There are a total of 8 mutations that account for the<unk>  in 8 of 14 studied families. These mutations are clustered in four regions throughout the channel: the linker between domains 2 and 3 (D2-3), the intracellular segment linking segments 4 and 5 in domain 3 (D3S4-5), the linker between domains 3 and 4 (D3-4) and the intracellular segment linking segments 4 and 5 in domain 4 (D4S4-5). The mutations in the D3S4-5 region (I1461T, F1462V and T1461I) are located in or next to an IFM motif that is conserved across all voltage-gated sodium channels. Mutagenesis studies of this region have shown that it acts as part of the inactivation gate, pivoting to block the central pore. Not surprisingly then, the two of these mutations that have received further study show incomplete inactivation. When the IFM motif pivots to block the central pore it interacts with residues in the D3S4-5 region. There are three mutations in this region (V1298F, F1298D and V1299F) that are believed to alter the interaction with the inactivation gate. While this region has been studied by mutagenesis these specific mutations have not all received attention, though they are expected to produce changes similar to the aforementioned IFM region mutations. The M1627K mutation in the D4S4-5 region may also affect a residue involved in interacting with the IFM inactivation motif. This would explain the observed alteration of inactivation and the broadening of a window current. One of the affected families with the R996C mutation, pedigree 12, has a single individual who also has the V1298D mutation. The individual in this family with the compound mutation is the most severely affected, suggesting that the R996C mutation may cause a less severe phenotype. The less severe phenotype of the pedigree 4 family is in concordance with this theory. It is unclear how the R996C mutation affects channel function. +Table 1. Summary of mutations found in patients diagnosed with PEPD Mutation Region Persistent Current? Physiological Effect Affected Pedigrees(Location) R996C D2-3 4(UK), 12(France) V1298F D3S4-5 15(UK) V1298D D3S4-5 12 (France) V1299F D3S4-5 11 (UK) I1461T D3-4 Yes Incomplete inactivation due to depolarizing shift of steady-state inactivation curve. 1 (UK) F1462V D3S4-5 9 (UK) T1464I D3S4-5 Yes Incomplete inactivation due to depolarizing shift of steady-state inactivation curve. 7 (UK) M1627K D4S4-5 Yes Creation of a notable "window current" due to shifting of the inactivation curve. 8 (France) Data from Fertleman 2006 and Fertleman 2007
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