The Molecular Genetics of the Benign Epilepsies of Infancy

Abstract

Clinical and Genetic Aspects of Epilepsy 96 overlaps with BFNE and BFIE. Seizure onset in BFNIE most commonly occurs at between 2 and 4 months of age. Clinically the condition was first described by Kaplan and Lacey (1983) and molecularly delineated two decades later (Heron et al., 2002). The aim of this chapter is to describe the current state of knowledge of the molecular genetics underlying these disorders and the significance that this has for patient care. The molecular genetics of benign familial neonatal epilepsyBenign familial neonatal epilepsy is most commonly caused by mutations in two related voltage-gated potassium channel subunit genes, KCNQ2 and KCNQ3. Together, these form the pore of the neuronal M-channel, which plays an important role in neuronal inhibition by acting as a "brake" on repetitive action potential discharges (Delmas & Brown, 2005). Mutations in KCNQ2 and KCNQ3 were originally described in 1998 (Biervert et al., 1998;Charlier et al., 1998;Singh et al., 1998). There are now more than 80 known mutations in KCNQ2; but only four described for KCNQ3. There may be other, rare, families with mutations in other genes. BFNE caused by mutations in the potassium channel subunit KCNQ2KCNQ2 (OMIM 602235) encodes one of the pore-forming subunits of the M-channel. The Mchannel is a heteromultimer consisting of two KCNQ2 and two KCNQ3 proteins, as well as accessory subunits. The gene is located close to the q-arm telomere of chromosome 20, at 20q13.3. It consists of 17 exons embedded within 87kb of genomic DNA. The gene codes for an 872 amino acid protein consisting of three domains: a short N-terminal domain; a transmembrane domain; and a large C-terminal domain, which contains regions that interact with other channel subunits. The gene has five splice variants, which produce proteins that differ in the C-terminal domains. The transmembrane domain consists of six transmembrane segments (S1-S6) and the pore-loop between segments S5 and S6, which forms the lining of the ion pore. The S4 domain is the voltage sensor and contains a number of positively charged arginine or lysine residues, which are required for normal channel function. The S4 segments move within the membrane in response to a change in voltage, opening the channel. BFNE was originally mapped to the KCNQ2 locus in 1989 (Leppert et al.) by linkage analysis of a large, four-generation pedigree. Further families were reported that confirmed the chromosome 20q localisation (Ryan et al., 1991;Malafosse et al., 1992). KCNQ2 was identified as the BFNE gene at this locus when a submicroscopic deletion containing KCNQ2 was detected in a single BFNE family. Screening of additional BFNE families revealed missense, frameshift and splice-site mutations in KCNQ2 . A frameshift mutation was simultaneously identified in KCNQ2 when it was screened as a candidate gene in another family mapped to the 20q locus (Biervert et al., 1998). In total, 85 mutations in KCNQ2 have been described in the scientific literature Soldovieri et al., 2007;Wuttke et al., 2...