Perhaps no development of the last decade will prove more revolutionary to medicine than the completion of the HGP in 2003. With our genetic sequence known and these technologies available, researchers' hunt for genetic factors underlying common, genetically complex diseases will be significantly accelerated. One of the priorities of the HGP is to identify the subtle genetic variations that make people susceptible to big killers such as cancer andÂ heart disease, in order to aim towards creating a genetic disease-free society. This review discusses the concepts of long QT syndrome (LQTS), a complex disease and a major cause of sudden cardiac death, including sudden infant death syndrome.
Long QT Syndrome
The LQTS has evolved into a paradigm for arrhythmia studies, where basic science and clinical research have gained fundamental insights into arrhythmia mechanisms and cardiac electrophysiology. These advances would probably have been unthinkable without information gleaned from the study of the human genome. In particular, recent advances in human molecular genetic research prepared the way for the identification of genes responsible for a number of inherited syndromes, for example the LQTS and the Brugada syndrome.
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TheÂ LQTSÂ is characterized by prolongation of the correctedÂ QTÂ (QTc) interval on the surface electrocardiogram (ECG). The QT interval extends from the QRS complex, to the end of the T wave representing ventricular depolarization and repolarization, respectively (Figure). Â The condition is associated withÂ sudden cardiac deathÂ due to malignantÂ ventricular arrhythmiasÂ in form ofÂ torsade de pointes (TdP).Â
The LQTS exists in two forms, congenital and acquired LQTS. Congenital LQTS is defined as an inherited disorder, caused by gene mutations and can be further subdivided according to locus specific characteristics (Table). The acquired LQTS is precipitated by co-factors such as exposure to certain drugs (Table) and electrolyte abnormalities, but it presents with symptoms similar to those of the congenital LQTS.
The molecular genetics of congenitalÂ LQTS
Two modes of inheritance are known for the familial forms ofÂ LQTS. Romano-WardÂ syndromeÂ (RWS) is the more common autosomal dominant form, and Jervell Lange-NeilsenÂ syndromeÂ (JLNS)Â is the rarer autosomal recessive form. Both forms show a prolongation of theÂ QTÂ interval butÂ JLNSÂ is more severe and also manifests withÂ deafness.
With the advances in molecular genetics, we now know that most forms ofÂ LQTSÂ are a result of gene mutations coded for ion channels or their sub-units. To date, mutations in 12 different genes have been associated withÂ LQTSÂ (Table 1),Â and are namedÂ LQT1-10. The two geneticÂ abnormalitiesÂ associated with autosomal recessive LQTSÂ are named JLN1 and JLN2. The incidence of RWÂ syndromeÂ is unknown, estimated to be about one gene carrier in 10,000 population. The JLNÂ syndromeÂ is much rarer, thought to occur in approximately 1-6 in 1 million children.
Autosomal dominantÂ LQTSÂ (Romano-WardÂ syndrome)
Ionic currents involved in shaping the cardiac action potential
The cardiac action potential (AP) reflects the integrated electrical activity of many ionic currents across the cell membrane through voltage-gated ion channels, ionic pumps and ionic exchangers. Depolarizing currents convey positively charged ions into the cell, whereas the repolarizing currents ferry positively charged ions out of the cell (Fig. 5.3c). This is illustrated with the help of an idealized AP, which can be divided into five phases (Fig. And text from Molecular genetics ofÂ long QT syndrome). In healthy people, the AP progresses through its five phases within 200-300 ms but in LQTS patients, it takes in excess of 440-460 ms, implying an imbalance of depolarizing and repolarising currents.
LQT1Â and the KcLQT1 (KCNQ1) gene
TheÂ LQT1Â locus was mapped to chromosome 11p15.5 and the LQT1Â gene, KvLQT1 (also known asÂ KCNQ1), that encodes aÂ voltage-gated potassium channelÂ protein was cloned. In conjunction with MinK, aÂ potassium channel protein, KvLQT1 produces the slow component of the delayed rectifierÂ potassiumÂ current (IKs) that is responsible for Phase 3 repolarization of the cardiac action potential (Figure). KVLQT1Â is expressed not only in theÂ heartÂ but also in otherÂ humanÂ tissues, and has also been shown by in situ hybridization thatÂ KVLQT1Â is expressed in theÂ stria vascularisÂ of mouseÂ inner ear, which is important in understanding theÂ deafnessÂ seen in JLNÂ syndrome. Mutations of this gene lead to a prolongation of repolarization by decreasing potassium efflux.Â Recently, recessive forms of RWÂ syndromeÂ withoutÂ deafnessÂ have been described in patients homozygous forÂ KVLQT1 mutations.
