Fine mapping of a seizure susceptibility locus on mouse Chromosome 1: nomination of Kcnj10 as a causative gene

Abstract

Previous quantitative trait loci (QTL) mapping studies document that the distal region of mouse Chromosome (Chr) 1 contains a gene(s) that is in large part responsible for the difference in seizure susceptibility between C57BL/6 (B6) (relatively seizure-resistant) and DBA/2 (D2) (relatively seizure-sensitive) mice. We now confirm this seizure-related QTL ( Szs1) using reciprocal, interval-specific congenic strains and map it to a 6.6-Mb segment between Pbx1 and D1Mit150. Haplotype conservation between strains within this segment suggests that Szs1 may be localized more precisely to a 4.1-Mb critical interval between Fcgr3 and D1Mit150. We compared the coding region sequences of candidate genes between B6 and D2 mice using RT-PCR, amplification from genomic DNA, and database searching and discovered 12 brain-expressed genes with SNPs that predict a protein amino acid variation. Of these, the most compelling seizure susceptibility candidate is Kcnj10. A survey of the Kcnj10 SNP among other inbred mouse strains revealed a significant effect on seizure sensitivity such that most strains possessing a haplotype containing the B6 variant of Kcnj10 have higher seizure thresholds than those strains possessing the D2 variant. The unique role of inward-rectifying potassium ion channels in membrane physiology coupled with previous strong association between ion channel gene mutations and seizure phenotypes puts even greater focus on Kcnj10 in the present model. In summary, we confirmed a seizure-related QTL of large effect on mouse Chr 1 and mapped it to a finely delimited region. The critical interval contains several candidate genes, one of which, Kcnj10, exhibits a potentially important polymorphism with regard to fundamental aspects of seizure susceptibility.

The relevance of individual genetic background and its role in animal models of epilepsy

“…It has previously been established that genetic background can considerably affect the seizure thresholds of mice. Loci responsible for strain differences in susceptibility to seizures, triggered by chemoconvulsants, such as kainic acid, or non-pharmacological manipulations, have been mapped to specific mouse chromosomes (Ferraro et al, 1997, 2001, 2004, 2007a,b, 2010, 2011; Todorova et al, 2006). The identified genomic loci map to chromosomes 1, 2, 4, 5, 7, 10, 11, 12, 15 and 18 with the highest density on chromosomes 1, 5, 7, and 10 where loci from several different crosses coincide.…”

Inhibition of Kir4.1 potassium channels by quinacrine

“…Recent studies showed that loss-of-function mutations of the human gene ( KCNJ10 ) encoding Kir4.1 channels are responsible for the SeSAME/EAST syndrome, an autosomal recessive disorder characterized by seizures, sensorineural deafness, ataxia, intellectual disability and electrolyte imbalance (Bockenhauer et al, 2009; Scholl et al, 2009; Reichold et al, 2010). Genetic variations of KCNJ10 have also been related to epilepsy (Buono et al, 2004; Ferraro et al, 2004; Lenzen et al, 2005; Dai et al, 2015), a group of neurological diseases characterized by seizure disorders. Other diseases associated to Kir4.1 channels include spinocerebellar ataxia (Gilliam et al, 2014), autism (Sicca et al, 2011), Alzheimer disease (Wilcock et al, 2009), and Huntington disease (Tong et al, 2014).…”

Lack of significant association between mutations of KCNJ10 or FOXI1 and SLC26A4 mutations in pendred syndrome/enlarged vestibular aqueducts

“…It has been shown that mice models that lacked the Slc26a4 gene ( Slc26a4 −/− ) did not express Kcnj10 and that lack of this protein led to the loss of the endocochlear potential via endolymphatic acidification and Ca 2+ absorption inhibition [25,26] which may be the direct cause of deafness in Pendred syndrome. Variants of KCNJ10 have also been considered as a risk factor for seizure susceptibility in genetic association studies [27] and biallelic mutations in KCNJ10 in humans are known to cause a syndromic form of hearing loss, EAST syndrome (epilepsy, ataxia, sensorineural deafness and renal tubulopathy) [28]. …”