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Int J Mol Sci
2021 Jan 23;223:. doi: 10.3390/ijms22031112.
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Molecular Mechanism of Autosomal Recessive Long QT-Syndrome 1 without Deafness.
Oertli A
,
Rinné S
,
Moss R
,
Kääb S
,
Seemann G
,
Beckmann BM
,
Decher N
.
???displayArticle.abstract??? KCNQ1 encodes the voltage-gated potassium (Kv) channel KCNQ1, also known as KvLQT1 or Kv7.1. Together with its ß-subunit KCNE1, also denoted as minK, this channel generates the slowly activating cardiac delayed rectifier current IKs, which is a key regulator of the heart rate dependent adaptation of the cardiac action potential duration (APD). Loss-of-function mutations in KCNQ1 cause congenital long QT1 (LQT1) syndrome, characterized by a delayed cardiac repolarization and a prolonged QT interval in the surface electrocardiogram. Autosomal dominant loss-of-function mutations in KCNQ1 result in long QT syndrome, called Romano-Ward Syndrome (RWS), while autosomal recessive mutations lead to Jervell and Lange-Nielsen syndrome (JLNS), associated with deafness. Here, we identified a homozygous KCNQ1 mutation, c.1892_1893insC (p.P631fs*20), in a patient with an isolated LQT syndrome (LQTS) without hearing loss. Nevertheless, the inheritance trait is autosomal recessive, with heterozygous family members being asymptomatic. The results of the electrophysiological characterization of the mutant, using voltage-clamp recordings in Xenopus laevis oocytes, are in agreement with an autosomal recessive disorder, since the IKs reduction was only observed in homomeric mutants, but not in heteromeric IKs channel complexes containing wild-type channel subunits. We found that KCNE1 rescues the KCNQ1 loss-of-function in mutant IKs channel complexes when they contain wild-type KCNQ1 subunits, as found in the heterozygous state. Action potential modellings confirmed that the recessive c.1892_1893insC LQT1 mutation only affects the APD of homozygous mutation carriers. Thus, our study provides the molecular mechanism for an atypical autosomal recessive LQT trait that lacks hearing impairment.
Figure 1. Identification of the homozygous KCNQ1P631fs*20 mutation in a patient with LQTS without hearing loss. (A) 12-lead ECG recording of the IP (PID1889) showing a QTc of 560 ms and a heart rate of 60 bpm under beta-blocker therapy. Paper speed was 50 mm/sec. (B) Partial nucleotide and amino acid sequence illustrated from amino acid 630 to 651 for KCNQ1WT (top) and the KCNQ1P631fs*20 variant (bottom). The cytidine insertion is highlighted in red as well as the novel amino acid sequence due to the frame shift. Please note that the mutated sequence shows a premature stop codon at amino acid position 651. (C) Cartoon showing the topology of the KCNQ1 channel α-subunit. The location of the mutation is indicated by a red circle and the resulting novel amino acid sequence due to the frameshift is provided in red. (D) Pedigree of the family of the IP (marked by a red arrow) with a KCNQ1P631fs*20 mutation as a result of a nucleotide insertion mutation (c.1892_1893insC). Filled symbols indicate patients and family members with a previous diagnosis of LQTS with or without symptoms. Squares and circles represent male and female subjects, respectively. In the top right of the symbol, genetic information is given: “+/−†heterozygous mutation carrier, “+/+“ homozygous mutation carrier, “N†no genetic information was available. Below the symbols, information about certain symptomatic or further diseases are given. “SCD†sudden cardiac death. In addition, the QTc is shown for the IP. If there are no symptoms, it was marked with “asymp.â€. Symbols with a line through mark deceased subjects, and the age and cause of death is indicated below.
