Alternative titles; symbols
HGNC Approved Gene Symbol: KCNQ1
SNOMEDCT: 20852007;
Cytogenetic location: 11p15.5-p15.4 Genomic coordinates (GRCh38): 11:2,445,008-2,849,105 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11p15.5-p15.4 | {Long QT syndrome 1, acquired, susceptibility to} | 192500 | Autosomal dominant | 3 |
| Atrial fibrillation, familial, 3 | 607554 | Autosomal dominant | 3 | |
| Jervell and Lange-Nielsen syndrome | 220400 | Autosomal recessive | 3 | |
| Long QT syndrome 1 | 192500 | Autosomal dominant | 3 | |
| Short QT syndrome 2 | 609621 | Autosomal dominant | 3 |
Potassium channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Present in all eukaryotic cells, their diverse functions include maintaining membrane potential, regulating cell volume, and modulating electrical excitability in neurons. The delayed rectifier function of potassium channels allows nerve cells to efficiently repolarize following an action potential. In Drosophila, 4 sequence-related K+ channel genes--Shaker, Shaw, Shab, and Shal--have been identified. Each has been shown to have a human homolog (Chandy et al., 1990; McPherson et al., 1991).
Using positional cloning methods, Wang et al. (1996) identified a gene, which they called KVLQT1, within the critical region for long QT syndrome-1 locus (LQT1; 192500) on chromosome 11. KVLQT1 is strongly expressed in the heart and encodes a protein with structural features of a voltage-gated potassium channel. The longest open reading frame of the KVLQT1 cDNA spans 1,645 bp.
Sanguinetti et al. (1996) identified an apparently full-length human cDNA clone for KVLQT1. This clone predicted a 581-amino acid protein. Northern blot analysis detected a single 3.2-kb mRNA in human pancreas, heart, kidney, lung, and placenta. No message was detected in brain, liver, or skeletal muscle.
Yang et al. (1997) described the cloning of a full-length KVLQT1 cDNA encoding a 676-amino acid polypeptide with structural characteristics similar to voltage-gated potassium channels.
Barhanin et al. (1996) cloned a full-length KVLQT1 cDNA from a mouse heart library. Its sequence revealed an open reading frame encoding a 604-amino acid polypeptide sharing 90.5% identity with a human KVLQT1 partial sequence. Hydrophobicity analysis predicted a classic voltage-dependent potassium channel topology with 6 transmembrane segments (of the Shaker type) and a long unique C-terminal cytoplasmic domain.
By genomic sequence analysis, Splawski et al. (1998) found that the KCNQ1 gene contains 16 exons and spans 400 kb. The exon sizes range from 47 to 1,122 bp. Neyroud et al. (1999) comprehensively detailed the genomic structure of KCNQ1. They determined that the gene contains 19 exons and spans more than 400 kb. The authors presented the sequences of exon-intron boundaries and of oligonucleotide primers designed to allow PCR amplification of all exons from genomic DNA.
By positional cloning methods, Wang et al. (1996) identified the KVLQT1 gene within the critical region for long QT syndrome on chromosome 11p15. Sanguinetti et al. (1996) showed that a fragment of the KVLQT1 cDNA mapped to the short arm of chromosome 11. Neyroud et al. (1999) mapped the KCNQ1 gene to 11p15.5.
To define the function of the KVLQT1 gene, Sanguinetti et al. (1996) transfected KVLQT1 cDNA into Chinese hamster ovary (CHO) cells. The biophysical properties of the transfected KVLQT1 cDNA clone were unlike those of other known cardiac potassium channels. Through cotransfection studies, they demonstrated that KVLQT1 and ISK (KCNE1; 176261) coassemble to form the cardiac I(Ks) channel. They noted that 2 delayed-rectifier potassium channels, I(Kr) and I(Ks), modulate action potential duration in cardiac myocytes and that dysfunction of both of the channels contributes to the risk of sudden death from cardiac arrhythmia.
Barhanin et al. (1996) expressed KVLQT1 in COS cells and carried out electrophysiologic studies. They demonstrated that KVLQT1 encodes a subunit forming the cardiac ion channel underlying the I(Ks) cardiac current. They observed, however, that an additional subunit, ISK, was required to form the I(Ks) channel. Barhanin et al. (1996) noted that the I(Kr) and the I(Ks) currents are the targets of antiarrhythmic drugs and have an important impact in controlling the ventricular repolarization process. They postulated that the molecular identification of the I(Ks) channel should help with the design of new antiarrhythmic drugs.
Expression of KVLQT1 in Xenopus oocytes and human embryonic kidney cells by Yang et al. (1997) elicited a rapidly activating, K(+)-selective outward current. They found that clofilium, a class III antiarrhythmic agent with the propensity to induce torsade de pointes, substantially inhibited the current. Elevation of cAMP levels in oocytes nearly doubled the amplitude of KVLQT1 currents.
Marx et al. (2002) demonstrated that beta-adrenergic receptor modulation of the slow outward potassium ion current (I-KS) requires targeting of cAMP-dependent protein kinase A (188830) and protein phosphatase 1 (PP1; e.g., 176875) to KCNQ1 through the targeting protein yotiao (604001). Yotiao binds to KCNQ1 by a leucine zipper motif, which is disrupted by an LQTS mutation (KCNQ1-G589D; 607542.0029). Identification of the KCNQ1 macromolecular complex provides a mechanism for sympathetic nervous system modulation of cardiac action potential duration through I-KS.
Melman et al. (2004) showed that multiple segments of KCNQ1, including the pore and C terminus, bind the accessory proteins KCNE1 and KCNE3 (604433). They demonstrated that all KCNE-binding sites of KCNQ1 are required for proper regulation by the accessory subunit.
To resolve the controversy about messengers regulating KCNQ ion channels during phospholipase C (see 600810)-mediated suppression of current, Suh et al. (2006) designed translocatable enzymes that quickly altered the phosphoinositide composition of the plasma membrane after application of a chemical cue. The KCNQ current fell rapidly to zero when phosphatidylinositol 4,5-bisphosphate was depleted without changing calcium ion, diacylglycerol, or inositol 1,4,5-trisphosphate. Current rose by 30% when phosphatidylinositol 4,5-bisphosphate was overproduced and did not change when phosphatidylinositol 3,4,5-trisphosphate was raised. Hence Suh et al. (2006) concluded that the depletion of phosphatidylinositol 4,5-bisphosphate suffices to suppress current fully, and other second messengers are not needed. Furthermore, their development of these new compounds allowed additional study of biologic signaling networks involving membrane phosphoinositides.
Roepke et al. (2009) demonstrated that both KCNQ1 and KCNE2 (603796) were expressed and partially colocalized in human and mouse thyroid glands with the basolaterally located Na(+)/I(-) symporter (NIS) that mediates active I(-) transport, the first step in thyroid hormone biosynthesis. Using the rat thyroid-derived FRTL5 cell line, the authors detected endogenous expression of KCNQ1 and KCNE2 proteins that was upregulated by thyroid-stimulating hormone (TSH; see 188540) or its major downstream effector cAMP in the cell membrane fraction. The authors identified a TSH-stimulated K(+) current in FRTL5 cells that bore the signature linear current-voltage relationship of KCNQ1-KCNE2 channels and was inhibited by a KCNQ1-specific antagonist. Kcne2 -/- pups nursing from Kcne2 -/- dams had an 87% reduction in thyroid I(-) accumulation compared to wildtype pups. Roepke et al. (2009) concluded that the potassium channel subunits KCNQ1 and KCNE2 form a TSH-stimulated constitutively active thyrocyte K(+) channel that is required for normal thyroid hormone biosynthesis.
Osteen et al. (2010) found that coexpression of KCNE1 with KCNQ1 in Xenopus oocytes separated voltage dependence of KCNQ1/KCNE1 potassium channel opening and movement, suggesting an imposed requirement for movement of multiple voltage sensors before channel opening. Multiple separate voltage sensor movements were not needed to activate KCNQ1 alone. The results indicated that KCNE1 modulates KCNQ1 to slow down activation of the KCNQ1/KCNE1 channel by altering the voltage sensor movements necessary to open the channel.
Long QT Syndrome 1
Discrepancies in the codon numbers of the allelic variants exist because of changes in information about the sequence of KCNQ1. Yang et al. (1997) demonstrated that the full-length KCNQ1 cDNA codes for 676 amino acids. Thus, for example, the A341V mutation (607542.0010), one of the most frequent causes of type 1 long QT syndrome (192500), was denoted A212V by Wang et al. (1996) and A246V by Li et al. (1998).
Wang et al. (1996) found KVLQT1 mutations in affected members of 16 families with long QT syndrome-1, including 1 intragenic deletion (607542.0001) and 10 different missense mutations (607542.0002-607542.0011).
