Long Qt Syndrome In Gene Therapy Biology Essay


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 and 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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The LQTS is characterized by prolongation of the corrected QT (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).  The condition is associated with sudden cardiac death due to malignant ventricular arrhythmias in form of torsade de pointes (TdP). 

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 congenital LQTS

Two modes of inheritance are known for the familial forms of LQTS. Romano-Ward syndrome (RWS) is the more common autosomal dominant form, and Jervell Lange-Neilsen syndrome (JLNS) is the rarer autosomal recessive form. Both forms show a prolongation of the QT interval but JLNS is more severe and also manifests with deafness.

With the advances in molecular genetics, we now know that most forms of LQTS are a result of gene mutations coded for ion channels or their sub-units. To date, mutations in 12 different genes have been associated with LQTS (Table 1), and are named LQT1-10. The two genetic abnormalities associated with autosomal recessive LQTS are named JLN1 and JLN2. The incidence of RW syndrome is unknown, estimated to be about one gene carrier in 10,000 population. The JLN syndrome is much rarer, thought to occur in approximately 1-6 in 1 million children.

Autosomal dominant LQTS (Romano-Ward 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 of 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.

LQT1 and the KcLQT1 (KCNQ1) gene

The LQT1 locus was mapped to chromosome 11p15.5 and the LQT1 gene, KvLQT1 (also known as KCNQ1), that encodes a voltage-gated potassium channel protein was cloned. In conjunction with MinK, a potassium channel protein, KvLQT1 produces the slow component of the delayed rectifier potassium current (IKs) that is responsible for Phase 3 repolarization of the cardiac action potential (Figure). KVLQT1 is expressed not only in the heart but also in other human tissues, and has also been shown by in situ hybridization that KVLQT1 is expressed in the stria vascularis of mouse inner ear, which is important in understanding the deafness seen in JLN syndrome. Mutations of this gene lead to a prolongation of repolarization by decreasing potassium efflux. Recently, recessive forms of RW syndrome without deafness have been described in patients homozygous for KVLQT1 mutations.

LQT2 and the HERG 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 a potassium channel abnormality. HERG generates the rapid component of the delayed-rectifier potassium current (IKr) that is responsible for Phase 3 repolarization of the action potential, recorded from human myocytes. As with KVLQT1, mutations of the gene cause loss-of-function or dominant-negative IKr suppression to decrease the repolarizing currents.

LQT3 and the SCN5A gene

The gene responsible for LQT3 is located on chromosome 3p21-24. The mutation in this form of autosomal dominant LQTS occurs in the cardiac sodium channel gene SCN5A. SCN5A controls the inward sodium current, INa, responsible for generating phase 0 and contributing to the plateau phase (Phase 2) of the cardiac action potential. Mutations of SCN5A alter the cardiac action potential by a 'gain-of-function' mechanism through which mutant SCN5A channels are incompletely inactivated or reopen early, resulting in persistent inward sodium current and prolongation.

Unlike the case with potassium channels, expression of a single sodium channel 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.  Mapped to chromosome 4q25-27, the ANKB gene encodes for the ankyrin-B adaptor protein.  Ankyrin-B (LQT4) is involved in targeting a complex of proteins to the cell membrane. Mutation in ANK2 results in elevation of calcium transients and persistent inward Na+ current (via SCN5A), as well as been associated with prolonged QTc.

LQT5 and the KCNE1 (MinK) gene

As mentioned earlier, MinK works in conjunction with KvLQT1 to form the potassium current IKs. Compared with α 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 IKs by altering voltage-dependent activation and accelerating potassium channel deactivation, thereby prolonging cardiac repolarisation. As with 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 of deafness; therefore, these patients exhibit an autosomal dominant phenotype of LQTS.

LQT6 and the MiRP1 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 the LQT5 gene (MinK). The gene encodes MinK-related peptide 1 (MiRP1), a small membrane protein that assembles with HERG to alter its function. Mutations of MiRP1 decrease IKr currents by forming abnormal channels that open slowly and close rapidly, thereby diminishing potassium currents.

