doi: 10.1161/CIRCULATIONAHA.106.643866
(Circulation. 2006;114:360-362.)
© 2006 American Heart Association, Inc.
Editorial |
Molecular Underpinning of "Good Luck"
From Molecular Cardiology, Fondazione Salvatore Maugeri (S.G.P., C.N.), and Department of Cardiology, University of Pavia (S.G.P.), Pavia, Italy.
Correspondence to Silvia G. Priori, MD, PhD, Molecular Cardiology, Fondazione Salvatore Maugeri, Via Ferrata 8, 27100 Pavia, Italy. E-mail spriori{at}fsm.it
Key Words: Editorials • genes • genetics
The concept that the phenotype observed in patients affected by inherited arrhythmogenic diseases is determined exclusively by the primary genetic defect, transmitted as a mendelian trait, has been questioned by a substantial body of clinical literature showing that incomplete penetrance and variable expressivity are common features of these diseases.1,2 Investigations demonstrating genotype–phenotype correlations have provided major advances in the understanding of arrhythmogenic disease.3–6 These studies defined the average behavior (symptoms, prognosis, and response to therapy) of a population of individuals who carry a mutation in a given disease-related gene. From these studies, we now know, for example, that long-QT syndrome (LQTS) patients with mutations on the HERG gene have greater QT interval prolongation and a more malignant clinical course than LQTS patients with mutations of the KCNQ1 gene and that they are less likely to respond to antiadrenergic therapy.5,6
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These data are extremely helpful in guiding our therapeutic decisions but do not explain why some individuals belonging to a high-risk group remain asymptomatic for their entire lives or why other subjects with a benign clinical profile experience cardiac arrest. The issue of incomplete penetrance is particularly puzzling in Brugada syndrome,7,8 a disease in which the clinical manifestations can be highly variable within the same family and in which it is the rule, rather the exception, to find close relatives who share the same mutation in the SCN5A gene with different manifestations. While one family member with the mutation may show a completely normal ECG, another may have overt ECG manifestations of the syndrome and recurrent cardiac arrest. Therefore, the study by Poelzing et al9 in this issue of Circulation not only is a stimulating basic science report but more importantly provides clinicians with insight into the complexity of inherited arrhythmogenic syndromes.
This article challenges a common perception that the in vitro characterization of mutations identified in patients with inherited arrhythmogenic diseases is no longer advancing the field of genetics of arrhythmias and should be regarded as "me too" science. The interesting study by Poelzing et al demonstrates that functional characterization of mutants by a multidisciplinary team, performed in an attempt to explain the clinical phenotype, may lead to very important and innovative observations.
The evidence that 
5% of patients with LQTS10 and a similar number of individuals with hypertrophic cardiomyopathy11 carry 2 mutations on the same or different disease-associated genes has been the initial proof of concept that genetic modifiers are probably an important determinant of the phenotype manifested by patients with inherited arrhythmogenic syndromes. Subsequently, additional studies showed how polymorphisms, ie, genetic abnormalities that are prevalent in the general population, may modulate the phenotype of arrhythmic diseases.12,13 These studies showed that a polymorphism that has no functional effect when present in the wild-type protein may unexpectedly modulate the biophysical properties of a mutant protein. By interfering with the disease-causing mutation, polymorphisms may improve13 or worsen14 the clinical manifestations of the mutation and thus may be very important players in determining disease severity.
Thus, a family member who has inherited the mutation but never experienced symptoms of the disease that caused life-threatening arrhythmias in his relatives is no longer a "lucky" person protected by some celestial benevolence. His "good luck" derives from the inheritance of a favorable mixture of genetic variations.
Ion channels are proteins that have been highly conserved throughout evolution; therefore, the number of variations that have been introduced and preserved is quite limited. Nonetheless, our own data15 show that 53% of genotyped LQTS patients carry >1 polymorphism in LQTS-causing genes (see the Table). It is intriguing to think that the combination of different coding variations accounts for the great heterogeneity of phenotypic expression observed within an individual family.