Shalaby et al. (1997) used site-directed mutagenesis to generate 3 mutant human KVLQT1 cDNAs, equivalent to mutations previously described by Wang et al. (1996). The corresponding mutant KVLQT1 proteins were coexpressed in Xenopus oocytes with wildtype KVLQT1 and minK (176261) proteins. Channel currents were studied using a voltage clamp technique. Shalaby et al. (1997) showed that mutations in the putative cytoplasmic loop (e.g., 607542.0002) and pore signature sequence (e.g., 607542.0008) abolished KVLQT1 activity when expressed individually. A mutation in the transmembrane region (e.g., 607542.0006) significantly reduced KVLQT1 activity. When coexpressed with wildtype KVLQT1 protein with or without minK protein, each mutant exerted a dominant-negative effect on the wildtype KVLQT1 current. Shalaby et al. (1997) concluded that in patients carrying such mutant alleles, diminution in the repolarizing I(ks) current would result in prolongation of the cardiac action potential and predispose to cardiac arrhythmias.
Russell et al. (1996) used SSCP analysis to screen 2 large and 9 small LQT families for mutations of the KVLQT1 potassium channel gene. They identified a novel missense mutation in 2 unrelated families: a gly314-to-ser substitution (607542.0012) in the KVLQT1 gene. In a third family, an ala341-to-val substitution (607542.0010) resulted in the spontaneous occurrence of LQT in monozygotic twin offspring of unaffected parents. Russell et al. (1996) noted that mutations at this same nucleotide had been observed in 8 of 19 LQT families determined to have KVLQT1 mutations to that time, suggesting a mutation hotspot. Both of the mutations reported in this study occurred at CpG dinucleotides. Russell et al. (1996) observed that both of the mutations alter the amino acid sequence in, or adjacent to, the pore of the channel and may diminish the channel's ability to conduct a repolarizing potassium current. Russell et al. (1996) reported that their data confirm the role of KVLQT1 in LQT. They noted that all the KVLQT1 mutations reported to that time were missense mutations and suggested that mutant KVLQT1 proteins may exert a dominant-negative effect on repolarizing potassium currents by forming multimers with normal potassium channel protein subunits, dramatically reducing the number of fully functional KVLQT1 channels.
Among 32 Japanese families with LQT, Tanaka et al. (1997) identified mutations in KCNQ1 in 4 families comprising 16 patients.
Jongbloed et al. (1999) screened 24 Dutch LQTS families for mutations in the KCNQ1 and HERG genes. Fourteen missense mutations were identified. Eight of these missense mutations were novel: 3 in the KCNQ1 gene and 5 in the HERG gene. The KCNQ1 mutation G189R (607542.0003) and the novel HERG mutation R582C (607542.0009) were detected in 2 families each. Genotype-phenotype studies indicated that auditory stimuli trigger cardiac events differentiating LQTS2 from LQTS1. In LQTS1, exercise was the predominant trigger. In addition, a number of asymptomatic gene defect carriers were identified. Jongbloed et al. (1999) concluded that asymptomatic carriers are still at risk of the development of life-threatening arrhythmias, underlining the importance of DNA analysis for unequivocal diagnosis of patients with LQTS.
Neyroud et al. (1999) identified 5 novel mutations in LQTS patients within the C-terminal part of KCNQ1 (see 607542.0025, 607542.0026, and 607542.0027). Neyroud et al. (1999) commented that the low mutation detection rate in large cohorts of LQTS patients may reflect the fact that the C-terminal region had not been analyzed to that time.
A comprehensive review of the genetic and molecular basis of long QT syndromes was given by Priori et al. (1999, 1999).
In 2 severely affected sisters from a large Belgian family with LQTS, Berthet et al. (1999) identified biallelic digenic mutations: a missense mutation in the KCNQ1 gene (A341E; 607542.0009) and a splice site mutation in the KCNH2 gene (2592+1G-A; 152427.0019). Berthet et al. (1999) stated that this was the first description of double heterozygosity in long QT syndrome.
Splawski et al. (2000) screened 262 unrelated individuals with LQT syndrome for mutations in the 5 defined genes (KCNQ1; KCNH2, 152427; SCN5A, 600163; KCNE1; and KCNE2) and identified mutations in 177 individuals (68%). KCNQ1 and KCNH2 accounted for 87% of mutations (42% and 45%, respectively), and SCN5A, KCNE1, and KCNE2 for the remaining 13% (8%, 3%, and 2%, respectively).
Yang et al. (2002) analyzed the KCNQ1, KCNH2, and SCN5A genes in 92 patients with drug-induced long QT syndrome and identified 2 missense mutations, 1 in KCNQ1 (607542.0031) and 1 in KCNH2 (152427.0014), not found in 228 controls, that were shown to reduce K+ currents in vitro.
In a 13-year-old girl with long QT syndrome, Aizawa et al. (2004) identified a frameshift mutation in the KCNQ1 gene (607542.0036) that eliminates the S3 to S6 domains and the C terminus of the KCNQ1 channel. Coexpression experiments in COS-7 cells showed that mutant and wildtype KCNQ1 remained within the cytoplasm rather than being distributed to the plasma membrane. Aizawa et al. (2004) suggested that the truncated mutant forms a heteromultimer with wildtype KCNQ1 and causes a dominant-negative effect due to a trafficking defect.
Tester et al. (2005) analyzed 5 LQTS-associated cardiac channel genes in 541 consecutive unrelated patients with LQT syndrome (average QTc, 482 ms). In 272 (50%) patients, they identified 211 different pathogenic mutations, including 88 in KCNQ1, 89 in KCNH2, 32 in SCN5A, and 1 each in KCNE1 and KCNE2. Mutations considered pathogenic were absent in more than 1,400 reference alleles. Among the mutation-positive patients, 29 (11%) had 2 LQTS-causing mutations, of which 16 (8%) were in 2 different LQTS genes (biallelic digenic). Tester et al. (2005) noted that patients with multiple mutations were younger at diagnosis, but they did not discern any genotype/phenotype correlations associated with location or type of mutation.
Napolitano et al. (2005) screened the KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 genes in 430 consecutive patients with LQT syndrome and identified 235 different mutations in 310 (72%) of the patients, 49% of whom had mutations in KCNQ1, 39% in KCNH2, 10% in SCN5A, 1.7% in KCNE1, and 0.7% in KCNE2. Fourteen (4.5%) of the patients carried more than 1 mutation in a gene. Fifty-eight percent of probands carried nonprivate mutations in 64 codons of the KCNQ1, KCNH2, and SCN5A genes; screening in a prospective cohort of 75 probands confirmed the occurrence of mutations at these codons (52%).
In 44 unrelated patients with LQT syndrome, Millat et al. (2006) used DHLP chromatography to analyze the KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 genes for mutations and SNPs. Most of the patients (84%) showed a complex molecular pattern, with an identified mutation associated with 1 or more SNPs located in several LQTS genes; 4 of the patients also had a second mutation in a different LQTS gene (biallelic digenic inheritance; see, e.g., 607542.0038 and 607542.0039).
Arbour et al. (2008) identified a missense mutation (607542.0040) causing long QT syndrome-1 among a First Nations community of northern British Columbia.
Jervell and Lange-Nielsen Syndrome 1
Neyroud et al. (1997) used homozygosity mapping to locate the gene for the Jervell and Lange-Nielsen cardioauditory syndrome (JLNS1; 220400) to the same region of 11p15.5 where the KVLQT1 gene maps. In 3 affected children of 2 families with the disorder, they demonstrated homozygosity for a deletion-insertion mutation in the C-terminal domain of the KVLQT1 gene (607542.0013). They noted that this is another instance of dominant or recessive inheritance of disorders due to different mutations in the same gene. Schmitt et al. (2000) identified a small domain between residues 589 and 620 in the KCNQ1 C terminus that may function as an assembly domain for KCNQ1 subunits. KCNQ1 C termini do not assemble and KCNQ1 subunits do not express functional potassium channels without this domain. The authors showed that the deletion-insertion mutation at KCNQ1 residue 540 identified by Neyroud et al. (1997) eliminated important parts of the C-terminal assembly domain. Therefore, JLNS mutants may be defective in KCNQ1 subunit assembly. The results provided a molecular basis for the clinical observation that heterozygous JLNS carriers show slight cardiac dysfunction and that the severe JLNS phenotype is characterized by the absence of the KCNQ1 channel.
Tyson et al. (2000) studied 10 JLNS families from Great Britain and Norway and identified 9 different mutations in the KCNQ1 gene, 2 of which were novel. Truncation of the protein proximal to the C-terminal assembly domain was expected to preclude assembly of KCNQ1 monomers into tetramers, explaining the recessive inheritance of JLNS.
