Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias

The long QT syndrome (LQTS) is a genetic disorder responsible for many sudden deaths before age 20. The identification of several LQTS genes, all encoding cardiac ion channels, has had a major impact on the management strategy for both patients and family members. Genotype-guided therapy allows more effective individually tailored therapy. Therapeutic options, including b-blockers, left cardiac sympathetic denervation, and implantable defibrillators are discussed for patients of known and of unknown genotype. The recent identification of modifier genes which amplify the effect of an LQTS mutation may change the approach to risk stratification.

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“…In 1995 and 1996, the three main genes for LQTS were identified [13][14][15]. Their identification modified understanding and even terminology.…”

Section: Lqts Genesmentioning

confidence: 99%

“…Mutations in KCNQ1 [15] and KCNE1 [19,20] are responsible also for the J-LN syndrome [21], when present as homozygous or compound heterozygous defects [22].…”

Section: Lqts Genesmentioning

confidence: 99%

The congenital long QT syndromes from genotype to phenotype: clinical implications

Schwartz

2005

Journal of Internal Medicine

211

125

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“…Among the 10 K þ channel genes that have been associated with human genetic diseases, four belong to the KCNQ subfamily. 35,36 Mutations in KCNQ2, but also in KCNQ3 that can form heteromeric association with KCNQ2, are responsible for the same epileptic disorder, BFNC. 37,38 Owing to their slow deactivation kinetics, M-type channels act as 'damping' components that prevent neuronal hyperactivity.…”

Section: Pp2a-bc and Kcnq2 In Bipolar Diseasementioning

confidence: 99%

PP2A-Bγ subunit and KCNQ2 K+ channels in bipolar disorder

Borsotto

Cavarec²,

Bouillot³

et al. 2006

Pharmacogenomics J

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Many bipolar affective disorder (BD) susceptibility loci have been identified but the molecular mechanisms responsible for the disease remain to be elucidated. In the locus 4p16, several candidate genes were identified but none of them was definitively shown to be associated with BD. In this region, the PPP2R2C gene encodes the Bg-regulatory subunit of the protein phosphatase 2A (PP2A-Bg). First, we identified, in two different populations, single nucleotide polymorphisms and risk haplotypes for this gene that are associated to BD. Then, we used the Bg subunit as bait to screen a human brain cDNA library with the yeast two-hybrid technique. This led us to two new splice variants of KCNQ2 channels and to the KCNQ2 channel itself. This unusual K þ channel has particularly interesting functional properties and belongs to a channel family that is already known to be implicated in several other monogenic diseases. In one of the BD populations, we also found a genetic association between the KCNQ2 gene and BD. We show that KCNQ2 splice variants differ from native channels by their shortened C-terminal sequences and are unique as they are active and exert a dominant-negative effect on KCNQ2 wild-type (wt) channel activity. We also show that the PP2A-Bg subunit significantly increases the current generated by KCNQ2wt, a channel normally inhibited by phosphorylation. The kinase glycogen synthase kinase 3 beta (GSK3b) is considered as an interesting target of lithium, the classical drug used in BD. GSK3b phosphorylates the KCNQ2 channel and this phosphorylation is decreased by Li þ .

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“…KCNQ1 was the first LQTS gene cloned. It spans approximately 400 kb, and encodes a novel cardiac potassium channel (4). KCNQ1 is the α-subunit for a functional potassium channel in the heart and has a conserved potassium-selective pore-signature sequence flanked by six membrane-spanning segments.…”

Section: Introductionmentioning

confidence: 99%

KCNQ1 mutations in patients with a family history of lethal cardiac arrhythmias and sudden death

et al. 2003

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Long QT syndrome (LQTS) is the prototype of the cardiac ion channelopathies which cause syncope and sudden death. LQT1, due to mutations of KCNQ1 (KVLQT1), is the most common form. This study describes the genotype-phenotype characteristics in 10 families with mutations of KCNQ1, including 5 novel mutations. One hundred and two families with a history of lethal cardiac events, 55 LQTS, 9 Brugada syndrome, 18 idiopathic ventricular fibrillation (IVF), and 20 acquired LQTS, were studied by single-strand conformational polymorphism (SSCP) and DNA sequence analyzes. Families found to have KCNQ1 mutations were phenotyped using ECG parameters and cardiac event history, and genotype-phenotype correlation was performed. No mutations were found in Brugada syndrome, IVF, or acquired LQTS families. Ten out of 55 LQTS families had KCNQ1 mutations and 62 carriers were identified. Mutations included G269S in domain S5; W305X, G314C, Y315C, and D317N in the pore region; A341E and Q357R in domain S6; and 1338insC, G568A and T587M mutations in the C-terminus. W305X, G314C, Q357R, 1338insC, and G568A, appeared to be novel mutations. Gene carriers were 26 ± 19 years (32 females). Baseline QTc was 0.47 ± 0.03 s (range 0.40-0.57 s) and 40% had normal to borderline QTc (≤0.46 s). Typical LQT1 T wave patterns were present in at least one affected member of each family, and in 73% of all affected members. A history of cardiac events was present in 19/62 (31%), 18 with syncope, 2 with aborted cardiac arrest (ACA) and six with sudden death (SD). Two out of 6 SDs (33%) occurred as the first symptom. No difference in phenotype was evident in pore vs. non-pore mutations. KCNQ1 mutations were limited to LQTS families. All five novel mutations produced a typical LQT1 phenotype. Findings emphasize (1) reduced penetrance of QTc and symptoms, resulting in diagnostic challenges, (2) the problem of sudden death as the first symptom (33% of those who died), and (3) genetic testing is important for Mutations in KCNQ1 are the most common cause of LQTS and over 100 mutations have been reported. In addition to the genetic heterogeneity, there is prominent phenotypic heterogeneity with reduced penetrance and variable expression, causing challenges for accurate diagnosis of some patients (9). Therefore, to identify additional mutations and further expand the genotypephenotype correlations in LQT1 we screened 102 families for mutations in KCNQ1 and correlated mutation findings with clinical features in mutation carriers. Methods Identification of LQTS patientsOne hundred and two families with cardiac ion channelopathy phenotype or acquired LQTS were referred to the Q. Isolation of genomic DNA Genomic DNA was prepared from whole blood using the DNA Isolation Kit for Mammalian Blood (Roche Diagnostic Co., Indianapolis, IN). SSCP analysisSingle-strand conformational polymorphism (SSCP) analysis was carried out as described previously (4,10). The coding region and the intron splice sites of the KCNQ1 gene were screened by SSCP analysis for mutations i...

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Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias

Cited by 1,625 publications

References 32 publications

The congenital long QT syndromes from genotype to phenotype: clinical implications

The congenital long QT syndromes from genotype to phenotype: clinical implications

PP2A-Bγ subunit and KCNQ2 K+ channels in bipolar disorder

KCNQ1 mutations in patients with a family history of lethal cardiac arrhythmias and sudden death

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