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(Circulation. 1997;96:1733-1736.)
© 1997 American Heart Association, Inc.

Articles

Dominant-Negative KvLQT1 Mutations Underlie the LQT1 Form of Long QT Syndrome

Fouad Y. Shalaby, PhD; Paul C. Levesque, PhD; Wen-Pin Yang, PhD; Wayne A. Little, MS; Mary Lee Conder, BS; Tonya Jenkins-West, BS; ; Michael A. Blanar, PhD

From the Department of Cardiovascular Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ.

Correspondence to Dr Michael A. Blanar, Department of Cardiovascular Drug Discovery, Mail Code K14-01, Room K.4125A, Bristol-Myers Squibb Pharmaceutical Research Institute, Route 206 and Provinceline Road, Princeton, NJ 08543-4000. E-mail blanar{at}bms.com

	Abstract

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Background Mutations that map to the KvLQT1 gene on human chromosome 11 account for more than 50% of inherited long QT syndrome (LQTS). It has been discovered recently that the KvLQT1 and minK proteins functionally interact to generate a current with biophysical properties similar to I_Ks, the slowly activating delayed-rectifier cardiac potassium current. Since I_Ks modulates the repolarization of cardiac action potentials it is reasonable to hypothesize that mutations in KvLQT1 reduce I_Ks, resulting in the prolongation of cardiac action potential duration.

Methods and Results We expressed LQTS-associated KvLQT1 mutants in Xenopus oocytes either individually or in combination with wild-type KvLQT1 or in combination with both wild-type KvLQT1 and minK. Substitutions of alanine with proline in the S2-S3 cytoplasmic loop (A177P) or threonine with isoleucine in the highly conserved signature sequence of the pore (T311I) yield inactive channels when expressed individually, whereas substitution of leucine with phenylalanine in the S5 transmembrane domain (L272F) yields a functional channel with reduced macroscopic conductance. However, all these mutants inhibit wild-type KvLQT1 currents in a dominant-negative fashion.

Conclusions In LQTS-affected individuals these mutations would be predicted to result in a diminution of the cardiac I_Ks current, subsequent prolongation of cardiac repolarization, and an increased risk of arrhythmias.

Key Words: arrhythmia • potassium channels • long QT syndrome

	Introduction

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Prolongation of the QT interval of the ECG of patients with congenital long QT syndrome (LQTS) reflects delayed repolarization of the action potential, a function performed mainly by delayed rectifier potassium currents, I_K.¹ The genes mutated at two of the four LQTS-linked loci, LQT1 and LQT2, encode voltage-regulated potassium ion channels of the delayed-rectifier type, KvLQT1 and HERG, respectively. HERG is responsible for the rapidly activating component of I_K (I_Kr).² Here, we describe the functional characterization of three LQTS-associated mutations in KvLQT1, which has been suggested recently to comprise the slowly activating (I_Ks) component of I_K.^{3 4 5}

	Methods

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In Vitro Mutagenesis
An 1.8-kb cDNA clone in pBSII KS+ comprising the 5' part of the human KvLQT1 cDNA⁵ was used to generate the three mutants described in the present study. Point mutations⁶ were introduced by the Transformer site-directed mutagenesis kit (Clontech), which is based on the unique site elimination method. Plasmid DNA was hybridized to both a selection oligonucleotide and a mutagenic oligonucleotide. The selection primer sequence was GCGGCCGCTCTTGAACTAGTGGAT. The underlined point mutation eliminates the unique

Xba I restriction enzyme recognition site in pBSII KS+. The mutagenic oligonucleotide primers encoding the appropriate amino acid substitution are A177P, GTCCGCCTCTGGTCCCCCGGCTGCCGCAGCAAGTAC; L272F, CGGCTTCCTGGGCTTCATCTTCTCCTCGTAC; T311I, GGTGGTCACAGTCACCATCATCGGCTATGG. The underlined residues are those that encode the amino acid substitution mutations. Clones containing the desired mutations were identified, among transfected mismatch repair-defective bacteria, by DNA sequence analysis. A 0.8-kb Xho I Bgl II fragment, harboring the KvLQT1 mutation, was used to replace the corresponding fragment in an expression vector containing the full-length wild-type KvLQT1 cDNA.⁵