Atrial Fibrillation 3
Chen et al. (2003) identified a ser140-to-gly missense mutation (607542.0032) in the KCNQ1 gene in affected members of a Chinese family with autosomal dominant atrial fibrillation (ATFB3; 607554). Functional analysis of this mutant revealed a gain-of-function effect on the KCNQ1/KCNE1 and KCNQ1/KCNE2 currents, which contrasts with the dominant-negative or loss-of-function effects of the KCNQ1 mutations previously identified in patients with long QT syndrome. Chen et al. (2003) concluded that the ser140-to-gly mutation is likely to initiate and maintain atrial fibrillation by reducing action potential duration and effective refractory period in atrial myocytes.
Johnson et al. (2008) reported a female patient with onset of atrial fibrillation in the first year of life who was heterozygous for a missense mutation in the KCNQ1 gene (R231H; 607542.0043). The patient was also found to have a long QT interval at 1 year of age, with a QTc of 479 ms.
In affected members of a 3-generation family with lone atrial fibrillation, Das et al. (2009) identified heterozygosity for a missense mutation in the KCNQ1 gene (S209P; 607542.0042).
In a cohort of 231 patients with atrial fibrillation, Abraham et al. (2010) analyzed the KCNQ1 and NPPA (108780) genes and identified heterozygosity for a 9-bp duplication in KCNQ1 (607542.0041) in the proband of a Caucasian kindred with early-onset lone atrial fibrillation; the duplication segregated with disease in the family. Abraham et al. (2010) also identified a missense mutation in the NPPA gene (108780.0002) in another family with atrial fibrillation (ATFB6; 602201) in the cohort; functional analysis revealed strikingly similar gain-of-function defects associated with the mutants, with atrial action potential shortening and altered calcium current as a common mechanism.
In affected members of 4 families with early-onset atrial fibrillation, Bartos et al. (2013) identified heterozygosity for the R231H mutation in KCNQ1. Twelve of 13 mutation-positive individuals had a normal QTc, and 1 had a prolonged QT interval.
In affected members of a family with atrial fibrillation, Guerrier et al. (2013) identified heterozygosity for the R231H missense mutation in KCNQ1. Guerrier et al. (2013) noted that the R231H mutation had previously been identified by Napolitano et al. (2005) in a study of patients with long QT syndrome, but stated that none of the family members with atrial fibrillation had documented prolonged QT intervals.
Hasegawa et al. (2014) screened 30 patients with juvenile-onset atrial fibrillation for mutations in the KCNQ1, KCNH2 (152427), KCNE1 (176261), KCNE2 (603796), KCNE3 (604433), KCNE5 (300328), KCNJ2 (600681), and SCN5A (600163) genes, and identified heterozygosity for a missense mutation in KCNQ1 (G229D; 607542.0044) in a Japanese boy who was diagnosed at 16 years of age with atrial fibrillation. At that time, ECG showed a normal QT interval, but he was later found to have borderline QT prolongation (QTc 452 ms to 480 ms). The mutation was also present in his asymptomatic mother, who also had borderline QT prolongation (QTc 468 ms). Functional analysis indicated that G229D causes constitutively open I(Ks) channels.
Short QT Syndrome 2
In a 70-year-old man with short QT syndrome-2 (SQT2; 609621) who survived an episode of ventricular fibrillation, Bellocq et al. (2004) identified a missense mutation in the KCNQ1 gene (607542.0037). Functional studies of the mutant channel revealed that both a pronounced shift of the half-activation potential and an acceleration of the activation kinetics led to a gain of function in I(Ks).
In a female infant with short QT syndrome, atrial fibrillation (AF), and bradycardia Hong et al. (2005) identified heterozygosity for a de novo missense mutation in the KCNQ1 gene (V141M; 607542.0045). Functional analysis in Xenopus oocytes demonstrated that in contrast to wildtype channels, which exhibited a slowly activating and deactivating voltage-dependent and K(+)-selective current, the V141M mutant channel current developed instantly at all voltages tested, consistent with a constitutively open channel.
In 2 unrelated girls with short QT syndrome, AF, and bradycardia, Villafane et al. (2014) identified heterozygosity for the V141M mutation in the KCNQ1 gene.
In a 23-year-old man with a slightly shortened QT interval, whose father had died unexpectedly at age 37 years, Moreno et al. (2015) identified heterozygosity for a missense mutation in the KCNQ1 gene (F279I; 607542.0046) that was not found in his unaffected sister or mother. Functional analysis showed a negative shift in the activation curve of mutant channels, with acceleration of the activation kinetics resulting in a gain of function in I(Ks).
Imprinting
Genomic imprinting is the process by which a subset of mammalian genes is 'marked' during gametogenesis such that they are expressed differentially in somatic cells depending on their parental origin. This mark may be differential methylation, because DNA methylation is necessary for the proper regulation of imprinted genes. Furthermore, some differentially methylated regions (DMRs) are thought to represent gametic imprints, because they are differentially methylated in male and female germ cells and remain so throughout development. The DMRs of most imprinted genes are associated with short, G-rich, direct repeat sequences, which may facilitate heterochromatization and gene silencing at imprinted loci. Another characteristic of imprinted genes is their association, in some cases, with imprinted antisense RNA transcripts. At the paternally expressed mouse and human IGF2 (147470) and ZPF127 loci, antisense transcripts that are also expressed paternally have been identified and overlap with the protein coding gene. For the maternally expressed IGF2R (147280) and UBE3A (601623) genes, overlapping antisense transcripts (see SNHG14, 616259) have been found and are oppositely imprinted with respect to the protein coding gene. Antisense transcripts may serve to regulate overlapping genes by promoter or transcript occlusion or by competing with these loci for regulatory elements such as transcription factors or enhancers (Smilinich et al., 1999). Imprinting control elements are proposed to exist within the KVLQT1 locus, because multiple chromosome rearrangements associated with Beckwith-Wiedemann syndrome (BWS; 130650) disrupt this gene. The imprinting control regions on chromosome 11p15 associated with H19 (103280)/IGF2 and KCNQ1 are referred to as ICR1 (616186) and ICR2, respectively.
Lee et al. (1997) demonstrated that the KVLQT1 gene spans much of the interval between p57(KIP2) (CDKN1C; 600856) and IGF2 and that, like those 2 genes, it is imprinted. They demonstrated, furthermore, that the KVLQT1 gene is disrupted by chromosomal rearrangements in patients with Beckwith-Wiedemann syndrome, as well as by a balanced chromosomal translocation in an embryonal rhabdoid tumor. They concluded that the lack of parent-of-origin effect in the long QT syndrome (192500) must reflect a relative lack of imprinting in the affected tissue, cardiac muscle, thereby representing a novel mechanism for incomplete penetrance of a human disease gene. Mannens and Wilde (1997) and Barlow (1997) discussed the findings of Lee et al. (1997) and Neyroud et al. (1997) and hypothesized that aberrant expression of the KVLQT1 gene may be responsible for the profound growth abnormalities seen in BWS. Four isoforms of KVLQT1 exist, 2 of which (isoforms 3 and 4) seem to be untranslated. KVLQT1 imprinting may be associated with specific isoforms, as has been shown for IGF2. KVLQT1 isoform 2 seems to be most abundant in heart and is probably biallelically expressed. Isoform 1 is expressed in multiple tissues and is most likely paternally imprinted. The tissue-specific imprinting of KVLQT1 and the presence of multiple isoforms might explain the various modes of inheritance seen in LQT, JLNS, and BWS.
Smilinich et al. (1999) identified an evolutionarily conserved, maternally methylated CpG island, which they called KVDMR1, in an intron of the KVLQT1 gene. Among 12 cases of BWS with normal H19 methylation, 5 showed demethylation of KVDMR1 in fibroblast or lymphocyte DNA; on the other hand, in 4 cases of BWS with H19 hypermethylation, methylation at KVDMR1 was normal. Thus, inactivation of H19 and hypomethylation of KVDMR1 (or an associated phenomenon) represented distinct epigenetic anomalies associated with biallelic expression of IGF2. Reverse transcription-PCR analysis of the human and syntenic mouse loci identified a KVDMR1-associated RNA transcribed exclusively from the paternal allele and in the opposite orientation with respect to the maternally expressed KVLQT1 gene. Smilinich et al. (1999) proposed that KVDMR1 and/or its associated antisense RNA represents an additional imprinting control element or center in human 11p15.5 and mouse distal 7 imprinted domains.
To explore the importance of imprinted gene clustering, Cleary et al. (2001) used the Cre/loxP recombination system to disrupt a cluster of imprinted genes on mouse distal chromosome 7. In mice carrying a site-specific translocation, t(7;11), separating Cdkn1c and Kcnq1, imprinting of the genes retained on chromosome 7, including Kcnq1, Kcnq1ot1 (604115), Ascl2 (601886), H19 (103280), and Igf2 (147470), was unaffected, demonstrating that these genes are not regulated by elements near or telomeric to Cdkn1c. In contrast, expression and imprinting of the translocated Cdkn1c, Slc22a1l (602631), and Tssc3 (602131) genes on chromosome 11 were affected, consistent with the hypothesis that elements regulating both expression and imprinting of these genes lie within or proximal to Kcnq1. The findings supported the proposal that chromosomal abnormalities, including translocations, within KCNQ1 that are associated with Beckwith-Wiedemann syndrome may disrupt CDKN1C expression.