Figure 3. Functional effects of the KCNQ1P631fs*20 mutant co-expressed with KCNE1. (A) Representative current traces of oocytes injected with KCNQ1WT (8.1 ng/oocyte), KCNQ1P631fs*20 (8.1 ng/oocyte), KCNQ1WT 50% (4 ng/oocyte) or KCNQ1WT plus KCNQ1P631fs*20 (4 ng/oocyte each), all together with 0.1 ng KCNE1 cRNA or only KCNE1 cRNA (0.1 ng/oocyte), to obtain Xenopus (x)KCNQ1/KCNE1 (xIKs) channels. Voltage was stepped from -40 to +40 mV in 20 mV increments lasting 7000 ms, from a holding potential of −80 mV. (B) Current voltage relationships obtained by blotting the current at the end of each voltage step for each voltage applied normalized to KCNQ1WT plus KCNE1. In order to obtain the current-voltage relationship (I/V curve), all wild-type recordings were normalized to the value at +60 mV. The data of all the other constructs were also divided by the average current amplitude of the wild-type at +60 mV of the respective recording day. (C) Current amplitudes analyzed at +40 mV and normalized to KCNQ1WT plus KCNE1. All the data, also that of the wild-type recordings, were divided by the average current amplitude of the wild-type at +40 mV of the respective recording day. (A–C) All data are presented without subtraction of xKCNQ1 background currents. Numbers of oocytes recorded are indicated within the bar graphs. Values are expressed as means ± S.E.M. Error bars represent S.E.M. values. Significance was assessed using two tailed Student’s t-test. Asterisks indicate significance: ***, p < 0.001.
Figure 4. Voltage-dependence of activation of the KCNQ1P631fs*20 mutant co-expressed with KCNE1. (A) Voltage-dependence of activation for KCNQ1+KCNE1, xKCNQ1+KCNE1, KCNQ1P631fs*20+KCNE1 and KCNQ1WT/KCNQ1P631fs*20+KCNE1. Recordings were performed with the protocol as described in Figure 3. The tail currents recorded after the 7000 ms pulse were normalized to the respective maximal tail current of each recording to obtain the conductance/voltage (G/V) curves. (B) Normalized tail currents were fitted to a Boltzmann function. The voltage of half-maximal activation (V½) of KCNQ1+KCNE1, xKCNQ1+KCNE1, KCNQ1P631fs*20+KCNE1 and KCNQ1WT/KCNQ1P631fs*20+KCNE1 are illustrated, together with the numbers of oocytes analyzed.
Figure 5. Action potential modelling with the homozygous or heterozygous KCNQ1P631fs*20 mutation in the IKs channel complex. (A) Mean current amplitudes of 100% KCNQ1WT injected together with KCNE1, 50% KCNQ1WT injected together with KCNE1, 100% KCNQ1P631fs*20 injected together with KCNE1 or 50% KCNQ1WT plus 50% KCNQ1P631fs*20 injected together with KCNE1. For all data, the endogenous xIKs current recorded by injection of KCNE1 alone was subtracted. Data were normalized to KCNQ1WT 100%. (B) Action potential simulations using the O’Hara-Rudy ventricular cell model. Conductivity of the IKs channel was set to 100% for wild-type (black), 0% for the homozygous (red, dashed line) and 89% for the heterozygous state (blue, dotted line) as calculated in (A). (C) APD at 90% repolarization (APD90) was evaluated for each configuration after the simulations achieved a steady state.
Figure 2. Functional effects of the KCNQ1P631fs*20 mutation. (A) Representative current traces of oocytes injected with KCNQ1WT 100% (14.5 ng/oocyte), KCNQ1P631fs*20 (14.5 ng/oocyte), KCNQ1WT 50% (7.25 ng/oocyte) or KCNQ1WT plus KCNQ1P631fs*20 (7.25 ng/oocyte each), respectively. Voltage was stepped from -60 to +60 mV in 20 mV steps lasting 3000 ms, from a holding potential of â80 mV. (B) Current voltage relationships obtained by blotting the current at the end of each voltage step for each voltage applied normalized to KCNQ1WT. In order to obtain the current-voltage relationship (I/V curve), all wild-type recordings were normalized to the value at +60 mV. The data of all the other constructs were also divided by the average current amplitude of the wild-type at +60 mV of the respective recording day. (C) Current amplitudes analyzed at +40 mV and normalized to KCNQ1WT (100%). All the data, also that of the wild-type recordings, were divided by the average current amplitude of the wild-type at +40 mV of the respective recording day. Numbers of oocytes recorded are indicated within the bar graphs. Values are expressed as means ± S.E.M. Error bars represent S.E.M. values. Significance was assessed using two tailed Studentâs t-test. Asterisks indicate significance: ***, p < 0.001.
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