treated with propafenone to prevent arrhythmia. The antitachycardia pacing (ATP) function in the ICD was turned off, and the threshold of ventricular tachycardia (VT) assessment was adjusted from 180 beats/min to 200 beats/min. The patient was followed up for 12 months without malignant arrhythmia and electric shock.ConclusionGenetic testing may be a useful tool to determine the origin of channelopathy, but the results should be interpreted in combination with the actual situation. Rational parameter settings for the ICD and application of antiarrhythmic drugs can reduce the mortality rates of children.

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“…Disease-associated pathogenic AKAP9 variants were rarely reported and associated with a broad phenotypic spectrum, including LQTS type 11 [ 1 , 2 , 3 , 4 ], Brugada syndrome [ 7 , 8 ], unexplained sudden death [ 9 , 10 , 11 , 12 ], severe ventricular arrhythmia [ 13 , 14 ], and cardiomyopathy [ 15 ] ( Table 1 ).…”

Section: Discussionmentioning

confidence: 99%

“…Deleterious AKAP9 pathogenic variants have been recently reported in patients with congenital LQTS type 11 (MIM #611820). To date, only five patients with LQTS harboring AKAP9 pathogenic variants were documented [ 1 , 2 , 3 , 4 ]. However, some AKAP9 -mutated patients also harbored a second genetic variant in channelopathy-associated genes [ 1 ].…”

Section: Introductionmentioning

confidence: 99%

AKAP9-Related Channelopathy: Novel Pathogenic Variant and Review of the Literature

Huynh

Proust

Bouligand

et al. 2022

Genes

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Disease-associated pathogenic variants in the A-Kinase Anchor Protein 9 (AKAP9) (MIM *604001) have been recently identified in patients with autosomal dominant long QT syndrome 11 (MIM #611820), lethal arrhythmia (ventricular fibrillation, polymorphic ventricular tachycardia), Brugada syndrome, and sudden unexpected death. However, AKAP9 sequence variations were rarely reported and AKAP9 was classified as a “disputed evidence” gene to support disease causation due to the insufficient genetic evidence and a limited number of reported AKAP9-mutated patients. Here, we describe a 47-year-old male carrying a novel frameshift AKAP9 pathogenic variant who presented recurrent syncopal attacks and sudden cardiac arrest that required a semi-automatic external defibrillator implant and an electric shock treatment of ventricular arrhythmia. This study provides insight into the mechanism underlying cardiac arrest and confirms that AKAP9 loss-of-function variants predispose to serious, life-threatening ventricular arrhythmias.

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Novel AKAP9 mutation and long QT syndrome in a patient with torsades des pointes

Cited by 7 publications

References 2 publications

Long QT syndrome – Bench to bedside

Long QT syndrome – Bench to bedside

Frequent torsades de pointes in a child with novel AKAP9 mutation: A case report and literature review

AKAP9-Related Channelopathy: Novel Pathogenic Variant and Review of the Literature

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