| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 20q13.12 | {Epilepsy, idiopathic generalized, susceptibility to, 14} | 616685 | Autosomal dominant | 3 | SLC12A5 | 606726 |
A number sign (#) is used with this entry because of evidence that susceptibility to idiopathic generalized epilepsy-14 (EIG14) is conferred by heterozygous mutation in the SLC12A5 gene (606726) on chromosome 20q13.
For a general phenotypic description and a discussion of genetic heterogeneity of idiopathic generalized epilepsy, see EIG (600669).
Kahle et al. (2014) reported 8 patients of French Canadian origin with idiopathic generalized epilepsy with onset between 3 and 21 years of age. Seizure types included generalized tonic-clonic, absence, and myoclonic. EEG results, when available, showed generalized spike-wave discharges or diffuse theta waves. None of the patients had febrile seizures.
Puskarjov et al. (2014) reported an Australian family in which several individuals had febrile seizures. Additional clinical details were not provided.
The transmission pattern of EIG14 in the families reported by Kahle et al. (2014) was consistent with autosomal dominant inheritance and incomplete penetrance.
Kahle et al. (2014) identified 2 different heterozygous missense variants in the SLC12A5 gene (R952H, 606726.0004 and R1049C, 606726.0005) that were enriched among individuals of French Canadian origin with EIG14 compared to controls. The R952H variant was found in 5 of 380 patients with EIG (allele frequency of 0.66%) and in 5 of 1,214 controls (allele frequency of 0.21%), yielding an odds ratio (OR) of 3.21 for development of EIG (p = 0.065). The R1049C variant was found in 3 of 380 patients with EIG (allele frequency of 0.39) and in 1 of 1,214 controls (allele frequency of 4.12 x 10(-4)), yielding an odds ratio (OR) of 9.61 (p = 0.044). In vitro functional expression studies showed that the variants impaired chloride extrusion capacities, resulting in less hyperpolarized glycine equilibrium potentials, and also impaired stimulatory phosphorylation at residue ser940, a key regulatory site of channel function. The overall effect impaired the function of SLC12A5. The authors used a targeted DNA-sequencing approach to screen the cytoplasmic C-terminal region of SLC12A5, which is an important regulatory region of transporter function.
Puskarjov et al. (2014) identified a heterozygous R952H variant in the SLC12A5 gene in 3 affected members of an Australian family with febrile seizures. Segregation of the variant in this kindred was difficult because of uncertain phenotyping, but there was some evidence of incomplete penetrance. In vitro functional expression studies showed markedly decreased surface expression of the mutant protein (61% of wildtype) as well as decreased chloride extrusion compared to wildtype. Thus, the mutant protein was associated with deficits in maintaining the chloride driving force required for hyperpolarizing GABA-mediated responses. Transfection of the variant into rats and into mouse cortical neurons showed that it compromised dendritic spine formation and maturation. Puskarjov et al. (2014) suggested that the decrease in SLC12A5-dependent hyperpolarizing inhibition would promote triggering of seizures, and that decreased dendritic spine formation could lead to desynchronization of overall excitability, which may also contribute to seizures.
Kahle, K. T., Merner, N. D., Friedel, P., Silayeva, L., Liang, B., Khanna, A., Shang, Y., Lachance-Touchette, P., Bourassa, C., Levert, A., Dion, P. A., Walcott, B., and 11 others. Genetically encoded impairment of neuronal KCC2 cotransporter function in human idiopathic generalized epilepsy. EMBO Rep. 15: 766-774, 2014. [PubMed: 24928908] [Full Text: https://doi.org/10.15252/embr.201438840]
Puskarjov, M., Seja, P., Heron, S. E., Williams, T. C., Ahmad, F., Iona, X., Oliver, K. L., Grinton, B. E., Vutskits, L., Scheffer, I. E., Petrou, S., Blaesse, P., Dibbens, L. M., Berkovic, S. F., Kaila, K. A variant of KCC2 from patients with febrile seizures impairs neuronal Cl- extrusion and dendritic spine formation. EMBO Rep. 15: 723-729, 2014. [PubMed: 24668262] [Full Text: https://doi.org/10.1002/embr.201438749]