ArticleHuman molecular genetics2014
Exome sequencing identifies de novo gain of function missense mutation in KCND2 in identical twins with autism and seizures that slows potassium channel inactivation.
Article in Human molecular genetics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 68 papers.
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Who cites it
68 citing papers in PubMed, 121 citations in OpenAlex.
- Article
- Discovery of Kv3.1 channel inhibitors reveals VU0521426 as a state-dependent inactivator preferentially active against pathogenic gain-of-function mutants.American journal of physiology. Cell physiology · 2026Article
- Kv4.2The Journal of neuroscience : the official journal of the Society for Neuroscience · 2026Article
- Astrocytes at the interface of peri-ictal breathing dysfunction and SUDEP.Frontiers in network physiology · 2026Review
- The Crucial Interplay Between the Lungs, Brain, and Heart to Understand Epilepsy-Linked SUDEP: A Literature Review.Brain sciences · 2025Review
- A deep learning model for prediction of autism status using whole-exome sequencing data.PLoS computational biology · 2024Article
- Article
- Zebrafish models of candidate human epilepsy-associated genes provide evidence of hyperexcitability.iScience · 2024Article
- Etiological involvement of KCND1 variants in an X-linked neurodevelopmental disorder with variable expressivity.American journal of human genetics · 2024Article
- Overexpression of KCNN4 channels in principal neurons produces an anti-seizure effect without reducing their coding ability.Gene therapy · 2024Article
- Design of Ultrapotent Genetically Encoded Inhibitors of Kv4.2 for Gating Neural Plasticity.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2024Article
- Zebrafish models of candidate human epilepsy-associated genes provide evidence of hyperexcitability.bioRxiv : the preprint server for biology · 2024Article
- Article
- Potential roles of voltage-gated ion channel disruption in Tuberous Sclerosis Complex.Frontiers in molecular neuroscience · 2024Article
- Loss of NSD2 causes dysregulation of synaptic genes and altered H3K36 dimethylation in mice.Frontiers in genetics · 2024Article
- Voltage-gated potassium channels and genetic epilepsy.Frontiers in neurology · 2024Review
- Ion currents through the voltage sensor domain of distinct families of proteins.Journal of biological physics · 2023Review
- De novo KCNA6 variants with attenuated KEpilepsia · 2023Article
- Developmental and epileptic encephalopathies: from genetic heterogeneity to phenotypic continuum.Physiological reviews · 2023Review
- Whole-genome sequencing reveals the genetic mechanisms of domestication in classical inbred mice.Genome biology · 2022Article
8 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
Abstract
Numerous studies and case reports show comorbidity of autism and epilepsy, suggesting some common molecular underpinnings of the two phenotypes. However, the relationship between the two, on the molecular level, remains unclear. Here, whole exome sequencing was performed on a family with identical twins affected with autism and severe, intractable seizures. A de novo variant was identified in the KCND2 gene, which encodes the Kv4.2 potassium channel. Kv4.2 is a major pore-forming subunit in somatodendritic subthreshold A-type potassium current (ISA) channels. The de novo mutation p.Val404Met is novel and occurs at a highly conserved residue within the C-terminal end of the transmembrane helix S6 region of the ion permeation pathway. Functional analysis revealed the likely pathogenicity of the variant in that the p.Val404Met mutant construct showed significantly slowed inactivation, either by itself or after equimolar coexpression with the wild-type Kv4.2 channel construct consistent with a dominant effect. Further, the effect of the mutation on closed-state inactivation was evident in the presence of auxiliary subunits that associate with Kv4 subunits to form ISA channels in vivo. Discovery of a functionally relevant novel de novo variant, coupled with physiological evidence that the mutant protein disrupts potassium current inactivation, strongly supports KCND2 as the causal gene for epilepsy in this family. Interaction of KCND2 with other genes implicated in autism and the role of KCND2 in synaptic plasticity provide suggestive evidence of an etiological role in autism.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.