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Identification of a novel de novo p.Phe932Ile KCNT1 mutation in a patient with leukoencephalopathy and severe epilepsy.

ABSTRACT: BACKGROUND:More than half of patients with genetic leukoencephalopathies remain without a specific diagnosis; this is particularly true in individuals with a likely primary neuronal etiology, such as those in which abnormal white matter occurs in combination with severe epilepsy. PATIENT:A child with a severe early infantile epileptic encephalopathy and abnormal myelination underwent whole exome sequencing. RESULTS:Whole exome sequencing identified a heterozygous de novo mutation in KCNT1, a sodium-gated potassium channel gene. CONCLUSIONS:Severely delayed myelination was anecdotally reported in previous patients with KCNT1 mutations. This case reinforces that KCNT1 sequencing should be included in an investigation of patients with severely delayed myelination and epilepsy.

SUBMITTER: Vanderver A

PROVIDER: S-EPMC4303471 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Identification of a novel de novo p.Phe932Ile KCNT1 mutation in a patient with leukoencephalopathy and severe epilepsy.

Vanderver Adeline A Simons Cas C Schmidt Johanna L JL Pearl Philip L PL Bloom Miriam M Lavenstein Bennett B Miller David D Grimmond Sean M SM Taft Ryan J RJ

Pediatric neurology 20131010 1

<h4>Background</h4>More than half of patients with genetic leukoencephalopathies remain without a specific diagnosis; this is particularly true in individuals with a likely primary neuronal etiology, such as those in which abnormal white matter occurs in combination with severe epilepsy.<h4>Patient</h4>A child with a severe early infantile epileptic encephalopathy and abnormal myelination underwent whole exome sequencing.<h4>Results</h4>Whole exome sequencing identified a heterozygous de novo mu ...[more]

PMID: 24120652

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The Phe932Ile mutation in KCNT1 channels associated with severe epilepsy, delayed myelination and leukoencephalopathy produces a loss-of-function channel phenotype.

Project description:Sodium-activated potassium (KNa) channels contribute to firing frequency adaptation and slow after hyperpolarization. The KCNT1 gene (also known as SLACK) encodes a KNa subunit that is expressed throughout the central and peripheral nervous systems. Missense mutations of the SLACK C-terminus have been reported in several patients with rare forms of early onset epilepsy and in some cases severely delayed myelination. To date, such mutations identified in patients with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), epilepsy of infancy with migrating focal seizures (EIMFS) and Ohtahara syndrome (OS) have been reported to be gain-of-function mutations (Villa and Combi, 2016). An exome sequencing study identified a p.Phe932Ile KCNT1 mutation as the disease-causing change in a child with severe early infantile epileptic encephalopathy and abnormal myelination (Vanderver et al., 2014). We characterized an analogous mutation in the rat Slack channel and unexpectedly found this mutation to produce a loss-of-function phenotype. In an effort to restore current, we tested the known Slack channel opener loxapine. Loxapine exhibited no effect, indicating that this mutation either caused the channel to be insensitive to this established opener or proper translation and trafficking to the membrane was disrupted. Protein analysis confirmed that while total mutant protein did not differ from wild type, membrane expression of the mutant channel was substantially reduced. Although gain-of-function mutations to the Slack channel are linked to epileptic phenotypes, this is the first reported loss-of-function mutation linked to severe epilepsy and delayed myelination.

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