LQT2 and theÂ HERGÂ gene
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LQT2, mapped to 7q35-36, was the human ether-a-go-go-related gene (HERG), also known as KCNH2, which also results from aÂ potassium channelÂ abnormality. HERG generates the rapid component of the delayed-rectifierÂ potassiumÂ current (IKr) that is responsible for Phase 3 repolarization of the action potential, recorded fromÂ humanÂ myocytes. As withÂ KVLQT1, mutations of the gene cause loss-of-function or dominant-negative IKrÂ suppression to decrease the repolarizing currents.
LQT3 and theÂ SCN5AÂ gene
The gene responsible forÂ LQT3Â is located on chromosome 3p21-24. The mutation in this form of autosomal dominantÂ LQTSÂ occurs in the cardiacÂ sodium channelÂ geneÂ SCN5A. SCN5AÂ controls the inwardÂ sodiumÂ current, INa, responsible for generating phase 0 and contributing to the plateau phase (Phase 2) of the cardiac action potential. Mutations ofÂ SCN5AÂ alter the cardiac action potential by a 'gain-of-function' mechanism through which mutantÂ SCN5AÂ channels are incompletely inactivated or reopen early, resulting in persistent inwardÂ sodiumÂ current and prolongation.
Unlike the case withÂ potassium channels, expression of a singleÂ sodium channelÂ protein is sufficient to recapitulate sodium current. Although sodium channel mutations causing the LQTS generally result in a "gain of function," and potassium channel mutations result in "loss of function" phenotype, the cellular consequences are comparable because both zstypes of defects lead to delayed repolarization and increased cellular excitability.
LQT4 and the ANK2 gene
The genetic mutation in this subtype affects sodium, potassium, and calcium ion flow.Â Â Mapped to chromosome 4q25-27, the ANKB gene encodes for the ankyrin-B adaptor protein.Â Â Ankyrin-BÂ (LQT4)Â is involved in targeting a complex of proteins to theÂ cell membrane. Mutation inÂ ANK2Â results in elevation of calcium transientsÂ and persistent inward Na+Â current (viaÂ SCN5A), as well as been associated with prolongedÂ QTc.
LQT5 and theÂ KCNE1Â (MinK) gene
As mentioned earlier, MinK works in conjunction with KvLQT1 to form theÂ potassiumÂ current IKs. Compared with Î± subunits, KCNE1 is a very small protein which lacks the classic pore region characteristic of voltage-gated potassium channels (Fig. 5.4a), located on chromosome 21q22.1-q22.2. When mutated, MinK reduces IKsÂ by altering voltage-dependent activation and acceleratingÂ potassium channelÂ deactivation, thereby prolonging cardiac repolarisation. As withÂ KVLQT1, homozygotes for minK mutations have been identified among JLN patients. In the heterozygous individuals, the presence of partially functional wild-type MinK is sufficient to prevent the development ofÂ deafness; therefore, these patients exhibit an autosomal dominant phenotype ofÂ LQTS.
LQT6Â and theÂ MiRP1Â gene
The second member to be cloned, KCNE2, was found to influence the biophysical and pharmacologic characteristics of the HERG-mediated IKr current. The LQT6 gene resides on chromosome 21p22, next to theÂ LQT5Â gene (MinK). The gene encodesÂ MinK-related peptide 1Â (MiRP1), a smallÂ membrane proteinÂ that assembles withÂ HERGÂ to alter its function. Mutations ofÂ MiRP1Â decrease IKr currents by forming abnormal channels that open slowly and close rapidly, thereby diminishing potassium currents.
