A novel epileptic encephalopathy mutation in <i>KCNB1</i> disrupts Kv2.1 ion selectivity, expression, and localization

Thiffault, Isabelle; Speca, David J.; Austin, Daniel C.; Cobb, Melanie M.; Eum, Kenneth S.; Safina, Nicole P.; Grote, Lauren; Farrow, Emily; Miller, Neil; Soden, Sarah E; Kingsmore, Stephen F.; Trimmer, James S.; Saunders, Carol J.; Sack, Jon T.

doi:10.1085/jgp.201511444

Cited by 80 publications

(117 citation statements)

References 70 publications

(116 reference statements)

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“…Developmental regression can occur in early childhood [21, 22]. In some cases, patients demonstrate behavioral abnormalities, like autistic features [23], stereotyped hand-wringing [24], hyperactivity, irritability, agitation, and aggression [25].…”

Section: Discussionmentioning

confidence: 99%

Monogenic disorders that mimic the phenotype of Rett syndrome

et al. 2018

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Background. Rett syndrome (RTT) is caused by mutations in methyl-CpG binding protein 2 (MECP2), but defects in a handful of other genes (e.g., CDKL5, FOXG1, MEF2C) can lead to presentations that resemble, but do not completely mirror, classical RTT. In this study, we attempted to identify other monogenic disorders that share features with RTT. Methods. We performed a retrospective chart review on n=319 patients who had undergone clinical whole exome sequencing (WES) for further etiological evaluation of neurodevelopmental diagnoses that remained unexplained despite extensive prior workup. From this group, we characterized those who (1) possessed features that were compatible with RTT based on clinical judgment (2) subsequently underwent MECP2 sequencing and/or MECP2 deletion/duplication analysis with negative results (3) ultimately arrived at a diagnosis other than RTT with WES. Results. n=7 patients had clinical features overlapping RTT with negative MECP2 analysis but positive WES providing a diagnosis. These 7 patients collectively possessed pathogenic variants in 6 different genes: two in KCNB1 and one each in FOXG1, IQSEC2, MEIS2, TCF4, and WDR45. n=2 (both with KCNB1 variants) fulfilled criteria for atypical RTT. RTT associated features included the following: loss of hand or language skills (n=3; IQSEC2, KCNB1 × 2); disrupted sleep (n=4; KNCB1, MEIS2, TCF4, WDR45); stereotyped hand movements (n=5; FOXG1, KNCB1 × 2, MEIS2, TCF4); bruxism (n=3; KCNB1 × 2; TCF4); and hypotonia (n=7). Conclusion. Clinically-based diagnoses can be misleading, evident by the increasing number of genetic conditions associated with features of RTT with negative MECP2 mutations.

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Section: Discussionmentioning

confidence: 99%

Monogenic disorders that mimic the phenotype of Rett syndrome

et al. 2018

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“…; Thiffault et al . ). While Kv1.2 is localized to axons and involved in the transmission of electrical signals, Kv2.1 is localized to soma and dendrites and contributes to the integration of the incoming signals.…”

Section: Genesmentioning

confidence: 97%

Models for discovery of targeted therapy in genetic epileptic encephalopathies

Maljevic

Reid

Petrou

2017

Journal of Neurochemistry

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Epileptic encephalopathies are severe disorders emerging in the first days to years of life that commonly include refractory seizures, various types of movement disorders, and different levels of developmental delay. In recent years, many de novo occurring variants have been identified in individuals with these devastating disorders. To unravel disease mechanisms, the functional impact of detected variants associated with epileptic encephalopathies is investigated in a range of cellular and animal models. This review addresses efforts to advance and use such models to identify specific molecular and cellular targets for the development of novel therapies. We focus on ion channels as the best-studied group of epilepsy genes. Given the clinical and genetic heterogeneity of epileptic encephalopathy disorders, experimental models that can reflect this complexity are critical for the development of disease mechanisms-based targeted therapy. The convergence of technological advances in gene sequencing, stem cell biology, genome editing, and high throughput functional screening together with massive unmet clinical needs provides unprecedented opportunities and imperatives for precision medicine in epileptic encephalopathies.

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“…Human mutations in KCNB1 cause several forms of epilepsy but no cardiac phenotype (Saitsu et al, 2015; Thiffault et al, 2015; Torkamani et al, 2014), suggesting that this gene does not play a prominent role in human cardiac function.…”

Section: Transmural Gradients In Delayed Rectifier Potassium Currentsmentioning

confidence: 99%

Transmural gradients in ion channel and auxiliary subunit expression

McKinnon

Rosati

2016

Progress in Biophysics and Molecular Biology

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Evolution has acted to shape the action potential in different regions of the heart in order to produce a maximally stable and efficient pump. This has been achieved by creating regional differences in ion channel expression levels within the heart as well as differences between equivalent cardiac tissues in different species. These region- and species-dependent differences in channel expression are established by regulatory evolution, evolution of the regulatory mechanisms that control channel expression levels. Ion channel auxiliary subunits are obvious targets for regulatory evolution, in order to change channel expression levels and/or modify channel function. This review focuses on the transmural gradients of ion channel expression in the heart and the role that regulation of auxiliary subunit expression plays in generating and shaping these gradients.

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A novel epileptic encephalopathy mutation in KCNB1 disrupts Kv2.1 ion selectivity, expression, and localization

Abstract: A missense mutation in the pore-forming α subunit of a delayed rectifier Kv channel is associated with epileptic encephalopathy, alters the cation selectivity of voltage-gated currents, and disrupts channel expression and localization.

Cited by 80 publications

References 70 publications

Monogenic disorders that mimic the phenotype of Rett syndrome

Monogenic disorders that mimic the phenotype of Rett syndrome

Models for discovery of targeted therapy in genetic epileptic encephalopathies

Transmural gradients in ion channel and auxiliary subunit expression

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