Dysfunction of the heteromeric KV7.3/KV7.5 potassium channel is associated with autism spectrum disorders

Mette Gilling Nielsen; Hanne Borger Rasmussen; Kirstine Callø; Ana F. Sequeira; Marta Baretto; Guiomar Oliveira; Joana  Almeida; Malene B. Lauritsen; Reinhard  Ullmann; Susanne Eriksen Boonen; Karen Brøndum-Nielsen; Vera M. Kalscheuer; Zeynep Tümer; Astrid M. Vicente; Nicole Schmitt; Niels Tommerup

doi:10.3389/fgene.2013.00054

Dysfunction of the heteromeric K_V7.3/K_V7.5 potassium channel is associated with autism spectrum disorders

Mette Gilling Nielsen, Hanne Borger Rasmussen, Kirstine Callø, Ana F. Sequeira, Marta Baretto, Guiomar Oliveira, Joana Almeida, Malene B. Lauritsen, Reinhard Ullmann, Susanne Eriksen Boonen, Karen Brøndum-Nielsen, Vera M. Kalscheuer, Zeynep Tümer, Astrid M. Vicente, Nicole Schmitt, Niels Tommerup

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Abstract

Heterozygous mutations in the KCNQ3 gene on chromosome 8q24 encoding the voltage-gated potassium channel KV7.3 subunit have previously been associated with rolandic epilepsy and idiopathic generalized epilepsy (IGE) including benign neonatal convulsions. We identified a de novo t(3;8) (q21;q24) translocation truncating KCNQ3 in a boy with childhood autism. In addition, we identified a c.1720C¿>¿T [p.P574S] nucleotide change in three unrelated individuals with childhood autism and no history of convulsions. This nucleotide change was previously reported in patients with rolandic epilepsy or IGE and has now been annotated as a very rare SNP (rs74582884) in dbSNP. The p.P574S KV7.3 variant significantly reduced potassium current amplitude in Xenopus laevis oocytes when co-expressed with KV7.5 but not with KV7.2 or KV7.4. The nucleotide change did not affect trafficking of heteromeric mutant KV7.3/2, KV7.3/4, or KV7.3/5 channels in HEK 293 cells or primary rat hippocampal neurons. Our results suggest that dysfunction of the heteromeric KV7.3/5 channel is implicated in the pathogenesis of some forms of autism spectrum disorders, epilepsy, and possibly other psychiatric disorders and therefore, KCNQ3 and KCNQ5 are suggested as candidate genes for these disorders.

Original language	English
Journal	Frontiers in Genetics
Volume	4
Issue number	54
Pages (from-to)	1-13
Number of pages	13
ISSN	1664-8021
DOIs	https://doi.org/10.3389/fgene.2013.00054
Publication status	Published - 2013

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Nielsen, M. G., Rasmussen, H. B., Callø, K., F. Sequeira, A., Baretto, M., Oliveira, G., Almeida, J., B. Lauritsen, M., Ullmann, R., Boonen, S. E., Brøndum-Nielsen, K., M. Kalscheuer, V., Tümer, Z., M. Vicente, A., Schmitt, N., & Tommerup, N. (2013). Dysfunction of the heteromeric K_V7.3/K_V7.5 potassium channel is associated with autism spectrum disorders. Frontiers in Genetics, 4(54), 1-13. https://doi.org/10.3389/fgene.2013.00054

Nielsen, MG, Rasmussen, HB , Callø, K, F. Sequeira, A, Baretto, M, Oliveira, G, Almeida, J, B. Lauritsen, M, Ullmann, R, Boonen, SE, Brøndum-Nielsen, K, M. Kalscheuer, V, Tümer, Z, M. Vicente, A, Schmitt, N & Tommerup, N 2013, 'Dysfunction of the heteromeric K_V7.3/K_V7.5 potassium channel is associated with autism spectrum disorders', Frontiers in Genetics, vol. 4, no. 54, pp. 1-13. https://doi.org/10.3389/fgene.2013.00054

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title = "Dysfunction of the heteromeric KV7.3/KV7.5 potassium channel is associated with autism spectrum disorders",

abstract = "Heterozygous mutations in the KCNQ3 gene on chromosome 8q24 encoding the voltage-gated potassium channel KV7.3 subunit have previously been associated with rolandic epilepsy and idiopathic generalized epilepsy (IGE) including benign neonatal convulsions. We identified a de novo t(3;8) (q21;q24) translocation truncating KCNQ3 in a boy with childhood autism. In addition, we identified a c.1720C¿>¿T [p.P574S] nucleotide change in three unrelated individuals with childhood autism and no history of convulsions. This nucleotide change was previously reported in patients with rolandic epilepsy or IGE and has now been annotated as a very rare SNP (rs74582884) in dbSNP. The p.P574S KV7.3 variant significantly reduced potassium current amplitude in Xenopus laevis oocytes when co-expressed with KV7.5 but not with KV7.2 or KV7.4. The nucleotide change did not affect trafficking of heteromeric mutant KV7.3/2, KV7.3/4, or KV7.3/5 channels in HEK 293 cells or primary rat hippocampal neurons. Our results suggest that dysfunction of the heteromeric KV7.3/5 channel is implicated in the pathogenesis of some forms of autism spectrum disorders, epilepsy, and possibly other psychiatric disorders and therefore, KCNQ3 and KCNQ5 are suggested as candidate genes for these disorders.",

