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  • br In Sanguinetti et al and Barhanin et al

    2019-05-06


    In 1996, Sanguinetti et al. and Barhanin et al. independently found that, when coassembled with the accessory subunit KCNE1, the KCNQ1 and KCNE1 complex could form a channel that very closely exhibited conductive and kinetic properties similar to that of cardiac IKs[14,56]. Kass and coworkers subsequently found that the targeting protein Yotiao, as a component of the macromolecular complex, is required to reconstitute cAMP-dependent regulation of IKs and provides a mechanistic link between the sympathetic nervous system and modulation of the cardiac ITF2357 cost duration (APD) [15]. The KCNQ1 and KCNE1 subunits coassemble with Yotiao adapter into the cardiac IKs, and mutation in KCNQ1, KCNE1, or AKAP9 (Yotiao) can cause functional reduction of IKs channels, leading to life-threatening cardiac arrhythmias corresponding to LQT1, LQT5, and LQT11, respectively. Previous studies indicate that two distinct biophysical mechanisms mediate the reduced I current in patients with KCNQ1 mutations: (1) coassembly or trafficking defects in which mutant subunits are not transported properly to the cell membrane and fail to incorporate into the tetrameric channel, with the net effect being a less than 50% reduction in channel function (haploinsufficiency); and (2) formation of defective channels involving mutant subunits with the altered channel protein transported to the cell membrane, resulting in a dysfunctional channel having a greater than 50% reduction in channel current (dominant-negative effect) [18]. Recently, Mousavi et al. evaluated the functional properties of eight KCNQ1 mutations that were identified in the S4 and S4-S5 linker (D242N, R243C, L250H), pore loop (G306V, D317N), and COOH terminus (L374fs+43X, N586D, L619M), respectively [7]. The results showed that D317N and L374fs+43X mutations exhibited ITF2357 cost a strong dominant-negative effect on KCNQ1-WT channel functions, which is consistent with previous findings for KCNQ1 mutations located in the NH2 terminus (Y111C), S2–S3 linker (R174C, A177P, Ala178fs/105, R190Q), S3-S4 (S225L), S4 domain (R243H), S5 domain (G269D, G269S, L272F), P-loop (Y281C, T311I, G314S, Y315S, Y315C, P320H, and P320A), S6 domain (ΔF339, L342F), and COOH terminus (R317N, R533W, R539W, R555H, K557E) [37,42,57–63]. The other mutations analyzed in that study were haploinsufficient for KCNQ1 channel function. Other reports have also indicated that membrane expression of the KCNQ1 channel protein can be reduced by trafficking defects in mutations located in the S2-S3 linker (A178T), S5 domain (ΔS276), pore loop (T322M), S6 domain (A336fs+16X), and COOH terminus (Y461X, R518X, A525T, Q530X, E543fs+107X, T587M, G589D, R594Q) [7,42,51,64–66]. The above data indicate that the correlation between the genotype and channel function in LQT1 is complicated and diversified. Even different mutations at the same position (e.g., KCNQ1-R243C and KCNQ1-R243H) cause different degrees of channel dysfunction. Moreover, not only do mutations with a dominant-negative effect occur in almost every location of the KCNQ1 gene, but those with a trafficking defect exist in the main domains of the gene as well. However, the number of KCNQ1 pore-loop mutations causing a dominant-negative effect is much great than the number of mutations causing haploinsufficiency, suggesting that the pore-loop mutations are more commonly associated with severe electrophysiological and clinical phenotypes. Interestingly, Aizawa et al. found that the KCNQ1 mutation Ala178fs/105 not only forms a hetero-multimer and causes a dominant-negative effect on the IKs channel, but that it also gives rise to a trafficking defect in the channel protein [63]. It is possible that both defective channel trafficking and defective channel formation mechanisms exist for some KCNQ1 mutations simultaneously. Another correlation between genotype and channel function has been described whereby some compound KCNQ1 mutations (e.g., T391I/Q530X, A525T/R518X, and A178T/K422fs39X) severely disrupt channel trafficking [67].