Cardiac phenotypic spectrum of<i>KCNT1</i>mutations

Kohli, Utkarsh; Ravishankar, Chitra; Nordli, Douglas R.

doi:10.1017/s1047951120002735

Cited by 10 publications

(7 citation statements)

References 17 publications

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“…LQTS2 patients with epilepsy have a higher prevalence and risk of arrhythmias than those without epilepsy, which partly depends on the shared genetic susceptibility between epilepsy and arrhythmia, in which channelopathies play a major role 18,36 . Kohli, U., C. Ravishankar, and D. Nordli reported a case of KCNT1 mutation associated with epilepsy, systemic‐to‐pulmonary artery “collateralopathy,” and intermittent QTc prolongation 37 . Although KCNT1 mutations are known to be more common in epilepsy, the risk of heart disorders should be considered due to the genetic susceptibility of the heart.…”

Section: Discussionmentioning

confidence: 99%

KCNH2 variants in a family with epilepsy and long QT syndrome: A case report and literature review

Zhou

Hao

Sander

et al. 2023

Epileptic Disorders

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Background Genes associated with Long QT syndromes (LQTS), such as KCNQ1, KCNH2, and SCN5A, are common causes of epilepsy. The Arg 744* variant of KCNH2 has been previously reported in people with epilepsy or LQTS, but none of these patients were reported to simultaneously suffer from epilepsy and LQTS.Case study Here, we report the case of a family with epilepsy and cardiac disorders. The proband, a 25-year-old woman, experienced her first seizure at the age of seven. Video electroencephalograms (vEEGs) showed epileptic discharges. Her 24-hour dynamic electrocardiograms (ECGs) showed QTc prolongation. The proband's mother, who is 50 years old, had her first generalized tonic-clonic seizure (GTCS) at the age of 18 years old. After she gave birth at the age of 25, the frequency of seizures increased, so antiepileptic therapy was initiated. When she was 28 years old, she complained of palpitations and syncope for the first time, and QTc prolongation was detected on her 24-hour dynamic ECGs. The proband's grandmother also had complaints of palpitations and syncope at the age of 73. Her 24-hour dynamic ECGs indicated supraventricular arrhythmia, with the lowest heart rate being 41 bpm, so she agreed to a pacemaker. A KCNH2 Arg 744*

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Section: Discussionmentioning

confidence: 99%

KCNH2 variants in a family with epilepsy and long QT syndrome: A case report and literature review

Zhou

Hao

Sander

et al. 2023

Epileptic Disorders

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“…To date, only one heterozygous LOF variant, that causes impaired K Na 1.1 trafficking, has been reported, and this was in a patient who exhibited severe generalised seizures and delayed myelination [35,36]. Cardiac effects have been more recently reported, and pathogenic KCNT1 variants were linked to systemic-to-pulmonary artery collateral-mediated heart disease, also known as 'collateralopathy' [37][38][39].…”

Section: Range Of Kcnt1 Disordersmentioning

confidence: 99%

“…Following the initial reports of pathogenic KCNT1 variants [28,29], the broad spectrum of disorders associated with K Na 1.1 has become apparent. Normal function of K Na 1.1 is important not only for regulating neuronal excitability [6][7][8][9][10] but also for cardiac and intellectual functions [11,37,38], as evidenced by the wide range of phenotypes resulting from pathogenic variants.…”

Section: Concluding Remarks and Future Perspectivesmentioning

confidence: 99%

Targeting KNa1.1 channels in KCNT1-associated epilepsy

Cole

Clapcote

Muench

et al. 2021

Trends in Pharmacological Sciences

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“…KCNT1 pathogenic variants are also linked to other hyperexcitability disorders such as Ohtahara syndrome (7), Lennox-Gastaut syndrome (8), Status Dystonicus (9), West syndrome, leukoencephalopathies and Brugada syndrome (2). Pathogenic cardiac effects and 'collateralopathies' arising from KCNT1 variants are becoming more widely reported (10)(11)(12). KCNT1 encodes the K Na 1.1 subunit (Slack, or previously Slo2.2 or K Ca 4.1), which forms a tetrameric potassium channel that is activated by intracellular Na + and is widely distributed in the central nervous system.…”

Section: Introductionmentioning

confidence: 99%

“…Pathogenic cardiac effects and 'collateralopathies' arising from KCNT1 variants are becoming more widely reported [10][11][12] .…”

Section: Introductionmentioning

confidence: 99%

Epilepsy-causing KCNT1 variants increase K_Na1.1 channel activity by disrupting the activation gate

Cole

Pilati

Lippiat

2021

Preprint

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Gain-of-function pathogenic missense KCNT1 variants are associated with several developmental and epileptic encephalopathies (DEE). With few exceptions, patients are heterozygous and there is a paucity of mechanistic information about how pathogenic variants increase KNa1.1 channel activity and the behaviour of heterotetrameric channels comprising both wild-type (WT) and variant subunits. To better understand these, we selected a range of variants across the DEE spectrum, involving mutations in different protein domains and studied their functional properties. Whole-cell electrophysiology was used to characterise homomeric and heteromeric KNa1.1 channel assemblies carrying DEE-causing variants in the presence and absence of 10 mM intracellular sodium. Voltage-dependent activation of homomeric variant KNa1.1 assemblies were more hyperpolarised than WT KNa1.1 and, unlike WT KNa1.1, exhibited voltage-dependent activation in the absence of intracellular sodium. Heteromeric channels formed by co-expression of WT and variant KNa1.1 had activation kinetics intermediate of homomeric WT and variant KNa1.1 channels, with residual sodium-independent activity. In general, WT and variant KNa1.1 activation followed a single exponential, with time constants unaffected by voltage or sodium. Mutating the threonine in the KNa1.1 selectivity filter disrupted voltage-dependent activation, but sodium-dependence remained intact. Our findings suggest that KNa1.1 gating involves a sodium-dependent activation gate that modulates a voltage-dependent selectivity filter gate. Collectively, all DEE-associated KNa1.1 mutations lowered the energetic barrier for sodium-dependent activation, but some also had direct effects on selectivity filter gating. Destabilisation of the inactivated unliganded channel conformation can explain how DEE-causing amino acid substitutions in diverse regions of the channel structure all cause gain-of-function.

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Cardiac phenotypic spectrum ofKCNT1mutations

Cited by 10 publications

References 17 publications

KCNH2 variants in a family with epilepsy and long QT syndrome: A case report and literature review

KCNH2 variants in a family with epilepsy and long QT syndrome: A case report and literature review

Targeting KNa1.1 channels in KCNT1-associated epilepsy

Epilepsy-causing KCNT1 variants increase K_Na1.1 channel activity by disrupting the activation gate

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Cardiac phenotypic spectrum ofKCNT1mutations

Cited by 10 publications

References 17 publications

KCNH2 variants in a family with epilepsy and long QT syndrome: A case report and literature review

KCNH2 variants in a family with epilepsy and long QT syndrome: A case report and literature review

Targeting KNa1.1 channels in KCNT1-associated epilepsy

Epilepsy-causing KCNT1 variants increase KNa1.1 channel activity by disrupting the activation gate

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Product

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Epilepsy-causing KCNT1 variants increase K_Na1.1 channel activity by disrupting the activation gate