Autosomal recessive LQTS

The Andersen syndrome (LQT7) - JLN1 and the KvLQT1 (KCNQ1) gene

One form of autosomal recessive LQTS is caused by a mutation of KvLQT1, the same gene associated with LQT1. The cardiac manifestations of JLN1 are identical to LQT1 in that mutant potassium channels diminish IKs 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 have deafness and LQT1 patients do not.

Timothy syndrome (LQT8) - JLN2 and the KCNE1 (MinK) gene

As with LQT5, abnormalities of MinK as a result of KCNE1 mutations have also been implicated in autosomal recessive LQTS (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 the CAV3 gene

As in LQT3, this subtype has prolonged activation of the rapid sodium channel. The gene CAV3 localized to chromosome 3p25 encodes for the Caveolin-3 protein.  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.  Mutations in the CAV3 gene lead to prolonged activation of rapid sodium channels and a prolonged phase 0 of the action potential. 

LQT10 and the SCN4B (RWS) gene

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The gene SCN4B located on chromosome 11q23 encodes for the beta subunit of the voltage-gated sodium channel.  Mutations of this gene lead to a gain-of-function of the sodium channel akin to the mutations that cause LQT32. 

LQT11 and the AKAP9 gene

The AKAP9 Yotiao domain forms macromolecular complexes with the slowly activating cardiac potassium channel (IKs) formed by KCNQ1 and mutation of AKAP9 has been reported in one individual with LQTS (LQT11) (Table 1).

LQT12 and the SNTA1 gene

Targetting and anchoring the channels in the membrane requires the involvement of membrane proteins. SNTA1 (LQT12) encodes a scaffolding protein that interacts with the pore-forming alpha subunit (SCN5A) of the cardiac sodium channel, implicated in LQT3, and alters sodium channel function in cardiac myocytes.  


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 of 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 in LQTS

The KCNQ1 gene is located on human chromosome 11 (11p15.5) in a region syntenic with the Kcnq1 region at the distal end of mouse 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. In mice a transcript called the Kcnq1 overlapping transcript 1 (Kcnq1ot1) is transcribed from a promoter in intron 10 of the Kcnq1 gene. The presence of Kcnq1ot1 blocks transcription of the cluster of genes. The promoter region of Kcnq1ot1 is a CpG island which undergoes methylation on the maternal chromosome, preventing transcription and thus allowing expression of the genes in the cluster, including Kcnq1. The 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. In humans the promoter of KCNQ1OT1 has been mapped to intron 11 of the KCNQ1 gene (Fig. 3). The expression of CDKN1C in the vicinity of KCNQ1 is known to be regulated by the KCNQ1OT1and disruption of this region results in Beckwith-Wiedemann syndrome.

This paternal imprinting of the Kcnq1 gene in mouse 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, with juvenile and adult animals showing transcription from both alleles in all tissues studied. The human 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 of KCNQ1 becomes critical for heart function. This is consistent with the relaxation of imprinting observed in most fetal hearts examined.

The variable imprinting of the KCNQ1 gene provides a possible explanation for the existence of LQTS in the absence of a coding sequence mutation in KCNQ1. As discussed above, in humans the paternal KCNQ1OT1 promoter is unmethylated in embryonic cells but this paternal imprinting is probably relieved in cardiac tissue. Therefore during differentiation, methylation of the paternal chromosome must occur, to block production of the suppressive KCNQ1OT1 transcript. A mutation which disrupted the CpG island (for example a small intronic deletion) could prevent this methylation during development, leading to silencing of the paternal allele in the heart. This would result in haploinsufficiency of IKs K+ channels and thus LQTS symptoms.

Because KCNQ1 is apparently not imprinted in cardiac tissue, the possibility of epigenetic effects in LQTS has not been extensively examined and the role of methylation and imprinting ofKCNQ1 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 some LQTS families. As genetic screening protocols are developed and improved, they should take these possibilities into account. Inclusion of the intronicKCNQ1OT1 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.

The long QT syndromes: genetic basis and clinical implications

Cardiovascular Genetics

Evaluation and treatment of pediatric patients with congenital or acquired long QT interval syndromes

Clinical and Genetic Characteristics of Long QT Syndrome

Clinical and therapeutic aspects of congenital and acquired long QT syndrome

Novel therapeutics for treatment of long-QT syndrome and torsade de pointes

Molecular genetics of long QT syndrome


The Human Genome Project and its importance in clinical medicine