Electrophysiological Analysis
Capped cRNAs encoding wild-type and mutant KvLQT1 and minK proteins were prepared by in vitro transcription using SP6 RNA polymerase (mMessage mMachine kit, Ambion). Production and purification of full-length cRNA was verified by denaturing agarose gel electrophoresis. These cRNAs were injected into collagenase-treated defolliculated stages V and VI Xenopus laevis oocytes as described previously.⁷ Experiments comparing wild-type and mutant channels were performed using the same batch of oocytes injected with cRNAs on the same day. Currents were recorded at room temperature using the two-microelectrode voltage clamp (Dagan TEV-200) technique 3 to 4 days after injection. Microelectrodes (0.8 to 1.5 M) were filled with 3 mol/L KCl. Bath solution contained (in mmol/L): 96 NaCl, 2 KCl, 0.5 CaCl₂, 1.5 MgCl₂, and 5 HEPES (pH 7.5). Axoclamp (Axon Instruments) was used to generate voltage clamp commands and for acquiring data. Data were sampled at rates at least two times the low-pass filter rate.

Comparisons of wild-type KvLQT1 currents, mutant KvLQT1 currents, and currents generated by coinjections were based on results from the same batch of oocytes injected on the same day. Before assaying for functional activity of mutant cRNAs and potential dominant-negative effects, a series of titrations were made to identify a concentration of wild-type KvLQT1 cRNA that would result in a doubling of the amplitude of expressed current when the amount of injected cRNA was doubled. Wild-type KvLQT1 current amplitudes measured in oocytes injected with 5 ng of cRNA were consistently 1.5- to 2.0-fold lower than in oocytes injected with 10 ng of cRNA. There was considerably less than a 2-fold difference in current amplitudes between groups injected with much higher concentrations of wild-type KvLQT1 cRNA. Thus, all wild-type or mutant KvLQT1 cRNAs were injected at 5 ng per oocyte (10 ng total for wild-type+mutant coinjections).

The potassium selectivity of expressed currents was examined by investigation of tail current reversal potentials in bath solutions containing 2, 10, 40, and 98 mmol/L K⁺. Currents were activated maximally by stepping to +20 mV for 1 second (wild-type and mutants alone) or 2 seconds (wild-type+mutants+minK) and then back to a series of test potentials ranging from -120 to +10 mV. This tail current protocol was repeated in each oocyte while switching from low to high external potassium concentrations.

The voltage dependence of current activation was estimated by fitting normalized tail current versus voltage curves with a Boltzmann function (Clampfit, Pclamp 6.03). Tail currents were recorded at -70 mV after 1-second (KvLQT1) or 3-second (minK+KvLQT1) depolarizing voltage steps from a holding potential of -80 mV to potentials ranging from -70 to +40 mV. Tail current amplitudes were determined by extrapolating deactivating currents to the end of the depolarizing test pulse. Tail currents were normalized to the maximal tail current in each experiment.

	Results

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LQTS Mutations Alter KvLQT1 Activity
The three point mutations characterized in the present study were described originally on a partial clone of KvLQT1,⁶ which is 129 amino acids shorter than the KvLQT1 clone used here.⁵ The missense mutation, A177P (kindred K13119⁶ ), occurs in the putative cytoplasmic loop between S2 and S3. The L272F mutation (kindred K1777⁶ ) replaces a leucine residue with phenylalanine in S5. The third missense mutation, T311I (kindred K20925⁶ ), replaces a threonine residue with an isoleucine in the highly conserved pore signature sequence.⁸

Fig 1A shows a typical family of wild-type KvLQT1 currents. As described recently,^{3 4 5} KvLQT1 potassium currents activate rapidly and show little rectification at positive voltages. In contrast, only small currents, identical to those recorded in water-injected control oocytes (not shown), were detectable in oocytes injected with either A177P or T311I mutants (Fig 1, B and D). The L272F mutant formed functional channels that resulted in a macroscopic current significantly smaller in amplitude than wild-type KvLQT1 (Fig 1C). Current amplitudes recorded at the end of 1-second test pulses to +20 mV are shown in the Table. Current-voltage relations of wild-type, A177P, T311I, and L272F currents are shown in Fig 1E. The voltage dependence of activation is the same for wild-type KvLQT1 and the L272F mutant. However, L272F current slowly inactivated during steps to positive voltages. The altered inactivation of the L272F mutant may suggest that the S5 region may play a role in inactivation of KvLQT1.