author = "Nielsen, {Mette Gilling} and Rasmussen, {Hanne Borger} and Kirstine Call{\o} and {F. Sequeira}, Ana and Marta Baretto and Guiomar Oliveira and Joana Almeida and {B. Lauritsen}, Malene and Reinhard Ullmann and Boonen, {Susanne Eriksen} and Karen Br{\o}ndum-Nielsen and {M. Kalscheuer}, Vera and Zeynep T{\"u}mer and {M. Vicente}, Astrid and Nicole Schmitt and Niels Tommerup",

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doi = "10.3389/fgene.2013.00054",

language = "English",

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T1 - Dysfunction of the heteromeric KV7.3/KV7.5 potassium channel is associated with autism spectrum disorders

AU - Nielsen, Mette Gilling

AU - Rasmussen, Hanne Borger

AU - Callø, Kirstine

AU - F. Sequeira, Ana

AU - Baretto, Marta

AU - Oliveira, Guiomar

AU - Almeida, Joana

AU - B. Lauritsen, Malene

AU - Ullmann, Reinhard

AU - Boonen, Susanne Eriksen

AU - Brøndum-Nielsen, Karen

AU - M. Kalscheuer, Vera

AU - Tümer, Zeynep

AU - M. Vicente, Astrid

AU - Schmitt, Nicole

AU - Tommerup, Niels

PY - 2013

Y1 - 2013

N2 - Heterozygous mutations in the KCNQ3 gene on chromosome 8q24 encoding the voltage-gated potassium channel KV7.3 subunit have previously been associated with rolandic epilepsy and idiopathic generalized epilepsy (IGE) including benign neonatal convulsions. We identified a de novo t(3;8) (q21;q24) translocation truncating KCNQ3 in a boy with childhood autism. In addition, we identified a c.1720C¿>¿T [p.P574S] nucleotide change in three unrelated individuals with childhood autism and no history of convulsions. This nucleotide change was previously reported in patients with rolandic epilepsy or IGE and has now been annotated as a very rare SNP (rs74582884) in dbSNP. The p.P574S KV7.3 variant significantly reduced potassium current amplitude in Xenopus laevis oocytes when co-expressed with KV7.5 but not with KV7.2 or KV7.4. The nucleotide change did not affect trafficking of heteromeric mutant KV7.3/2, KV7.3/4, or KV7.3/5 channels in HEK 293 cells or primary rat hippocampal neurons. Our results suggest that dysfunction of the heteromeric KV7.3/5 channel is implicated in the pathogenesis of some forms of autism spectrum disorders, epilepsy, and possibly other psychiatric disorders and therefore, KCNQ3 and KCNQ5 are suggested as candidate genes for these disorders.

AB - Heterozygous mutations in the KCNQ3 gene on chromosome 8q24 encoding the voltage-gated potassium channel KV7.3 subunit have previously been associated with rolandic epilepsy and idiopathic generalized epilepsy (IGE) including benign neonatal convulsions. We identified a de novo t(3;8) (q21;q24) translocation truncating KCNQ3 in a boy with childhood autism. In addition, we identified a c.1720C¿>¿T [p.P574S] nucleotide change in three unrelated individuals with childhood autism and no history of convulsions. This nucleotide change was previously reported in patients with rolandic epilepsy or IGE and has now been annotated as a very rare SNP (rs74582884) in dbSNP. The p.P574S KV7.3 variant significantly reduced potassium current amplitude in Xenopus laevis oocytes when co-expressed with KV7.5 but not with KV7.2 or KV7.4. The nucleotide change did not affect trafficking of heteromeric mutant KV7.3/2, KV7.3/4, or KV7.3/5 channels in HEK 293 cells or primary rat hippocampal neurons. Our results suggest that dysfunction of the heteromeric KV7.3/5 channel is implicated in the pathogenesis of some forms of autism spectrum disorders, epilepsy, and possibly other psychiatric disorders and therefore, KCNQ3 and KCNQ5 are suggested as candidate genes for these disorders.

U2 - 10.3389/fgene.2013.00054

DO - 10.3389/fgene.2013.00054

M3 - Journal article

C2 - 23596459

SN - 1664-8021

VL - 4

SP - 1

EP - 13

JO - Frontiers in Genetics

JF - Frontiers in Genetics

IS - 54

ER -

Dysfunction of the heteromeric KV7.3/KV7.5 potassium channel is associated with autism spectrum disorders

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Dysfunction of the heteromeric K_V7.3/K_V7.5 potassium channel is associated with autism spectrum disorders