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.2014 Jul 1;23(13):3481-9.
doi: 10.1093/hmg/ddu056. Epub 2014 Feb 5.

Exome sequencing identifies de novo gain of function missense mutation in KCND2 in identical twins with autism and seizures that slows potassium channel inactivation

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Exome sequencing identifies de novo gain of function missense mutation in KCND2 in identical twins with autism and seizures that slows potassium channel inactivation

Hane Lee et al. Hum Mol Genet..

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.

© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

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Figures

Figure 1.
Figure 1.
(A) Pedigree of the family. (B) Amino acid positions where predicted-to-be-damaging (probably damaging or possibly damaging by PolyPhen) missense variants are found in the population (exome variant server) are indicated. The *404 position is where thede novo variant was found.
Figure 2.
Figure 2.
p.Val404Met mutation impairs closed-state inactivation in Kv4.2 channels. (A,C andE) Representative current traces were recorded in Xenopus oocytes after expressing wild-type Kv4.2 (left), the p.Val404Met mutant protein (middle), or a 1:1 mixture of wild-type and mutant (right) in the A) absence or presence of the C) KChIP3a or E) DPP10a auxiliary subunits. Currents were evoked by pulsing for 150 ms from a holding potential of −100 mV to voltages ranging from −80 to +70 mV in 10 mV increments. For clarity, only every other trace is shown. (B,D andF) Current traces evoked at +60 mV have been scaled and overlaid after expressing wild-type Kv4.2 (WT, black), the p.Val404Met mutant protein (mutant, red), or a 1:1 mixture of wild-type and mutant (1:1, green) in the B) absence or presence of the D) KChIP3a or F) DPP10a auxiliary subunits. Pulse durations of 150 ms (left) and 1 s (right) are shown.
Figure 3.
Figure 3.
p.Val404Met mutation slows time to reach peak current amplitude and increases amplitude of current remaining at end of pulse. The box plots show the time to reach peak current amplitude at +60 mV (left panels) and the ratio of current amplitude at the end of a 150 ms pulse relative to the peak current amplitude measured at +60 mV (I150ms/Ipeak, right panels) after expressing wild-type Kv4.2, the p.Val404Met mutant protein, or a 1:1 mixture of wild-type and mutant (1:1) in the (A) absence or presence of the (B) KChIP3a or (C) DPP10a auxiliary subunits. The mean time to peak values (ms) ± SEM were: (A) wild-type, 7.7 ± 0.4 (n = 14); p.Val404Met, 19.8 ± 1.0 (n = 17); 1:1 mixture, 14.8 ± 1.4 (n = 6); (B) wild-type, 12.2 ± 1.3 (n = 8); p.Val404Met, 23.1 ± 1.7 (n = 9), 1:1 mixture, 17.3 ± 0.9 (n = 5); and (C) wild-type, 2.3 ± 0.5 (n = 4); p.Val404Met, 5.1 ± 1.6 (n = 4). The mean values of I150ms/Ipeak ± SEM were: (A) wild-type, 0.25 ± 0.02 (n = 11); p.Val404Met, 0.74 ± 0.02 (n = 21), and 1:1 mixture, 0.69 ± 0.02 (n = 6); (B) wild-type, 0.61 ± 0.03 (n = 8); p.Val404Met, 0.96 ± 0.01 (n = 9); 1:1 mixture, 0.91 ± 0.01 (n = 5); and C) wild-type, 0.16 ± 0.04 (n = 4); p.Val404Met, 0.54 ± 0.10 (n = 4). Statistical significance was evaluated by one-way ANOVA followed by Student'st-test: ****P < 0.00001 compared with wild-type alone; ***P < 0.0005 compared with wild-type alone; **P < 0.005 compared with wild-type alone; *P < 0.05 compared with wild-type alone; ‡,P < 0.05 compared with p.Val404Met alone.
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