TY - JOUR
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
VL - 4
SP - 1
EP - 13
JO - Frontiers in Genetics
JF - Frontiers in Genetics
SN - 1664-8021
IS - 54
ER -