Wilhelm Johannsen Centre for Functional Genome Research, Department of Cellular and Molecular Medicine, University of Copenhagen Copenhagen, Denmark ; Section for Neurogenetics, Department of Cellular and Molecular Medicine, University of Copenhagen Copenhagen, Denmark.
Front Genet. 2013 Apr 16;4:54. doi: 10.3389/fgene.2013.00054. eCollection 2013.
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.
先前，染色体 8q24 上编码电压门控钾通道 KV7.3 亚基的 KCNQ3 基因的杂合突变与 Rolandic 癫痫和特发性全面性癫痫（IGE）相关，包括良性新生儿惊厥。我们在一名患有儿童自闭症的男孩中鉴定出一种 KCNQ3 的新发 t(3;8)（q21;q24）易位截断。此外，我们在三名无癫痫发作史的自闭症儿童中鉴定出 c.1720C > T [p.P574S] 核苷酸变化。该核苷酸变化先前在 Rolandic 癫痫或 IGE 患者中被报道过，现在已经在 dbSNP 中被注释为非常罕见的 SNP（rs74582884）。当与 KV7.5 共表达时，p.P574S KV7.3 变体显著降低了非洲爪蟾卵母细胞中的钾电流幅度，但与 KV7.2 或 KV7.4 则没有。该核苷酸变化不影响异源突变型 KV7.3/2、KV7.3/4 或 KV7.3/5 通道在 HEK 293 细胞或原代大鼠海马神经元中的运输。我们的结果表明，杂合 KV7.3/5 通道的功能障碍与某些形式的自闭症谱系障碍、癫痫症以及可能其他精神疾病的发病机制有关，因此，KCNQ3 和 KCNQ5 被认为是这些疾病的候选基因。
