BFNC1 The most prevalent known cause of BFNE is mutation of KCNQ2, a gene encoding a voltage-gated potassium channel (KV7.2). There are at least 35 such mutations, see Table 1, primarily located in the voltage sensitive S4 segment through the C-terminus. Of these mutations, 5 are nonsense mutations, 13 are missense mutations and 11 cause a frameshift in the coding sequence. There are also 5 splice variants, one of which has been characterized at the protein level and leads to a nonsense mutation. Finally, there is one large deletion that removes much of the carboxy-terminus of the channel. While most BFNC1 mutations have not been further characterized, 14 have and all seem to lead to functional defects. Two of the mutations in the voltage-sensitive S4 segment, R207W and R214W, do not lead to a decrease in the whole-cell current (M current) produced by KCNQ2 channels but to a change in channel kinetics. The R207W mutation takes fourfold longer and the R214W mutation takes twofold longer to reach maximal current compared to wild-type channels. Since the time-course of an action potential is shorter than the time required for mutant KCNQ2 channels to reach proper levels of inactivation these mutants are expected to lead to neuronal hyperexcitability. Though many of the other characterized mutations lead to decreased whole-cell current that has not been further delineated, three mutations have. Y534fsX538, for example, leads to a truncation that removes much of the carboxy-terminus of the channel. This mutant has been studied and shown to not traffic properly to the membrane. Two other mutations, P709fs929X and W867fsX931, lead to altered carboxy-termini, though they actually lengthen rather than truncate the protein. These abnormal extended proteins have been shown to be more rapidly degraded within cells and, thus, produce little current. +Table 1. Mutations in KCNQ2 associated with BFNE Mutation Region Functional Consequence References Nucleotide Amino acid c.232delC Q78fsX132 N-Terminus c.314_316delCCT S105CfsX872 S1 c.387+1G→T Splicing S2 c.584_593del10insA S195X S4 c.C587T+c.T590C A196V+L197P S4 c.C619T R207W S4 Slowed activation c.G622A M208V S4 Current decreased by ~50% c.C641T R214W S4 Slowed activation and increased deactivation ,, c.C674G H228Q S4-S5 c.T727C L243F S5 c.C740G S247W S5 No current and dominant negative c.G807A W269X Pore c.848_849insGT K283fsX329 Pore , c.A851G Y284C Pore Current decreased by ~50% ,,,, c.G916A A306T S6 Current decreased by ~80% ,,, c.C967T Q323X C-Terminus Current reduction by ~50% c.G998A R333Q C-Terminus Current reduction by ~40% c.T1016G R339L C-Terminus c.1118+1G→A Splicing C-Terminus c.Intron 8_3' UTR del Deletion 382→3' UTR C-Terminus , c.1217+2T→G Splicing C-Terminus c.C1342T R448X C-Terminus Current reduction by ~40% , c.1369_1370delAA K457EfsX458 C-Terminus c.1564_1576del S522fsX524 C-Terminus , c.1600_1601insGCCCT Y534fsX538 C-Terminus No current due to no trafficking ,, c.1630-1G→A Splicing C-Terminus , c.G1658A R553Q C-Terminus c.G1662T* K554N C-Terminus Decreased voltage sensitivity of activation c.C1741T R581X C-Terminus c.1764-6C→A Splicing (V589X) C-Terminus c.1931delG S644TfsX901(extX56) C-Terminus c.1959del? T653fsX929(extX56) C-Terminus c.2127delT P709fs929X(extX57) C-Terminus No current due to increased degradation ,, c.2597delG G866AfsX929(extX56) C-Terminus Current decreased by ~95% due to increased degradation ,, c.2599_2600insGGGCC W867fsX931(extX58) C-Terminus Current reduction by ~75% * Misreported (twice in the same article) as G1662A (G1620A in the original numbering), which would not cause an amino acid change. N.B. Mutations nucleotide/amino acid positions in terms of transcript variant 1 ( NM_172107) available from PubMed. Consequently, some mutation positions differ from those reported in the original literature. BFNC2 Shortly after the discovery of mutations in KCNQ2 related to BFNE, a novel voltage-gated potassium channel was found that is highly homologous to KCNQ2 and contains mutations also associated with BFNE. This gene, KCNQ3, contains 3 known mutations associated with BFNE, all within the pore region of the channel. The first of these mutations, G310V, leads to a 50% reduction in whole-cell current compared to cells expressing wild-type channels. The reason for this change is unknown as the mutation does not lead to altered protein trafficking. A second mutation, W309G, has also been found to be associated with BFNE. This mutation was only found in one family and has not been further characterized. The final known BFNC2 mutation, D305G is also in the pore region of the channel. This mutation leads to an approximately 40% reduction in whole-cell current compared to wild-type expressing cells. The underlying mechanism for this current decrease has not been further delineated. BFNC3 The rarest cause of BFNE, occurring in only one known family, is a chromosomal inversion. This occurs on chromosome 5 and the inversion is of the p15 through q11 area. Affected individuals, thus, have the karyotype 46,XY,inv(5)(p15q11). Why this inversion leads to the BFNE phenotype is unknown.
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