H258R mutation in KCNAB3 gene in a family with genetic epilepsy and febrile seizures plus.

PURPOSE The aim of this was to discover disease-causing gene mutations linked to genetic epilepsy with febrile seizures plus (GEFS+) in a family in the Southern Chinese Han population. Of a three-generation pedigree of 18 members in this family, 4 were affected with GEFS+. METHOD Blood samples of 7 family members-3 affected and 4 unaffected individuals-were collected. Whole-exome sequencing was performed to assess for genetic mutations in two of the affected individuals and two of the unaffected individuals. RESULTS Fourteen potentially consequential mutations were found in the two affected individuals and were validated with the Sanger sequencing method. Blood DNA tested in polymerase chain reaction with KCNAB3 primers revealed that one novel missense mutation, c.773A>G (p.H258R) in the KCNAB3 gene, which encoded the potassium voltage-gated channel subfamily A regulatory β subunit 3 (KCNAB3), was shared by all three affected and one unaffected family member. However, this mutation did not appear in 300 unrelated control subjects. According to the bioinformatics tools SIFT and PROVEAN, p.H258R was thought to affect protein function. Functional verification showed that the KCNAB3 mutation could accelerate the inactivation of potassium channels, thus inhibiting potassium current, increasing neuronal excitability, and promoting epileptic convulsion. CONCLUSIONS These results reveal that mutations in the KCNAB3 gene may be associated with GEFS+.