One-third of individuals with Beckwith-Wiedemann syndrome lose maternal-specific methylation at KvDMR1, a putative imprinting control region within intron 10 of the KCNQ1 gene (Lee et al., 1999; Smilinich et al., 1999; Engel et al., 2000). It has been proposed that this epimutation results in aberrant imprinting and, consequently, BWS. Fitzpatrick et al. (2002) showed that paternal inheritance of this mutation in mice results in the derepression in cis of 6 genes, including Cdkn1c, which encodes cyclin-dependent kinase inhibitor 1C. Furthermore, fetuses and adult mice that inherited the deletion from their fathers were 20 to 25% smaller than their wildtype littermates. By contrast, maternal inheritance of this deletion had no effect on imprinted gene expression or growth. Thus, the unmethylated paternal KvDMR1 allele regulates imprinted expression by silencing genes on the paternal chromosome. These findings supported the hypothesis that loss of methylation in BWS patients activates the repressive function of KvDMR1 on the maternal chromosome, resulting in abnormal silencing of CDKN1C and the development of BWS.
Mancini-DiNardo et al. (2003) showed that the imprinting control region (ICR) on mouse distal chromosome 7 contains a promoter for a paternally expressed antisense transcript, Kcnq1ot1. Three paternal-specific nuclease-hypersensitive sites, which are required for full promoter activity, lie immediately upstream from the start site. The expression of Kcnq1ot1 during pre- and postnatal development was compared to that of other imprinted genes in its vicinity, Cdkn1c (600856) and Kcnq1; a lack of coordination in their expression did not support an enhancer competition model for the action of the ICR in imprinting control. Using a stable transfection assay, the authors showed that the region contains a position-independent and orientation-independent silencer. The authors proposed that the Kcnq1 ICR may function as a silencer on the paternal chromosome to effect the repression of neighboring genes.
Imboden et al. (2006) investigated the distribution of mutant alleles for the long-QT syndrome in 484 nuclear families with type I disease (LQT1 due to mutation in the KCNQ1 gene) and 269 nuclear families with type II disease (LQT2 (613688) due to mutation in the KCNH2 gene; 152427). In offspring of the female carriers of LQT1 or male and female carriers of LQT2, classic mendelian inheritance ratios were not observed. Among the 1,534 descendants, the proportion of genetically affected offspring was significantly greater than that expected according to mendelian inheritance: 870 were carriers of a mutation (57%), and 664 were noncarriers (43%) (P less than 0.001). Among the 870 carriers, the allele for the long-QT syndrome was transmitted more often to female offspring (476; 55%) than to male offspring (394; 45%) (P = 0.005). Increased maternal transmission of the long QT syndrome to daughters was also observed, possibly contributing to the excess of female patients with autosomal dominant long QT syndrome.
The relation of ion channels to disease was comprehensively reviewed by Ackerman and Clapham (1997).
In a large collaborative study, Zareba et al. (1998) demonstrated that the genotype of the long QT syndrome influences the clinical course. The risk of cardiac events (syncope, aborted cardiac arrest, or sudden death) was significantly higher among subjects with mutations at the LQT1 or LQT2 locus than among those with mutations at the LQT3 locus. Although the cumulative mortality was similar regardless of the genotype, the percentage of cardiac events that were lethal was significantly higher in families with mutations at the LQT3 locus. In this large study, 112 patients had mutations at the LQT1 locus, 72 at the LQT2 locus, and 62 at the LQT3 locus. Thus, paradoxically, cardiac events were less frequent in LQT3 but more likely to be lethal; the likelihood of dying during a cardiac event was 20% in families with an LQT3 mutation and 4% with either an LQT1 or an LQT2 mutation.
Using SSCP and DNA sequence analyses, Chen et al. (2003) studied the KCNQ1 gene in 102 families with a history of lethal cardiac events: 55 LQTS, 9 Brugada syndrome (601144), 18 idiopathic ventricular fibrillation (IVF; 603829), and 20 acquired LQTS. 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. Of the 55 LQTS families, 10 had KCNQ1 mutations and 62 carriers were identified. Five novel mutations were identified. There were 6 instances of sudden death and in 2 of these, death was the first symptom. The findings of this study emphasized the reduced penetrance of both the long QT and symptoms, resulting in diagnostic challenges, and the importance of genetic testing for identification of gene carriers with reduced penetrance in order to provide treatment and prevent lethal cardiac arrhythmias and sudden death.
Westenskow et al. (2004) analyzed the KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 genes in 252 probands with long QT syndrome and identified 19 with biallelic mutations in LQTS genes, of whom 18 were either compound (monogenic) or double (digenic) heterozygotes and 1 was a homozygote. They also identified 1 patient who had triallelic digenic mutations (see 152427.0021). Compared with probands who had 1 or no identified mutation, probands with 2 mutations had longer QTc intervals (p less than 0.001) and were 3.5-fold more likely to undergo cardiac arrest (p less than 0.01). Voltage clamp studies in Xenopus oocytes coexpressing wildtype and variant subunits demonstrated a reduction in I(Ks) density that was equivalent to the additive effects of the single mutations. Westenskow et al. (2004) concluded that biallelic mono- or digenic mutations (which the authors termed 'compound mutations') cause a severe phenotype and are relatively common in long QT syndrome. The authors noted that these findings support the concept of arrhythmia risk as a multi-hit process and suggested that genotype can be used to predict risk.
Brink et al. (2005) studied an LQTS founder population (SA-A341V) consisting of 22 apparently unrelated South African kindreds of Afrikaner origin (de Jager et al., 1996), all of which could be traced to a single founding couple of mixed Dutch and French Huguenot origin who married in approximately 1730. Brink et al. (2005) compared the 166 Afrikaner patients carrying the KCNQ1 A341V mutation (607542.0010) to the general LQT1 population (Priori et al., 2003) and found that the SA-A341V group exhibited a significantly more severe form of the disease, with an earlier age of onset, longer QTc intervals, and an increased incidence of a first cardiac event by age 20 years. Functional analysis in CHO cells demonstrated that coexpression of the A341V mutant reduced the magnitude of the wildtype channel repolarizing current I(Ks) by approximately 50%, indicating that the mutation exerts a dominant-negative effect. Brink et al. (2005) noted that this effect on I(Ks), which activates during increased heart rate and is essential for QT interval adaptation during tachycardia, might explain why 79% of lethal arrhythmic episodes in LQT1 patients with mutations impairing I(Ks) occur during exercise. In contrast, most lethal episodes in LQT2 and LQT3 patients occur during startle reaction and at rest or during sleep, respectively.
Lee et al. (2000) found that Kvlqt1 -/- mice were born at the expected mendelian ratio, were viable, and developed normally. However, by 4 weeks of age, Kvlqt1 -/- mice exhibited hyperactivity, with repetitive running, circling, nodding, and wobbling behaviors. Kvlqt1 -/- mice were completely deaf due to defects in inner ear development, and they displayed gastric hyperplasia, likely resulting from an altered cellular repertoire of lineage maturation in gastric mucosa. However, cardiac electrophysiology was normal, and Kvlqt1 -/- mice did not display features of BWS.
To produce a mouse model for Jervell and Lange-Nielsen syndrome, Casimiro et al. (2001) generated a line of transgenic mice that had a targeted disruption in the Kcnq1 gene. Behavioral analysis demonstrated that the homozygous-null mice were deaf and exhibited a shaker-waltzer phenotype. Histologic analysis of the inner ear structures of these mice showed gross morphologic anomalies because of drastic reduction in the volume of endolymph. ECGs recorded from the null mice demonstrated abnormal T- and P-wave morphologies and prolongation of the QT and JT intervals when measured in vivo, but not in isolated hearts. These changes were indicative of cardiac repolarization defects that appear to be induced by extracardiac signals.
Casimiro et al. (2004) noted that Kcnq1 knockout results in mice with more severe defects than those in human LQT1 or JLNS1. They developed mouse lines with point mutations in the Kcnq1 gene that cause LQT1 in humans. Mice with an ala340-to-glu mutation had normal hearing but a long QT and therefore modeled patients with LQT1. Mice with a thr311-to-ile mutation phenocopied JLNS1, but they also displayed the shaker/waltzer defect, which is specific to mouse.
