Correlation Analyses of Clinical Manifestations and Variant Effects in KCNB1-Related Neurodevelopmental Disorder

Xiong, Juan; Z, Liu; Chen, Shimeng; Kessi, Miriam; Chen, Baiyu; Duan, Haolin; Deng, Xingming; Yang, Lifen; Peng, Jing; Yin, Fei

doi:10.3389/fped.2021.755344

Cited by 7 publications

(11 citation statements)

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“…Of the 55 distinct missense or loss of function mutations previously described ( de Kovel et al, 2017 ; Bar et al, 2020 ; Xiong et al, 2022 ), 49 of them were located in the S1-S6 transmembrane segments of the protein, 5 were in the C terminus and just 1 of the mutations (a missense mutation, E43G) was located in the N terminus of the channel similar to P17T. Whilst the patient with this E43G mutation did suffer from epileptic seizures they also had a predicted damaging mutation in the GABA A receptor GABRA5 which may underlie many if not all of the clinical symptoms observed ( Bar et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

“…In this study, a 5 years old boy with neurodevelopmental delay, speech apraxia, normal growth, normal EKG, and normal EEG with no seizures, was found to have a de novo variant in KCNB1 (p.P17T; c49C>A). Proline 17 is located in the N-terminal region of the K V 2.1 channel, proximal to the inactivation domain, which is distinct from all but one of the mutations described above ( de Kovel et al, 2017 ; Bar et al, 2020 ; Xiong et al, 2022 , Figure 1 ). This is a non-conservative amino acid substitution likely to impact secondary protein structure and, as such, is predicted to be a likely pathogenic variant.…”

Section: Introductionmentioning

confidence: 95%

“…Mutations of K V 2.1 channels underlie epileptic encephalopathies, infantile epilepsy, autism and other neurodevelopmental disorders in identified individuals ( Torkamani et al, 2014 ; Saitsu et al, 2015 ; Thiffault et al, 2015 ; Calhoun et al, 2017 ). More recent studies have extended identification of K V 2.1 variants to 74 patients with 55 distinct missense or loss of function mutations ( de Kovel et al, 2017 ; Bar et al, 2020 ; Xiong et al, 2022 ). 85% of the patients examined (62/73) developed epilepsy and all examined (73/73) had developmental delays, albeit with varying degrees of severity ( de Kovel et al, 2017 ; Bar et al, 2020 ; Xiong et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

“…More recent studies have extended identification of K V 2.1 variants to 74 patients with 55 distinct missense or loss of function mutations ( de Kovel et al, 2017 ; Bar et al, 2020 ; Xiong et al, 2022 ). 85% of the patients examined (62/73) developed epilepsy and all examined (73/73) had developmental delays, albeit with varying degrees of severity ( de Kovel et al, 2017 ; Bar et al, 2020 ; Xiong et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

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A KCNB1 gain of function variant causes developmental delay and speech apraxia but not seizures

et al. 2022

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Objective: Numerous pathogenic variants in KCNB1, which encodes the voltage-gated potassium channel, KV2.1, are linked to developmental and epileptic encephalopathies and associated with loss-of-function, -regulation, and -expression of the channel. Here we describe a novel de novo variant (P17T) occurring in the KV2.1 channel that is associated with a gain-of-function (GoF), with altered steady-state inactivation and reduced sensitivity to the selective toxin, guanxitoxin-1E and is clinically associated with neurodevelopmental disorders, without seizures.Methods: The autosomal dominant variant was identified using whole exome sequencing (WES). The functional effects of the KCNB1 variant on the encoded KV2.1 channel were investigated using whole-cell patch-clamp recordings.Results: We identified a de novo missense variant in the coding region of the KCNB1 gene, c.49C>A which encodes a p.P17T mutation in the N-terminus of the voltage-gated, KV2.1 potassium channel. Electrophysiological studies measuring the impact of the variant on the functional properties of the channel, identified a gain of current, rightward shifts in the steady-state inactivation curve and reduced sensitivity to the blocker, guanxitoxin-1E.Interpretation: The clinical evaluation of this KCNB1 mutation describes a novel variant that is associated with global developmental delays, mild hypotonia and joint laxity, but without seizures. Most of the phenotypic features described are reported for other variants of the KCNB1 gene. However, the absence of early-onset epileptic disorders is a much less common occurrence. This lack of seizure activity may be because other variants reported have resulted in loss-of-function of the encoded KV2.1 potassium channel, whereas this variant causes a gain-of-function.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A KCNB1 gain of function variant causes developmental delay and speech apraxia but not seizures

