Dysfunction of the Heteromeric KV7.3/KV7.5 Potassium Channel is Associated with Autism Spectrum Disorders

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

Characterization of a supernumerary small marker X chromosome in two females with similar phenotypes

We describe two female patients mosaic for a cell line with an extra marker X chromosome in addition to a normal 46,XX cell line. To our knowledge, these cases are the first reports of females who had a cell line with a supernumerary marker X chromosome in addition to a normal cell line. They also had strikingly similar manifestations, including small hands and feet, minor facial anomalies, obesity, and mental retardation, The DNA content of the mar(X) chromosomes was investigated by fluorescent in situ hybridization using pericentromeric probes. The XIST gene, which is necessary for initiation of X-inactivation, was deleted from both marker chromosomes, suggesting that these chromosomes were not subject to inactivation. The short arm breakpoints of the mar(X)s were between the DNA markers DXS423E on Xp11.21 and UBE1 on Xp11.23. In Patient 1, mar(X) contained the androgen receptor gene and the DNA marker DXS1, both mapping to Xq11.2, whereas in Patient 2 the chromosome breakpoint was proximal to these markers. We suggest that the similar phenotypes of these patients may be due to the overexpression of genes in the common pericentromeric region of the X chromosome. (C) 1998 Wiley-Liss, Inc

Recurrent mutation pressure does not explain the prevalence of the marker (X) syndrome

In order to test the hypothesis that the high prevalence of the mar(X) syndrome is caused by a high mutation rate in male germ cells only, the fraction of new mutants among mothers of probands in 112 informative families has been examined by segregation analysis among their brothers and sisters. The estimated fraction of new mutants among these mothers is much lower than expected if a stable equilibrium existed between an unusually high mutation rate and a selective disadvantage of mentally retarded, male and female mar(X) carriers. Hence, the above-mentioned hypothesis could not be confirmed