View larger version (16K): [in this window] [in a new window]   Figure 1. Dominant-negative effects of KvLQT1 mutations on wild-type currents. Families of currents recorded in an oocyte injected with 12.5 ng of A, wild-type (WT) KvLQT1 cRNA; B, A177P cRNA; C, L272F cRNA; or D, T311I cRNA. E, Current-voltage relation for currents shown in A (n=6), B (n=5), C (n=5), and D (n=5). Families of currents recorded from oocytes injected with 5 ng each of F, WT KvLQT1 cRNA; G, WT KvLQT1 and A177P cRNAs; H, WT KvLQT1 and L272F cRNAs; or I, WT KvLQT1 and T311I cRNAs. J, Current-voltage relation for currents shown in F (n=6), G (n=5), H (n=6), and I (n=5). All currents were elicited by 1-second voltage steps from a holding potential of -80 mV to test potentials ranging from -60 to +40 mV (20-mV increments). Recordings were made 4 days after injection.

View this table: [in this window] [in a new window]   Table 1. Comparison of KvLQT1 Currents in Oocytes Injected With Wild-Type and Mutant KvLQT1 cRNAs in the Absence and Presence of minK

Dominant-Negative KvLQT1 Mutations
Since KvLQT1 most likely functions as a tetramer,⁹ it was of interest to determine whether the mutant KvLQT1 could exert a dominant-negative effect on wild-type channel activity. To test this, membrane currents were recorded from oocytes either injected with wild-type KvLQT1 cRNA alone or coinjected with equimolar amounts of mutant and wild-type KvLQT1 cRNAs. The A177P and T311I mutants reduced wild-type current by 75% (Fig 1, G and I, and Table). Neither mutant affected the potassium selectivity of the channel or the voltage dependence of activation (Table). The V_1/2 of wild-type KvLQT1 is close to the previously reported value.⁴ Although currents were not detected in oocytes injected with higher (2.5-fold) concentrations of A117P or T311I (Fig 1, B and D), the dramatic reduction of wild-type KvLQT1 current by coinjection with either mutant indicates that mutant channel proteins are probably competent to coassemble with wild-type KvLQT1 subunits, resulting in the dominant-negative suppression of wild-type current.

A family of currents recorded from an oocyte injected with both L272F and wild-type cRNA is shown in Fig 1H. The L272F mutant altered wild-type KvLQT1 function by introducing pronounced inactivation at positive voltages similar to that observed with the L272F alone (Fig 1C). Although L272F did not affect potassium ion selectivity, it caused a -10-mV shift in the voltage dependence of wild-type KvLQT1 activation (Table). The magnitude of the current observed in oocytes coinjected with 5 ng L272F+5 ng wild-type KvLQT1 cRNAs was less than the sum of currents recorded in oocytes injected with 5 ng wild-type KvLQT1 alone and with 5 ng L272F alone (data not shown). In addition, the magnitude of the current observed in oocytes coinjected with 5 ng L272F+5 ng wild-type KvLQT1 cRNAs was even less than the magnitude of the current elicted by 5 ng wild-type KvLQT1 cRNA alone (Table). Thus, the data suggest that the L272F mutant subunits coassemble with the wild-type subunits, alter normal KvLQT1 function, and suppress wild-type KvLQT1 activity in a dominant-negative manner. The effects of L272F on wild-type KvLQT1 current suggest that the S5 region affects the voltage dependence of KvLQT1 channel activation.¹⁰