et al. 2022

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“…In China, Lu et al 31 found a novel de novo KCNB1 variant leading to developmental and epileptic encephalopathy. Xiong et al 32 reported 10 Chinese children with KCNB1 ‐related neurodevelopmental disorders. Nine of those ten patients suffered from epilepsy.…”

Section: Kcnb1 In Epilepsymentioning

confidence: 99%

Potassium channels and epilepsy

Gao

Lin

Wen

et al. 2022

Acta Neuro Scandinavica

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With the development and application of next‐generation sequencing technology, the aetiological diagnosis of genetic epilepsy is rapidly becoming easier and less expensive. Additionally, there is a growing body of research into precision therapy based on genetic diagnosis. The numerous genes in the potassium ion channel family constitute the largest family of ion channels: this family is divided into different subtypes. Potassium ion channels play a crucial role in the electrical activity of neurons and are directly involved in the mechanism of epileptic seizures. In China, scientific research on genetic diagnosis and studies of precision therapy for genetic epilepsy are progressing rapidly. Many cases of epilepsy caused by mutation of potassium channel genes have been identified, and several potassium channel gene targets and drug candidates have been discovered. The purpose of this review is to briefly summarize the progress of research on the precise diagnosis and treatment of potassium ion channel‐related genetic epilepsy, especially the research conducted in China. Here in, we review several large cohort studies on the genetic diagnosis of epilepsy in China in recent years, summarized the proportion of potassium channel genes. We focus on the progress of precison therapy on some hot epilepsy related potassium channel genes: KCNA1, KCNA2, KCNB1, KCNC1, KCND2, KCNQ2, KCNQ3, KCNMA1, and KCNT1.

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Potassium channel‐related epilepsy: Pathogenesis and clinical features

Zhao,

Wang,

Chen

2024

Epilepsia Open

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Variants in potassium channel‐related genes are one of the most important mechanisms underlying abnormal neuronal excitation and disturbances in the cellular resting membrane potential. These variants can cause different forms of epilepsy, which can seriously affect the physical and mental health of patients, especially those with refractory epilepsy or status epilepticus, which are common among pediatric patients and are potentially life‐threatening. Variants in potassium ion channel‐related genes have been reported in few studies; however, to our knowledge, no systematic review has been published. This study aimed to summarize the epilepsy phenotypes, functional studies, and pharmacological advances associated with different potassium channel gene variants to assist clinical practitioners and drug development teams to develop evidence‐based medicine and guide research strategies. PubMed and Google Scholar were searched for relevant literature on potassium channel‐related epilepsy reported in the past 5–10 years. Various common potassium ion channel gene variants can lead to heterogeneous epilepsy phenotypes, and functional effects can result from gene deletions and compound effects. Administration of select anti‐seizure medications is the primary treatment for this type of epilepsy. Most patients are refractory to anti‐seizure medications, and some novel anti‐seizure medications have been found to improve seizures. Use of targeted drugs to correct aberrant channel function based on the type of potassium channel gene variant can be used as an evidence‐based pathway to achieve precise and individualized treatment for children with epilepsy.Plain Language SummaryIn this article, the pathogenesis and clinical characteristics of epilepsy caused by different types of potassium channel gene variants are reviewed in the light of the latest research literature at home and abroad, with the expectation of providing a certain theoretical basis for the diagnosis and treatment of children with this type of disease.

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Correlation Analyses of Clinical Manifestations and Variant Effects in KCNB1-Related Neurodevelopmental Disorder

Cited by 7 publications

References 33 publications

A KCNB1 gain of function variant causes developmental delay and speech apraxia but not seizures

A KCNB1 gain of function variant causes developmental delay and speech apraxia but not seizures

Potassium channels and epilepsy

Potassium channel‐related epilepsy: Pathogenesis and clinical features

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