Autosomal recessiveÂ LQTS
The Andersen syndrome (LQT7) - JLN1 and the KvLQT1 (KCNQ1) gene
One form of autosomal recessiveÂ LQTS is caused by a mutation of KvLQT1, the same gene associated withÂ LQT1. The cardiac manifestations of JLN1 are identical toÂ LQT1Â in that mutantÂ potassium channelsÂ diminish IKsÂ current resulting in prolongation of repolarization. The difference between the disorders is that JLN1 individuals are homozygous for KvLQT1 mutations. This explains why JLN1 patients haveÂ deafnessÂ andÂ LQT1Â patients do not.
Timothy syndrome (LQT8) - JLN2 and theÂ KCNE1Â (MinK) gene
As withÂ LQT5,Â abnormalitiesÂ of MinK as a result ofÂ KCNE1Â mutations have also been implicated in autosomal recessiveÂ LQTSÂ (JLN2). In LQT8, inactivation of the L-type calcium channel causes prolonged calcium inflow and markedly prolonged repolarization. Recently, a gain of function missense mutation in the cardiac L-type calcium channel CACNA1C was found to be responsible for the diverse physiologic and developmental defects in Timothy syndrome (Fig. 5.3a,b and Fig. 5.4c).
LQT9 and theÂ CAV3Â gene
As in LQT3, this subtype has prolonged activation of the rapid sodium channel.Â The gene CAV3 localized to chromosome 3p25 encodes for the Caveolin-3 protein.Â Â The Caveolin-3 protein forms an invagination in the cell membrane, and the voltage-gated sodium channel co-localizes within the "cave" on the cell membrane.Â Â Mutations in the CAV3 gene lead to prolonged activation of rapid sodium channels and a prolonged phase 0 of the action potential.Â
LQT10 and theÂ SCN4B (RWS)Â gene
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The gene SCN4B located on chromosome 11q23 encodes for the beta subunit of the voltage-gated sodium channel.Â Â Mutations of this gene lead to a gain-of-function of the sodium channel akin to the mutations that cause LQT32.Â
LQT11 and theÂ AKAP9Â gene
TheÂ AKAP9Â YotiaoÂ domainÂ formsÂ macromolecular complexesÂ with the slowly activating cardiacÂ potassium channelÂ (IKs) formed byÂ KCNQ1 and mutation ofÂ AKAP9Â has been reported in one individual withÂ LQTSÂ (LQT11) (Table 1).
LQT12 and theÂ SNTA1Â gene
Targetting and anchoring the channels in the membrane requires the involvement ofÂ membrane proteins.Â SNTA1Â (LQT12) encodes a scaffolding protein that interacts with the pore-forming alpha subunit (SCN5A) of the cardiacÂ sodium channel, implicated inÂ LQT3, and altersÂ sodium channelÂ function inÂ cardiac myocytes. Â
At the moment, there is no cure for LQTS, but it is treatable. However, with the knowledge gained from the sequenced human genome, the likelihood of curing LQTS looks optimistic. At present, short-term treatment is aimed at preventing the recurrences ofÂ TdP, whereas long-term management includes the use of beta-blockers, permanent pacemaker placement, and cardioverter-defibrillator implantation. A full list of the treatments currently being used can be seen in Table X.
USE TABLE FROM http://www.geneticheartdisease.org/lqts_gene_table.htm
Future Directions in curing LQTS
As researchers identify particular genes, they are beginning to understand the causes of long QT syndrome. This genetic research is leading to significant advances that will help doctors to make a more accurate diagnosis. It will also enable doctors to provide treatment options that treat the cause of the condition, rather than its effects. It is hoped that more specific and effective treatments will eventually replace beta-blockers. Genetic research and a better understanding of the way abnormal genes change the electrical properties of heart cells may eventually make it possible for doctors to silence or repair the abnormal gene that causes long QT syndrome. In the future, doctors may use genetic typing of each family to select a specific, more effective treatment for that family.
A cure is likely to come by developing the ability to specifically antagonize the electrophysiological consequences of the various mutations or by "silencing" those mutations that produce an excess of dangerous ion currents. This is exactly what we are working on right now. The progress during the last 10 years has been almost incredible, especially for a person like me who has been working on LQTS for almost 40 years, since the very early days. On this basis, I do believe that within the next 10 years a cure will become available for many LQTS patients.
