Informace o publikaci

T309I-Kv7.1 mutation as a feasible founder LQT1 mutation: clinical, genetic and biophysical analysis



Rok publikování 2017
Druh Konferenční abstrakty
Fakulta / Pracoviště MU

Lékařská fakulta

Popis Introduction: Ionic channel mutation associated with inherited arrhythmogenic syndrome is usually unique to a particular family. The same mutation identified in unrelated families from the same region may represent the so called founder mutation. Purpose: We aimed to analyse clinical, genetic, and biophysical characteristics of c.C926T mutation in KCNQ1 gene (p.T309I-Kv7.1); the gene encodes ?-subunit of the slowly activating delayed rectifier potassium (IKs) channel. This mutation is a feasible founder mutation of the long QT syndrome type 1 (LQT1) in our region. Methods: Clinical analysis (ECG at rest and during ergometry) and genetic analysis (mutation and pedigree analysis) were performed in 11 carriers (4 males and 7 females) of T309I-Kv7.1 mutation and their 12 healthy relatives (5 males and 7 females) in 5 presumably unrelated families. Biophysical analysis in Chinese hamster ovary cells transiently expressing wild-type or mutant human IKs channels (KCNQ1, KCNE1, Yotiao) was performed by the whole cell patch clamp technique at 37 ?C. Results: The duration of QT interval was significantly prolonged in the 4th minute of restitution after ergometry in carriers of the investigated mutation (to 490 ± 20 ms from 470 ± 20 ms at rest) but not in their healthy relatives (to 420 ± 20 ms from 410 ± 30 ms at rest). The respective QT interval durations significantly differed in the mutations carriers and in their healthy relatives. Two of the mutation carriers have experienced syncope or resuscitated cardiac arrest. The performed genetic analysis has not revealed any sings of congeniality of the 5 investigated families. Further testing is planned, namely analysis of short tandems repeats localized in the non-recombinant region of Y chromosome. Biophysical analysis of the wild-type human IKs channels showed a considerable current with properties typical for IKs (tail current at -40 mV 501.3 ± 75.0 pA following 5-s activation of the current at +60 mV, half steady-state activation at 7.0 ± 1.2 mV with the slope factor 16.4 ± 0.9, cell capacity 11.04 ± 0.85 pF, n = 17; exponential time course of activation and deactivation with time constants 2.6 ± 0.3 s at 0 mV, n = 13, and 191.6 ± 23.6 ms at -80 mV, n = 9, respectively). On the contrary, no measurable current was apparent in the mutant channels (n = 6). Conclusions: Our data support the hypothesis that p.T309I-Kv7.1 mutation might be the founder LQT1 mutation in our region. According to the preliminary biophysical data, p.T309I-Kv7.1 mutation is a loss-of-function mutation as is typical for mutations associated with LQT1; namely it generates non-functional IKs channels. Further biophysical analysis proceeds, focused on the mutant channels and newly also on the channels formed by both the wild-type and mutant KCNQ1 subunits to imitate heterozygous state present in patients.
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