Molecular genetics of arrhythmias - a new paradigm

Citation
E. Schulze-bahr et al., Molecular genetics of arrhythmias - a new paradigm, Z KARDIOL, 89, 2000, pp. 12-22
Citations number
78
Categorie Soggetti
Cardiovascular & Respiratory Systems","Cardiovascular & Hematology Research
Journal title
ZEITSCHRIFT FUR KARDIOLOGIE
ISSN journal
03005860 → ACNP
Volume
89
Year of publication
2000
Supplement
4
Pages
12 - 22
Database
ISI
SICI code
0300-5860(2000)89:<12:MGOA-A>2.0.ZU;2-5
Abstract
The molecular genetic background of inherited cardiac arrhythmias has only recently been uncovered. This late development in comparison to other inher ited cardiac disorders has partly been due to the high mortality and early disease onset of these arrhythmias resulting in mostly small nucleus famili es. Thus, traditional genetic linkage studies, which are based on the genet ic information obtained from large multi-generation families, were made dif ficult. Inherited arrhythmogenic disorders can be divided into 'primary ele ctrical disorders' (e.g., long-QT [LQT] syndrome) in which a detectable, or ganic heart disease is not evident, and into inherited diseases of the myoc ardial structure (e.g., hypertrophic cardiomyopathies) in which the arrhyth mias occur combined with the structural alterations. To date, all inherited arrhythmogenic disorders in which the causative gene s have been identified turned out to be channelopathies, since the genes en code channel subunits that regulate important ion currents that tune the ca rdiac action potential. The discovery of the genetic bases of the LQT syndr ome became a new methodologic paradigm; because with the use of 'classical' genetic linkage strategies (named [positional] candidate strategies) not o nly the causative genes have been found, but moreover, functional component s with a previously unknown but fundamental role for a normal repolarizatio n process were discovered. Disease mutations turned out to be not only a fa mily-specific event with a distinct phenotype and the potential of an addit ional diagnostic tool, but also, when expressed in heterologous expression systems, characterize the defective ion channel in a topological way and le ad to a more specific understanding of ion channel function. Most, if not all, primary electrical cardiac disorders show a high genetic diversity. For the LQT syndromes, sixth disease loci and the responsible ge ne have been recently discovered (socalled locus or genetic heterogeneity). Within all disease genes, the mutations are spread over the entire gene (a llelic heterogeneity); in addition, more than one disease mutation may be p resent. This complexity requires, at least, complete mutation analysis of a ll LQT genes before medical advice should be given. Meanwhile, genotype-phenotype correlations in large families are being used to evaluate intergene, interfamilial and intrafamilial differences in the clinical phenotype, reflecting gene specific, gene-site specific and indivi dual consequences of a given mutation. A widespread phenotypic heterogenity even within mutation carriers in the same family raises the importance of modifying factors and genes that are mostly unknown to date. The reduced pe netrance and variable expressivity associated with the LQT mutations remain still to be explained. First insights into the complex actions of mutation s are bring extracted, from expression data; these preliminary results may lead to potential implications for a specific (gene-site directed) therapy. This paper discusses the current data on molecular genetics and genotype-ph enotype correlations in LQT syndrome and related disorders and the potentia l implications for diagnosis and treatment.