De novo gain-of-function KCNT1 channel mutations cause malignant migrating partial seizures of infancy

Abstract

Malignant migrating partial seizures of infancy (MMPSI) is a rare epileptic encephalopathy of infancy that combines pharmacoresistant seizures with developmental delay1. We performed exome sequencing in 3 probands with MMPSI and identified de novo gain-of-function mutations in the C-terminal domain of the KCNT1 potassium channel. We sequenced KCNT1 in 9 additional patients with MMPSI and identified mutations in 4 of them, in total identifying mutations in 6 out of 12 unrelated patients. Functional studies showed that the mutations led to constitutive activation of the channel, mimicking the effects of phosphorylation of the C-terminal domain by protein kinase C. In addition to regulating ion flux, KCNT1 has a non conducting function as its C terminus interacts with cytoplasmic proteins involved in developmental signaling pathways. These results provide a target for future diagnostic approaches and research in this devastating condition.

An ALS-Associated Mutant SOD1 Rapidly Suppresses KCNT1 (Slack) Na+-Activated K+Channels inAplysiaNeurons

“…Slack and the closely related Slick (K Na 1.2) channels are broadly distributed in the CNS and highly expressed in a variety of motor neurons . Slack channels coimmunoprecipitate with neuronal mRNAs, and their cytoplasmic C terminus binds proteins that regulate mRNA translation, suggesting that channel activity may regulate protein synthesis (Brown et al, 2010;Zhang et al, 2012). Moreover, activation of Slack channels causes the dissociation of Phactr-1, a protein that interacts with phosphatases and with the actin cytoskeleton (Fleming et al, 2016).…”

“…The activation of these channels produces an outward current that directly opposes the inward current that flows through Na ϩ channels, and the resultant persistent current is determined by the balance of Na ϩ and K Na currents (Hage and Salkoff, 2012). Human genetic mutations in KCNT1 cause earlyonset epilepsies but also severely impact neuronal development and intellectual function, likely because these channels interact directly with proteins that regulate activity-dependent translation of mRNAs (Brown et al, 2010;Barcia et al, 2012;Heron et al, 2012;Kim and Kaczmarek, 2014).…”

“…Both in vitro studies and examination of transgenic mice have enabled study of the physiology and toxicity of mutant SOD1. Toxicity likely relates to misfolding and oligomerization/aggregation of misfolded species (Bruijn et al, 2004;Lindberg et al, 2005;Valentine et al, 2005;Hart, 2006). The proximate targets of the misfolded SOD1 species that mediate toxicity are not precisely known, but effects have been reported on mitochondria, ER, and axonal trafficking (Pasinelli and Brown, 2006;Matus et al, 2013).…”

Genetic Epilepsy Syndromes Without Structural Brain Abnormalities: Clinical Features and Experimental Models

“…WES studies or targeted sequencing of panels of selected genes of probands and their parents, or of small families with affected siblings, also show that genes previously associated with milder nonlesional phenotypes, including GABRA1 and, as highlighted above, SCN2A and KCNQ2, might also cause EE in some patients [115]. De novo gainof-function mutations in the KCNT1 gene, on chromosome 9q34, have been identified in patients with malignant migrating partial seizures of infancy, a rare syndrome with infantile onset intractable and migrating focal seizures with severe impairment of psychomotor development [118]. Likewise, most of the currently known epilepsy genes and mutations in KCNT1 gene have been associated with additional and very different epilepsy phenotypes, including autosomal dominant nocturnal frontal lobe epilepsy [119].…”

Epileptic Encephalopathies: New Genes and New Pathways

“…Although the prevalence is unknown, only approximately 100 cases of MMPSI have been described in the medical literature. De novo gain of function mutations in the KCNT1 gene have been found in several individuals with this condition and are the most common known cause of MMPSI [54]. A recent study reported a mutation in SCNA8 in one of 6 MMPSI cases [55].…”