Imprinted genes are clustered in domains, and their allelic repression is mediated by imprinting control regions. These imprinting control regions are marked by DNA methylation, which is essential to maintain imprinting in the embryo. To explore how imprinting is regulated in placenta, Umlauf et al. (2004) studied the Kcnq1 domain on mouse distal chromosome 7. This large domain is controlled by an intronic imprinting control region (Fitzpatrick et al., 2002; Mancini-DiNardo et al., 2003) and comprises multiple genes that are imprinted in placenta, without the involvement of promoter DNA methylation. Umlauf et al. (2004) found that the paternal repression along the domain involves acquisition of trimethylation at lys27 and dimethylation at lys9 of histone H3 (see 602810). Eed (605984)-Ezh2 (601573) Polycomb complexes are recruited to the paternal chromosome and potentially regulate its repressive histone methylation. Studies on embryonic stem cells and early embryos supported the proposal of Umlauf et al. (2004) that chromatin repression is established early in development and is maintained in the placenta. In the embryo, on the other hand, imprinting is stably maintained only at genes that have promoter DNA methylation. Random X inactivation in the embryo proper also involves repressive histone methylation and recruitment of Eed-Ezh2 complexes (Silva et al., 2003). Umlauf et al. (2004) concluded that their data underscored the importance of histone methylation in placental imprinting and identified mechanistic similarities with X chromosome inactivation in extraembryonic tissues, suggesting that the 2 epigenetic mechanisms are evolutionarily linked.
Studying imprinting in the placenta in the region of distal mouse chromosome 7, Lewis et al. (2004) found that the silent paternal alleles of imprinted genes are marked in the trophoblast by repressive histone modifications (dimethylation at lys9 of histone H3 and trimethylation at lys27 of histone H3), which were disrupted when imprinting center-2 (IC2) on mouse distal chromosome 7 was deleted. The deletion led to reactivation of the paternal alleles. Lewis et al. (2004) proposed that an evolutionarily older imprinting mechanism limited to extraembryonic tissues was based on histone modifications.
Elso et al. (2004) characterized 2 mouse lines carrying mutant alleles of Kcnq1, which very rapidly established chronic gastritis in a bacterial pathogen-exposed environment. Independent of infection, mutant mice developed gastric hyperplasia, hypochlorhydria, and mucin dysregulation, as well as metaplasia, dysplasia, and premalignant adenomatous hyperplasia of the stomach.
Using pharmacologic inhibition and gene knockout in mice, Vallon et al. (2005) demonstrated the importance of Kcnq1 channel complexes in maintenance of the driving force for proximal tubular and intestinal Na+ absorption, gastric acid secretion, and cAMP-induced jejunal Cl- secretion. In the kidney, Kcnq1 was dispensable under basal conditions; however, luminal Kcnq1 repolarized the proximal tubule and stabilized the driving force for Na+ reabsorption under conditions of increased glucose or amino acid resorption. In mice lacking functional Kcnq1, impaired intestinal absorption was associated with reduced serum vitamin B12 concentrations, mild macrocytic anemia, and fecal loss of Na+ and K+, the latter affecting K+ homeostasis.
In studies of Drosophila, Ocorr et al. (2007) observed a markedly elevated incidence of cardiac dysfunction and arrhythmias in aging fruit fly hearts and a concomitant decrease in expression of Kcnq, which is the Drosophila homolog of human KCNQ1. Hearts from young Kcnq-mutant fruit flies exhibited arrhythmias reminiscent of torsade de pointes and had severely increased susceptibility to pacing-induced cardiac dysfunction at young ages, characteristics that are observed only at advanced ages in wildtype flies. Alterations in rhythmicity of the mutant flies was rescued by transgenic wildtype Kcnq, and heart-specific Kcnq overexpression in old wildtype flies reversed the age-dependent increase in arrhythmias. Ocorr et al. (2007) suggested that an age-dependent decrease in KCNQ1 expression within the heart may contribute to the increased incidence of arrhythmia observed with age.
Using SSCP analysis, Wang et al. (1996) demonstrated a deletion in the KVLQT1 gene in a sporadic case of long QT syndrome-1 (LQT1; 192500). Deletion of 3 nucleotides, TCG, changed codon 72 from TTC (phe) to TGG (trp) and deleted the first G of codon 73. (Codon 72 used to be known as codon 38 and codon 73 as codon 39.)
Using SSCP analysis, Wang et al. (1996) found a GCC (ala) to CCC (pro) transversion in codon 83 of the KVLQT1 gene in a sporadic case of LQT1 (192500). (This variant used to be known as ALA49PRO and ALA83PRO.)
In a family in which 3 members had LQT1 (192500), Wang et al. (1996) demonstrated a GGG (gly) to AGG (arg) transition in codon 189 of the KVLQT1 gene. Jongbloed et al. (1999) identified this mutation in 2 families with LQT1. (This variant used to be known as GLY60ARG and GLY94ARG.)
In a family with 2 members affected by LQT1 (192500), Wang et al. (1996) used SSCP analysis to demonstrate a CGG (arg) to CAG (gln) transition in codon 95 of the KVLQT1 gene. (This variant used to be known as ARG61GLN and ARG95GLN.)
Moretti et al. (2010) reported the creation of patient-specific induced pluripotent stem (IPS) cells containing the R190Q mutation in KCNQ1. They compared IPS cells derived from dermal fibroblasts from 2 patients with this mutation with those from 2 control individuals. The cells were able to generate functional myocytes that showed a ventricular, atrial, or nodal phenotype, as evidenced by expression of cell type-specific markers and as seen in recordings of the action potentials in single cells. The duration of the action potential was markedly prolonged in ventricular and atrial cells derived from patients with LQTS1, as compared with cells from control subjects. Further characterization of the role of the R190Q KCNQ1 mutation in the pathogenesis of LQTS1 revealed a dominant-negative trafficking defect associated with a 70 to 80% reduction in I(Ks) current and altered channel activation and deactivation properties. Moreover, Moretti et al. (2010) showed that myocytes derived from patients with LQTS1 had an increased susceptibility to catecholamine-induced tachyarrhythmia and that beta-blockade attenuated this phenotype, as was demonstrated in the patients themselves.
In a kindred in which 70 members were affected by LQT1 (192500), Wang et al. (1996) used SSCP analysis to demonstrate a GTG (val) to ATG (met) transition in codon 159 of the KVLQT1 gene. (This variant used to be known as VAL125MET and VAL159MET.)
In a kindred in which 2 members were affected by LQT1 (192500), Wang et al. (1996) demonstrated a CTC (leu) to TTC (phe) transition in codon 273 of the KVLQT1 gene. (This variant used to be known as LEU144PHE and LEU178PHE.)
In a sporadic case of LQT1 (192500), Wang et al. (1996) demonstrated a GGG (gly) to AGG (arg) transition in codon 211 of the KVLQT1 gene. (This mutation used to be known as GLY177ARG and GLY211ARG.)
In a sporadic case of LQT1 (192500), Wang et al. (1996) demonstrated a ACC (thr) to ATC (ile) transition in codon 217 of the KVLQT1 gene. (This mutation used to be known as THR183ILE and THR217ILE.)
In 2 kindreds with 8 members affected by LQT1 (192500), Wang et al. (1996) demonstrated a GCG (ala) to GAG (glu) transversion in codon 341 (A341E) of the KCNQ1 gene. (This variant used to be known as ALA212GLU and ALA246GLU.)
In 2 severely affected sisters from a large Belgian family with long QT syndrome (see 192500), Berthet et al. (1999) identified biallelic digenic mutations: the A341E substitution in exon 6, within the S6 transmembrane domain of KCNQ1; and a splice site mutation in the KCNH2 gene (2592+1G-A; 152427.0019). The father and his affected relatives were heterozygous for the A341E mutation in KCNQ1; the mother, a more mildly affected sister, and a grandson were heterozygous for the splice site mutation in KCNH2. Neither mutation was found in 2 unaffected sibs or in other unaffected family members. Berthet et al. (1999) stated that this was the first description of double heterozygosity in long QT syndrome.
In 5 kindreds (K1807, K161, K162, K163, and K164) with 47 members affected by LQT1 (192500), Wang et al. (1996) demonstrated a GCG (ala) to GTG (val) transversion in codon 341 of the KVLQT1 gene. The mutation segregated with disease in the families and was not found in DNA samples from 200 unrelated controls.
In affected members of a South African family of Afrikaner origin with LQT (pedigree 166), de Jager et al. (1996) identified heterozygosity for the A341V mutation in the KVLQT1 gene. Haplotype analysis of this family and 4 Afrikaner families previously studied by Wang et al. (1996) (pedigrees 161, 162, 163, and 164) revealed that all 5 families shared a common haplotype, indicating a founder effect. Noting differences in severity of disease between the 2 largest families, 161 and 162, de Jager et al. (1996) suggested that the spectrum of clinical symptoms might reflect the influence of different modulating environmental or genetic backgrounds on expression of the same mutant allele.
Russell et al. (1996) detected this mutation in the spontaneous occurrence of LQT in monozygotic twin offspring of normal parents. This mutation would be expected to encode a potassium channel with altered conductance properties. They noted that mutations at this same nucleotide have been observed in 8 of 19 LQT families determined to have KVLQT1 mutations to that time, suggesting a mutation hotspot. (This variant used to be known as ALA212VAL and ALA246VAL.)
