title: Exome sequencing identifies de novo gain of function missense mutation in KCND2 in identical twins with autism and seizures that slows potassium channel inactivation.
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.
authors: Department of Pathology and Laboratory Medicine.
authors: Hane
authors: H
authors: Lee
authors: Department of Physiology.
authors: Meng-chin A
authors: MC
authors: Lin
authors: Department of Psychiatry, Department of Molecular and Medical Pharmacology, Department of Pediatrics.
authors: Harley I
authors: HI
authors: Kornblum
authors: Department of Physiology.
authors: Diane M
authors: DM
authors: Papazian
authors: Department of Pathology and Laboratory Medicine, Department of Human Genetics, University of California, Los Angeles, CA 90095, USA snelson@ucla.edu.
authors: Stanley F
authors: SF
authors: Nelson
mesh_terms: D001321:Autistic Disorder / Q000235:genetics*; D004594:Electrophysiology; D059472:Exome / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D009154:Mutation; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism*; D012640:Seizures / Q000235:genetics*; D051672:Shal Potassium Channels / Q000235:genetics* / Q000378:metabolism
chemical_list: C497018:KCND2 protein, human; D015221:Potassium Channels; D051672:Shal Potassium Channels