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A recent study by Bezzina et al16 showed that 6 polymorphisms in a portion of the SCN5A gene reduced transcription of the cardiac sodium channel mRNA. This observation suggests that human beings are not born equal in terms of the amount of sodium current present in their cardiac myocytes that contributes to the electrical properties of their cardiac cells. One may therefore argue that individuals who inherit this set of polymorphisms, in addition to a loss of function mutation of the SCN5A gene, are more likely to have a severe form of Brugada syndrome compared with patients without these polymorphisms. Similarly, those lacking the detrimental haplotype are likely to be the lucky asymptomatic carriers of the mutation. Interestingly, the authors also found that the 6 polymorphisms are more common in black and oriental individuals compared with whites, thus adding ethnicity to gender5 as a factor that clinicians should consider when attempting to define the risk of cardiac events in patients with inherited arrhythmias syndromes.
In this context, the study by Poelzing et al brings to light an even more complex view of how genetic factors modulate the phenotypical manifestations of a disease-causing mutation. It had previously been shown that when the combination of a mutation plus a polymorphism present on the same allele results in a protein with 2 simultaneous variations in amino acid composition, the function of the protein is different from when only the mutation is present. The present report provides evidence for the first time that a polymorphism present on an allele other than the disease-causing mutation may still interfere with the fundamental properties of the mutant protein encoded by the affected allele.
Defining the factors that modulate the phenotype of genetic diseases will occupy substantial research efforts for years to come, particularly considering that the role of polymorphisms located on the same gene that harbors the primary disease-causing mutation may simply be the tip of the iceberg. There is now robust evidence that the QT interval and other ECG parameters are heritable traits in the general population.17,18 Furthermore, it seems logical that the genes harboring mutations/polymorphisms that influence cardiac electrophysiology expand beyond those anticipated on the basis of candidate gene approaches. The use of genome-wide searches to identify the genetic determinants of cardiac repolarization has already directed attention to regions of the genome that encode for proteins that would not have been considered logical targets on the basis of previous knowledge.19
The task of accurately distinguishing individuals at high risk for sudden death from those with the same disease who are at low risk is highly ambitious and unlikely to be achieved soon. A robust risk stratification model will need to incorporate not only the clinical parameters assessed by the cardiologist and the features of the primary mutation identified by the geneticist but also the effects of gender and ethnicity, the role of sets of hereditable traits that influence the electrophysiological background on which the primary mutation is acting, and the contribution of polymorphisms on the same gene in which the primary mutation is located. Last but not least, we should also remember that the occurrence of cardiac events is modulated by environmental stresses.20 Needless to say, it will take a long time and a lot of work to achieve the level of knowledge required to develop such an integrated approach to assess risk for individual patients. Meanwhile, it is important to acknowledge that research in the field of inherited arrhythmogenic diseases has extended far beyond what we anticipated 20 years ago, and the field is still so fertile that it is attracting the interest of investigators from various areas of science.
The evidence that a rather common DNA variation like the H558R polymorphism21 is able to influence the QT interval duration18 and to rescue a trafficking defect in SCN5A9 certainly should stimulate better characterization of the other common DNA variations that we currently dismiss as "silent" polymorphisms.
The study by Poelzing et al also should stimulate broad interest in how the human genome is constantly changing, evolving to improve survival, and suggests that our understanding of these changes may help identify new therapeutic strategies for human diseases. This study shows that even the acquisition of a minor genetic variation (polymorphism) may exert a "curative" influence in an individual affected by a genetic disease. In a teleological view, the individual with the polymorphism and the mutation will have better survival and a better probability of reaching a reproductive age, creating a selective pressure to preserve the "healthier" phenotype for the integrity of the species.
Considering that clinical medicine has yet to find a therapy to reduce the occurrence of life-threatening cardiac arrhythmias in Brugada syndrome, it is fascinating to find that nature itself has identified a molecular strategy to mitigate the disease.
Despite these considerations, a word of caution is needed. Poelzing et al have proved the ability of the H558R polymorphism to rescue trafficking of mutant Nav 1.5 in HEK293 cells, but there are no data showing that the effect would be the same in cardiac myocytes. Additional studies are needed before we can envision the possibility of a molecular therapy using gene transfer strategies to induce the expression of a polymorphism that may control the occurrence of arrhythmias at least in some Brugada syndrome patients. However, research is driven by individuals committed to defeat the impossible. It is expected that the therapeutic implication of the data provided by the present study will stimulate many of us involved in this field to elaborate on this novel concept.
Once more, translational science that places clinicians and basic scientists side by side has created a win-win situation in which both basic and clinical science benefit from the interaction.
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Acknowledgments |
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Disclosures
None.
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Footnotes |
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The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
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References |
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