Recurrent pulmonary hemorrhage in juvenile patients with <i>KCNT1</i> mutation

Ikeda, Azusa; Ueda, Hideaki; Iai, Mizue; Goto, Tomohide

doi:10.1111/ped.14427

Cited by 4 publications

(4 citation statements)

References 5 publications

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“…Even after multiple catheter-based interventions, these patients can have recalcitrant pulmonary haemorrhage, which may result in repeated hospitalizations or death. 4,5 In a young child with developmental delay, pulmonary haemorrhage may masquerade as epistaxis or haematemesis. A high index of suspicion is required to diagnose and treat pulmonary haemorrhage in these patients.…”

Section: Discussionmentioning

confidence: 99%

Life-threatening pulmonary haemorrhage treated with coil embolisation followed by lobectomy in a patient with KCNT1 mutation

Chauhan,

Verhoeven,

Kohli

et al. 2024

Cardiol Young

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Section: Discussionmentioning

confidence: 99%

Life-threatening pulmonary haemorrhage treated with coil embolisation followed by lobectomy in a patient with KCNT1 mutation

Chauhan,

Verhoeven,

Kohli

et al. 2024

Cardiol Young

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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%

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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Recurrent pulmonary hemorrhage in juvenile patients with KCNT1 mutation

Cited by 4 publications

References 5 publications

Life-threatening pulmonary haemorrhage treated with coil embolisation followed by lobectomy in a patient with KCNT1 mutation

Life-threatening pulmonary haemorrhage treated with coil embolisation followed by lobectomy in a patient with KCNT1 mutation

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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Recurrent pulmonary hemorrhage in juvenile patients with KCNT1 mutation

Cited by 4 publications

References 5 publications

Life-threatening pulmonary haemorrhage treated with coil embolisation followed by lobectomy in a patient with KCNT1 mutation

Life-threatening pulmonary haemorrhage treated with coil embolisation followed by lobectomy in a patient with KCNT1 mutation

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