Brink et al. (2005) studied an LQTS founder population (SA-A341V) consisting of 22 apparently unrelated South African kindreds of Afrikaner origin (including pedigrees 161, 162, 163, 164, and 166), all of which could be traced to a single founding couple of mixed Dutch and French Huguenot origin who married in approximately 1730. Comparing the Afrikaner patients to the general LQT1 population, Brink et al. (2005) found that the SA-A341V group exhibited a significantly more severe form of the disease, with an earlier age of onset, longer QTc intervals, and an increased incidence of first cardiac event by age 20 years. Functional analysis in CHO cells demonstrated that coexpression of the A341V mutant reduced the magnitude of wildtype channel repolarizing current by approximately 50%, indicating that the mutation exerts a dominant-negative effect.
Modifier Effects of Variation in the AKAP9 Gene
In 349 members of a South African founder population of Afrikaner origin with LQT1, 168 of whom carried an identical-by-descent A341V mutation, de Villiers et al. (2014) genotyped 4 SNPs in the AKAP9 gene (604001) and found statistically significant associations between certain alleles, genotypes, and haplotypes and phenotypic traits such as QTc interval length, risk of cardiac events, and/or disease severity. De Villiers et al. (2014) stated that these results clearly demonstrated that AKAP9 contributes to LQTS phenotypic variability; however, the authors noted that because these SNPs are located in intronic regions of the gene, functional or regulatory variants in linkage disequilibrium with the SNPs were likely to be responsible for the modifying effects.
In a family with 11 members affected by LQT1 (192500), Wang et al. (1996) demonstrated a GGG (gly) to GAG (glu) transversion in codon 250 of the KVLQT1 gene. (This variant used to be known as GLY216GLU and GLY250GLU.)
Russell et al. (1996) reported a mutation resulting in a gly219-to-ser substitution in 2 LQT1 (192500) families. (This variant used to be known as GLY185SER and GLY219SER.) This mutation would be expected to encode a potassium channel with altered conductance properties.
In 3 children with Jervell and Lange-Nielsen cardioauditory syndrome (JLNS1; 220400) from 2 consanguineous families, Neyroud et al. (1997) found homozygosity for a deletion-insertion mutation in the C-terminal domain of the KVLQT1 gene. At nucleotide 1244, a deletion of 7 bp and an insertion of 8 bp was found in affected individuals. The mutation resulted in a frameshift from codon 415, leading to a premature stop signal at codon 522 close to the end of the coding sequence, which is at codon 547. Several other members of the 2 families were heterozygous for the mutation. Both families originated from Kabylia, which suggested founder effect.
In a patient with Jervell and Lange-Nielson syndrome (JLNS1; 220400), Splawski et al. (1997) found homozygosity for a 1-bp insertion (G) after nucleotide 282 of the KVLQT1 gene. The insertion caused a frameshift, disrupting the coding sequence after the second putative membrane-spanning domain of the KVLQT1 protein and leading to a premature stop codon at nucleotide 564. The proband was born to second-cousin parents. At 35 weeks' gestation, the obstetrician informed the mother that the fetal heart rate had dropped to 70 to 80 beats per minute. At 38 weeks, the heart rate continued to be slow, and slow heart rate persisted after birth. One hour after delivery, at the time of the first bottle feeding, the infant had cyanosis and hypotonia. A diagnosis of LQT was made and treatment with propranolol was started. On the eighth day, audiograms indicated bilateral sensory deafness. The family members were not evaluated at that time. Seven months after the delivery of the proband, the mother had a cardiac arrest and died when her alarm clock sounded. She was exhausted and very anxious at the time. Investigation of the family demonstrated an extensive involvement of many members with typical heterozygous LQT. Linkage analysis showed that the disorder mapped to the KVLQT1 region on 11p15.5.
In a study of 20 WRS (LQT1; 192500) families originating from France, Donger et al. (1997) identified a C-to-T transition at nucleotide 1663 of the KVLQT1 gene causing a missense arg555-to-cys substitution in the C-terminal domain. In 3 large kindreds, there was a total of 44 carriers of this mutation. Only 5 living subjects experienced syncope and there were 2 sudden deaths. Syncope or death occurred only in the presence of drugs known to modify ventricular repolarization (terfenadine, disopyramide, meflaquine, and diuretics). Carriers of the arg555-to-cys mutation had only minor or no prolongation of the QT interval. Donger et al. (1997) proposed that this allelic variant causes a forme fruste LQT1 phenotype.
In 2 consanguineous Jervell and Lange-Nielsen syndrome (JLNS1; 220400) families, Neyroud et al. (1998) identified a trp305-to-ser mutation in the pore region of KCNQ1 by PCR-SSCP analysis. In contrast to several missense mutations found in the same region of the KCNQ1 gene in heterozygous state in Ward-Romano syndrome patients, which are associated with severe cardiac phenotypes, the heterozygous state of the W305S mutation yielded an apparently normal phenotype. This is the same phenomenon as that observed in a number of other situations: different mutations in the same gene produce a phenotype that may be recessive or dominant and the phenotype may be the same or different in the case of the 2 modes of inheritance.
Priori et al. (1998) described a 9-year-old boy with classic Romano-Ward syndrome (LQT1; 192500) (syncope, prolonged QT interval, normal audiogram) born to second cousins. Two brothers of the proband had died suddenly, one at rest and the other while swimming. Sequence analysis in the proband demonstrated a novel homozygous missense mutation, a G-to-A transition resulting in an alanine-to-threonine amino acid substitution at position 300 of the KVLQT1 protein. Both parents were heterozygous for this mutation and had normal QT intervals. None of 100 control chromosomes exhibited this mutation. Coexpression of the mutant KVLQT1 protein with minK (176261) in Xenopus oocytes demonstrated a mild electrophysiologic effect on ion flux. The authors commented that this mutation in the homozygous state caused Romano-Ward syndrome and not Jervell and Lange-Nielson syndrome (220400), citing it as evidence for a recessive variant of Romano-Ward syndrome.
After identifying a 10-year-old boy with long QT syndrome (192500) after a near-drowning that required defibrillation from torsade de pointes, Ackerman et al. (1998) evaluated first-degree relatives and found a 4-generation family comprising 26 individuals with 4 additional symptomatic and 8 asymptomatic members harboring an abnormally prolonged QT interval. Linkage to the 11p15.5 region was found with a maximum lod score of 3.36. A mutation search revealed a 3-bp deletion resulting in an in-frame deletion of codon 339 for phenylalanine. Ackerman et al. (1998) pointed out that the delF339 mutation is closely situated to codon 341, which is the site of 2 common mutations, A341V (607542.0010) and A341E (607542.0009).
In a 19-year-old woman with LQT1 (192500) who had been asymptomatic but who died after a near-drowning, Ackerman et al. (1999) demonstrated by molecular tests at autopsy a 9-bp deletion involving nucleotides 373 through 381 of the KCNQ1 gene. The 9-bp deletion (GCCGCGCCC) resulted in an in-frame deletion of 3 amino acids (alanine, alanine, and proline) from position 71 through 73 in the cytoplasmic N-terminal region of the KCNQ1 ion channel subunit. The woman's maternal grandfather, mother, and 18-year-old sister also had the 9-bp deletion. It appears that a substantial number of unexplained drownings may have a basis in the long QT syndrome. Although the mother had electrocardiographic changes of long QT syndrome, the 18-year-old sister who was a carrier had equivocal or normal electrocardiogram in the view of half a panel of expert electrocardiographers. The resuscitation of the proband, although ultimately unsuccessful because of the extended period of anoxia, did allow electrocardiographic documentation of QT prolongation, which was a notable finding, given the entirely asymptomatic personal and family history.
Larsen et al. (1999) described a Swedish family in which the proband and his brother suffered from severe Romano-Ward syndrome (LQT1; 192500) associated with compound heterozygosity for 2 mutations in the KCNQ1 gene: R518X and A525T. The mutations were found to segregate in heterozygosity in the maternal and paternal lineage, respectively. None of the those heterozygous for a mutation exhibited clinical long QT syndrome. No hearing defects were found in the proband. The data strongly indicated that compound heterozygosity for these 2 mutations is the cause of the autosomal recessive form of RWS in this family. A recessive variant of the Ward-Romano long QT syndrome (607542.0017) was suggested by Priori et al. (1998) on the basis of a finding of homozygosity in a consanguineous family. Larsen et al. (1999) suggested that 'sporadic RWS' should be considered as potentially recessive RWS, and efforts made to determine the molecular defects and identify carriers in the family, since they may be at risk of dying suddenly from drug-induced LQTS.
For discussion of the ala525-to-thr (A525T) mutation in the KCNQ1 gene that was found in compound heterozygous state in 2 brothers with severe Romano-Ward syndrome (LQT1; 192500) by Larsen et al. (1999), see 607542.0020.