Epigenetic factors inÂ LQTS
TheÂ KCNQ1Â gene is located onÂ human chromosomeÂ 11 (11p15.5) in a region syntenic with theÂ Kcnq1Â region at theÂ distalÂ end ofÂ mouseÂ chromosome 7. This region contains a cluster of six genes which are expressed from only the maternal or paternal allele (imprinted) in at least some tissues. InÂ miceÂ a transcript called theÂ Kcnq1Â overlapping transcript 1 (Kcnq1ot1)Â is transcribed from a promoter in intron 10 of theÂ Kcnq1Â gene. The presence ofÂ Kcnq1ot1Â blocks transcription of the cluster of genes. The promoter region ofÂ Kcnq1ot1Â is a CpG island which undergoesÂ methylationÂ on the maternal chromosome, preventing transcription and thus allowing expression of the genes in the cluster, includingÂ Kcnq1. TheÂ Kcnq1ot1promoter region is not methylated on the paternal chromosome. This permits expression of the regulatory transcript, so that expression of the cluster of genes is suppressed. InÂ humans the promoter ofÂ KCNQ1OT1Â has been mapped to intron 11 of theÂ KCNQ1Â gene (Fig. 3). The expression ofÂ CDKN1CÂ in the vicinity ofÂ KCNQ1Â is known to be regulated by theÂ KCNQ1OT1and disruption of this region results in Beckwith-WiedemannÂ syndrome.
This paternal imprinting of theÂ Kcnq1Â gene inÂ mouseÂ means that only the maternal allele is transcribed in early development. The paternal allele is progressively methylated and therefore becomes increasingly active during late embryogenesis, withÂ juvenileÂ and adult animals showing transcription from both alleles in all tissues studied. TheÂ humanÂ gene is also believed to be imprinted in at least some tissues. However, there appears to be no parent of origin effect for LQT1, since affected children of male patients have been reported, suggesting that the gene is not imprinted in cardiac tissue once expression ofÂ KCNQ1Â becomes critical forÂ heartÂ function. This is consistent with the relaxation of imprinting observed in mostÂ fetal heartsÂ examined.
The variable imprinting of theÂ KCNQ1Â gene provides a possible explanation for the existence ofÂ LQTSÂ in the absence of a coding sequence mutation inÂ KCNQ1. As discussed above, in humansÂ the paternalÂ KCNQ1OT1Â promoter is unmethylated in embryonic cellsÂ but this paternal imprinting is probably relieved in cardiac tissue. Therefore during differentiation, methylationÂ of the paternal chromosome must occur, to block production of the suppressiveÂ KCNQ1OT1Â transcript. A mutation which disrupted the CpG island (for example a small intronic deletion) could prevent thisÂ methylationÂ during development, leading toÂ silencingÂ of the paternal allele in theÂ heart. This would result in haploinsufficiency of IKsÂ K+Â channels and thusÂ LQTSÂ symptoms.
BecauseÂ KCNQ1Â is apparently not imprinted in cardiac tissue, the possibility of epigenetic effects inÂ LQTSÂ has not been extensively examined and the role ofÂ methylationÂ and imprinting ofKCNQ1Â in determining gene expression and ion channel function is not fully understood. These processes may be important in explaining segregation anomalies and inheritance patterns for someÂ LQTSÂ families. AsÂ geneticÂ screening protocols are developed and improved, they should take these possibilities into account. Inclusion of the intronicKCNQ1OT1Â region in the assessment of sequence variants in index cases could yield a class of mutations which disrupt the release of imprinting and explain some cases that lack coding sequence mutations.
TheÂ long QT syndromes:Â genetic basis and clinical implications
Evaluation and treatment of pediatric patients with congenital or acquiredÂ long QTÂ intervalÂ syndromes
Clinical and Genetic Characteristics ofÂ Long QT Syndrome
Clinical and therapeutic aspects of congenital and acquiredÂ long QT syndrome
Novel therapeutics for treatment ofÂ long-QT syndromeÂ andÂ torsade de pointes
Molecular genetics ofÂ long QT syndrome
TheÂ HumanÂ Genome Project and its importanceÂ in clinical medicine