Coexpression of Mutant and Wild-Type KvLQT1 With minK
Consistent with the previous observations,^{3 4 5} coexpression of wild-type KvLQT1 and minK cRNAs in oocytes results in a current more similar to native I_Ks; the current activates more slowly and the activation threshold is shifted to the right by 20 mV (Fig 2, A and E). Wild-type KvLQT1+minK currents have a much larger amplitude than KvLQT1 currents alone (Table). The half-maximal voltage of wild-type KvLQT1+minK current was estimated to be 9.2±1.8 mV (Table), which is nearly identical to that of human cardiac I_Ks.¹¹

View larger version (18K): [in this window] [in a new window]   Figure 2. Dominant-negative effects of KvLQT1 mutations on wild-type KvLQT1+minK current. Families of currents from oocytes injected with A, 5 ng WT KvLQT1+1.6 ng minK cRNAs; B, 5 ng WT KvLQT1+5 ng A177P+1.6 ng minK cRNAs; C, 5 ng WT KvLQT1+5 ng L272F+1.6 ng minK cRNAs; or D, 5 ng WT KvLQT1+5 ng T311I+1.6 ng minK cRNAs. E, Current-voltage relation for WT+minK (n=5), WT+A177P+minK (n=5), WT+L272F+minK (n=5), and WT+T311I+minK (n=5) channels. All currents were elicited by 3-second voltage steps from a holding potential of -80 mV to test potentials ranging from -60 to +40 mV in 20-mV increments. Recordings were made 4 days after injection.

Coexpression of either the A177P or T311I mutants reduced KvLQT1+minK current amplitude by 75% (Fig 2, B and D). Neither mutant significantly altered the potassium ion selectivity of KvLQT1+minK current (Table). Both mutants shifted the half-maximal voltage of KvLQT1+minK current activation by >10 mV (Table). These mutations, which did not affect the voltage dependence of KvLQT1 current activation, may alter the ability of minK to affect the voltage dependence of KvLQT1 activation. A family of currents recorded from an oocyte coinjected with wild-type KvLQT1+minK+L272F cRNAs is shown in Fig 2C. L272F reduced KvLQT1+minK current recorded at +20 mV by 31% (Table). As with the other mutants, the magnitude of the effect of L272F on KvLQT1 and KvLQT1+minK current was very similar. Interestingly, the pronounced inactivation observed with both L272F alone (Fig 1C) and wild-type+L272F (Fig 1H) was not detected in the presence of minK (Fig 2, C and E). L272F did not alter the potassium ion selectivity but did produce a small positive shift in the V_1/2 of KvLQT1+minK current (Table). As reported previously,⁵ KvLQT1 currents are less sensitive to inhibition by clofilium in the presence of minK; this was not affected by any of the mutations described (Table).

	Discussion

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The KvLQT1 mutations studied here all exert a dominant-negative effect on the wild-type KvLQT1 current both in the absence and in the presence of minK. The mechanism underlying these dominant-negative effects is not known. However, assuming that coassembly of the tetrameric KvLQT1 channel is random, producing all possible stoichiometric combinations of wild-type and mutant subunits, and that only wild-type homotetramers are functional, equimolar coexpression of either the A177P or T311I mutant subunits should inhibit the wild-type current by 94%. If these assumptions are correct, our results would suggest that some heterotetramers containing A177P or T311I mutant subunits may be functional, since coexpression of either mutant with wild-type KvLQT1 yielded currents that were reduced only by 75% (Fig 1, G and I).

If KvLQT1+minK does, in fact, constitute the endogenous human cardiac I_Ks current, the suppressive effects of these mutant KvLQT1 subunits would be physiologically relevant to the origin of LQTS. In a patient carrying one of these KvLQT1 mutant alleles, diminution of the repolarizing I_Ks current would be expected to result in the prolongation of the cardiac action potential duration and a subsequent increased risk of cardiac arrhythmias. Mutations in the HERG gene cause similar effects by reducing the I_Kr-type current.¹⁰ It will be of interest to correlate the effects of the various KvLQT1 mutations to the severity of disease in patients with chromosome 11-linked LQTS.¹²

	Acknowledgments

 
We thank B. Kienzel for sequencing. This work was supported by the Bristol-Myers Squibb Pharmaceutical Research Institute.

Received May 13, 1997; revision received June 23, 1997; accepted July 1, 1997.

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