Chen et al. (1999) reported a small Amish family in which 2 sibs fulfilled the diagnostic criteria for Jervell and Lange-Nielsen syndrome (JLNS1; 220400). Both were homozygous for a novel 2-bp deletion in the S2 transmembrane domain of KVLQT1. This mutation predicts a frameshift leading to protein truncation. The protein product was predicted to be functionless due to most transmembrane domains and the pore region of the KVLQT1 protein having been deleted.
Murray et al. (1999) examined a French LQTS (192500) family and found a novel G-to-C transversion at position 922 -1 in the splice acceptor site of intron 5 of the KCNQ1 gene. The effect on splicing efficiency was not determined.
Murray et al. (1999) found linkage to KCNQ1 in a families with LQTS (192500) and detected a G-to-C transversion at position 1032 within the last codon of exon 6. The coded alanine was conserved. RT-PCR from fresh blood samples from the proband and his affected mother demonstrated transcripts lacking exons 6 and 7. Transcripts lacking exon 7 were also found in lymphocyte DNA from a patient with this mutation and in normal cardiac tissue from a patient without LQTS. The reading frame remained intact, resulting in the deletion of the pore, or S6, domain. These observations suggested that the G-to-C transversion in the exon 6/intron 7 consensus splice donor sequence affects splicing efficiency.
The authors also found a G-to-A transition at position 1032 in 2 unrelated French families. This had been independently reported in 5 other families by Li et al. (1998) and Kanters et al. (1998). Murray et al. (1999) suggested that base position 1032 represented a mutation hotspot within KCNQ1. The commonest site for mutation is codon 341, in association with a methylated CpG dinucleotide.
In affected individuals in a family with Romano-Ward syndrome (LQT1; 192500), Neyroud et al. (1999), detected insertion of a C at nucleotide position 1893 in exon 15. This created a frameshift with a premature stop codon 19 amino acids later, resulting in a largely intact protein.
Neyroud et al. (1999) found that a male with Jervell and Lange-Nielsen syndrome (JLNS1; 220400) was compound heterozygous for a frameshift mutation in exon 15 of the KCNQ1 gene and another mutation that was not identified. The frameshift, caused by a 20-bp deletion at nucleotide position 1892, created a premature stop codon 13 amino acids later.
Neyroud et al. (1999) reported that a male patient (family JLN12664) with Jervell Lange-Nielsen syndrome (JLNS1; 220400) was compound heterozygous for 2 mutations in the KCNQ1 gene: a de novo 1760C-T transition in exon 14, resulting in a thr587-to-met substitution, on the paternal allele, and a maternally derived splice site mutation in intron 1 (607542.0028).
Neyroud et al. (1999) reported that a male patient with Jervell Lange-Nielsen syndrome (JLNS1; 220400) was compound heterozygous for 2 mutations in the KCNQ1 gene: a de novo 1760C-T transition in exon 14, resulting in a thr587-to-met substitution (607542.0027), on the paternal allele, and a maternally derived splice mutation in intron 1. No additional information was provided for the intron 1 mutation.
Piippo et al. (2001) identified a novel missense mutation in the KCNQ1 gene in Finns with Jervell and Lange-Nielsen syndrome (JLNS1; 220400) or long QT syndrome (192500). The mutation, a glycine-to-aspartic acid substitution at codon 589 (G589D) in the C terminus, was identified in homozygous state in 2 sibs with Jervell and Lange-Nielsen syndrome and in heterozygous state in 34 of 114 probands with Romano-Ward syndrome and 282 family members. The mean rate-corrected QT intervals of the 316 heterozygous subjects and 423 noncarriers were 460 +/- 40 ms and 410 +/- 20 ms (p less than 0.001), respectively. Piippo et al. (2001) concluded that the G589D mutation accounts for 30% of Finnish cases with long QT syndrome and may be associated with both Romano-Ward and Jervell and Lange-Nielsen phenotypes of the syndrome. They suggested that the relative enrichment of this mutation most likely represents a founder gene effect.
Schwartz et al. (2001) identified 2 Italian families with LQT1 (192500) with the same heterozygous 350C-T transition in the KCNQ1 gene, resulting in a pro117-to-leu (P117L) substitution. In 1 family, an infant had died of SIDS and was found postmortem to have a de novo mutation. In the other family, several members had long QT syndrome. The mutation was not found in 800 reference alleles of Italian origin.
In a patient with long QT syndrome (192500), Splawski et al. (2000) identified heterozygosity for a 1747C-T transition in exon 15 of the KCNQ1 gene, resulting in an arg583-to-cys (R583C) substitution.
In a patient who developed QT prolongation and torsade de pointes while taking the drug dofetilide (see 192500), Yang et al. (2002) identified heterozygosity for an R583C mutation in the KCNQ1 gene. The mutation was not found in 228 controls. In vitro expression studies of the mutant protein confirmed a significant reduction in potassium currents, suggesting that the R583C mutation was responsible for the patient's response to dofetilide.
In a 4-generation family with autosomal dominant atrial fibrillation (ATFB3; 607554) from Shandong Province, China, Chen et al. (2003) identified an A-to-G substitution at nucleotide 418 of the KCNQ1 gene leading to a ser-to-gly substitution at codon 140 in all affected family members. This mutation was not observed in normal individuals in the family with 1 exception, which Chen et al. (2003) ascribed to delayed manifestation or incomplete penetrance. A prolonged QTc interval was observed in 9 of the 16 affected family members, ranging from 450 to 530 ms. The mutation was absent in 188 healthy control individuals. The serine at position 140 is well conserved among different species and is located in the S1 transmembrane segment of KCNQ1 in a position close to the extracellular surface of the plasma membrane.
Using Xenopus oocytes expressing human KCNQ1 in the presence or absence of KCNE1 (176261), Peng et al. (2017) characterized 2 KCNQ1 gain-of-function mutations that cause atrial fibrillation, S140G and val141 to met (V141M; 607542.0045). In the absence of KCNE1, S140G, but not V141M, slowed voltage sensor movement, leading to indirect slowing of current deactivation. Slowing of voltage sensor deactivation by S140G in the absence of KCNE1 was independent of channel opening. When KCNE1 was coexpressed, S140G slowed both current deactivation and voltage sensor movement, whereas V141M slowed current deactivation without slowing voltage sensor movement. Slowing of voltage sensor deactivation by S140G in the presence of KCNE1 was dependent on channel opening. The authors proposed a molecular mechanism underlying the effects of the KCNQ1 mutations on channel gating and suggested that KCNE1 mediates changes in pore movement and voltage sensor-pore coupling to slow channel deactivation.
Reardon et al. (1993) reported a family in which the proband had a cardiac arrest at 4 years of age; she and her brother were then found to have a QTc of 490 ms. The parents of the proband were first cousins and there were hearing abnormalities reported in several family members. It was uncertain whether the diagnosis should be Romano-Ward syndrome (192500), which is dominant, or Jervell and Lange-Nielsen syndrome (220400), which is recessive. Murray et al. (2002) identified a gly269-to-ser (G269S) mutation in the KCNQ1 gene in homozygous state in the proband and her brother. Functional studies indicated that the mutation had both recessive and dominant characteristics.
In 8 affected members of a family with a severe form of dominantly inherited Romano-Ward syndrome (192500), 5 of whom had sudden deaths, Donger et al. (1997) identified a gly269-to-asp (G269D) mutation in the KCNQ1 gene.
Wedekind et al. (2004) described a 4-generation family with long QT syndrome (192500) in which 7 members were carriers of 2 amino acid alterations in cis in the KCNQ1 gene: val254 to met (V254M) and val417 to met (V417M). Voltage clamp recordings of mutant KCNQ1 protein in Xenopus oocytes showed that only the V254M mutation reduced the I(Ks) current and that the effect of the V417M variant was negligible. The family exhibited the complete clinical spectrum of the disease, from asymptomatic patients to victims of sudden death before beta-blocker therapy. Of 9 family members, 1 female died suddenly before treatment, 3 females of the second generation were asymptomatic, and 4 members of the third and fourth generations were symptomatic. All mutation carriers were treated with beta-blockers and remained asymptomatic for a follow-up of up to 23 years.
In a 13-year-old girl with long QT syndrome (192500), Aizawa et al. (2004) identified a C-to-GG substitution at nucleotide 533 in the KCNQ1 gene, causing a frameshift at alanine-178 and resulting in a truncated protein with elimination of the S3 to S6 domains and the C terminus of the KCNQ1 channel. Coexpression experiments in COS-7 cells showed that mutant and wildtype KCNQ1 remained within the cytoplasm rather than being distributed to the plasma membrane, suggesting that the truncated mutant forms a heteromultimer with wildtype KCNQ1 and causes a dominant-negative effect due to a trafficking defect.
In a 70-year-old man with short QT syndrome-2 (SQT2; 609621) who survived an episode of ventricular fibrillation, Bellocq et al. (2004) identified a 919G-C transversion in the KCNQ1 gene, resulting in a val307-to-leu (V307L) substitution. Functional studies of the mutant channel revealed that both a pronounced shift of the half-activation potential and an acceleration of the activation kinetics led to a gain of function in I(Ks).
Functional studies of the mutant channel revealed that both a pronounced shift of the half-activation potential and an acceleration of the activation kinetics led to a gain of function in I(Ks).
In a female infant with a family history of sudden death, who had severe, continuous bradycardia in utero that was confirmed after birth and a QTc of 485 ms (see 192500), Millat et al. (2006) identified biallelic digenic mutations: a 1-bp deletion (562delT) in exon 2 of the KCNQ1 gene, causing a frameshift at trp188, and an insertion in the KCNH2 gene (2775insG; 152427.0020).
In a female infant with fetal and neonatal bradycardia and a QTc of 570 ms (see 192500), Millat et al. (2006) identified biallelic digenic mutations: a 728G-C transversion in exon 4 of the KCNQ1 gene, resulting in an arg243-to-pro (R243P) substitution, and a missense mutation in the KCNH2 gene (R948C; 152427.0022).
In 2 severely affected index cases with long QT syndrome (LQT1; 192500) from a First Nations community in northern British Columbia (Gitxsan), Arbour et al. (2008) identified a G-to-A transition in exon 4 of the KCNQ1 gene that resulted in a val-to-met substitution at codon 205 (V205M). Identification of the mutation prompted the ascertainment of 122 relatives using community-based participatory research principles. The 22 further mutation carriers identified had a significantly higher mean corrected QT interval than noncarriers (465 +/- 28 milliseconds vs 434 +/- 26 milliseconds, P less than 0.0001); however, 30% of carriers had a corrected QT interval below 440 milliseconds. In transfected mouse Itk cells this mutation suppressed I(Ks) by causing a dramatic depolarizing shift in activation voltage coupled with acceleration of channel deactivation. Arbour et al. (2008) concluded that this mutation likely conferred increased susceptibility to arrhythmias because of decreased I(Ks) current. Even with a common mutation within a relatively homogeneous population, clinical expression remains variable, supporting the difficulty of definitive diagnosis without genetic testing.
In affected members of a Caucasian kindred segregating autosomal dominant early-onset lone atrial fibrillation (ATFB3; 607554), Abraham et al. (2010) identified heterozygosity for a 9-bp duplication in the KCNQ1 gene, resulting in insertion of isoleucine, alanine, and proline at positions 54 to 56. The duplication was present in all 4 affected family members and in 2 symptomatic family members in whom atrial fibrillation had not yet been documented. It was not found in 3 unaffected family members or in Caucasian, Han Chinese, and Asian population controls; however, the duplication was detected in 2 (2.1%) of 94 African American control chromosomes that had been obtained from the anonymous Coriell repository, for which no clinical information was available. Functional analysis in CHO cells demonstrated that coexpression of mutant KCNQ1 with its ancillary subunit KCNE1 (176261) generated approximately 3-fold larger currents that also activated much earlier than wildtype currents. The mutant accelerated both activation and deactivation over all voltages.
In affected members of a 3-generation family with lone atrial fibrillation (ATFB3; 607554), Das et al. (2009) identified heterozygosity for a c.625C-T transition in the KCNQ1 gene, resulting in a ser209-to-pro (S209P) substitution at a highly conserved residue in the C-terminal half of the third transmembrane region (S3b) of the channel protein. The mutation was incompletely penetrant, as 1 carrier individual with an affected child was unaffected both by history and by longitudinal ECG monitoring; however, the mutation was not found in more than 1,000 control chromosomes. Mutation carriers had a longer QRS duration and a trend toward larger left atrial dimension than noncarriers, but there was no difference in PR or corrected QT interval. Functional analysis in COS-7 cells demonstrated that S209P mutant channels activate more rapidly, deactivate more slowly, and have a hyperpolarizing shift in the voltage deactivation curve compared to wildtype. In addition, a fraction of mutant channels are constitutively open at all voltages, resulting in a net increase in I(Ks) current.
Johnson et al. (2008) reported a female patient with onset of atrial fibrillation (ATFB3; 607554) in the first year of life who was heterozygous for a c.692G-A transition in exon 5 of the KCNQ1 gene, resulting in an arg231-to-his (R231H) substitution. The patient was also found to have a long QT interval (see 192500) at 1 year of age, with a QTc of 479 ms.
In affected members of 4 families with early-onset atrial fibrillation, Bartos et al. (2013) identified heterozygosity for the R231H mutation in KCNQ1. Twelve of 13 mutation-positive individuals had a normal QTc, and 1 had a prolonged QT interval. Functional analysis indicated that the R231H mutation increases the amount of KCNQ1 current during the atrial action potential, thus dramatically shortening its duration. R231H also disrupts PKA (see 188830) regulation of the KCNQ1 current and is associated with borderline and adrenergic-induced QT interval prolongation in patients.
In affected members of a family with atrial fibrillation, Guerrier et al. (2013) identified heterozygosity for the R231H missense mutation in KCNQ1. Guerrier et al. (2013) noted that the R231H mutation had previously been identified by Napolitano et al. (2005) in a study of patients with long QT syndrome, but stated that none of the family members with atrial fibrillation had documented prolonged QT intervals.
In a Japanese boy who was diagnosed at 16 years of age with atrial fibrillation (ATFB3; 607554), Hasegawa et al. (2014) identified heterozygosity for a c.686G-A transition in the KCNQ1 gene, resulting in a gly229-to-asp (G229D) substitution at a highly conserved residue in the fourth transmembrane segment (S4), which is known to be a voltage sensor. Although ECG at the time of diagnosis showed a normal QT interval, the proband was later found to have borderline QT prolongation (QTc 452 ms to 480 ms), and the mutation was detected in his asymptomatic mother, who also had borderline QT prolongation (QTc 468 ms). The mutation was not found in 400 Japanese control alleles or in the NHLBI Exome Sequencing Project Exome Variant Server database. G229D mutant channels in CHO cells displayed unique functional properties, including a large instantaneous activating component without deactivation after repolarization. Hasegawa et al. (2014) concluded that G229D alters I(Ks) activity and kinetics, thereby increasing arrhythmogenicity to atrial fibrillation.
In a female infant with short QT interval, atrial fibrillation, and bradycardia (SQT2; 609621), Hong et al. (2005) identified heterozygosity for a c.421G-A transition in the KCNQ1 gene, resulting in a val141-to-met (V141M) substitution within transmembrane domain S1. Functional analysis in Xenopus oocytes demonstrated that in contrast to wildtype channels, which exhibited a slowly activating and deactivating voltage-dependent and K(+)-selective current, the V141M mutant channel current developed instantly at all voltages tested, consistent with a constitutively open channel.
In 2 unrelated girls with short QT syndrome, AF, and bradycardia, Villafane et al. (2014) identified heterozygosity for the V141M mutation in the KCNQ1 gene.
Using Xenopus oocytes expressing human KCNQ1 in the presence or absence of KCNE1 (176261), Peng et al. (2017) characterized 2 KCNQ1 gain-of-function mutations that cause atrial fibrillation, ser140 to gly (S140G; 607542.0032) and V141M. In the absence of KCNE1, S140G, but not V141M, slowed voltage sensor movement, leading to indirect slowing of current deactivation. Slowing of voltage sensor deactivation by S140G in the absence of KCNE1 was independent of channel opening. When KCNE1 was coexpressed, S140G slowed both current deactivation and voltage sensor movement, whereas V141M slowed current deactivation without slowing voltage sensor movement. Slowing of voltage sensor deactivation by S140G in the presence of KCNE1 was dependent on channel opening. The authors proposed a molecular mechanism underlying the effects of the KCNQ1 mutations on channel gating and suggested that KCNE1 mediates changes in pore movement and voltage sensor-pore coupling to slow channel deactivation.
In a 23-year-old man with a slightly shortened QT interval and a family history of sudden cardiac death (SQT2; 609621), Moreno et al. (2015) identified heterozygosity for a c.127910T-A transversion in exon 6 of the KCNQ1 gene, resulting in a phe279-to-ile (F279I) substitution at a conserved residue within the S5 transmembrane segment. The mutation was not present in his unaffected sister or mother; no DNA was available from his father, who had died unexpectedly at age 37 years. Functional analysis of the F279I mutant in the presence of KCNE1 (176261) showed a negative shift in the activation curve and an acceleration of the activation kinetics resulting in a gain of function in I(Ks). In addition, coimmunoprecipitation studies and Foster resonance energy transfer (FRET) experiments demonstrated that coassembly between F279I channels and KCNE1 was markedly decreased compared to wildtype channels.
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