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Novel gene found to cause Brugada syndrome
Researchers identified the mutation in DNA from a multi-generation family.
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Brugada Syndrome, identified in the 1990’s, is an autosomal dominant form of hereditary arrhythmia consisting of right bundle branch block and ST-segment elevation in the right precordial leads of the surface echocardiogram.
The clinical features are primarily syncope, ventricular arrhythmias and sudden death. About 20% of Brugada syndrome is due to more than 80 mutations in the cardiac sodium channel (SCN5A) located on chromosome 3p21.
Recently, mutations identified in the calcium channel CACNA1c and its subunit have been shown to induce either a short QT interval or Brugada syndrome. Thus, all of the genes identified to cause Brugada syndrome up until recently have been defects in genes that encode for ion channels. Furthermore, they all exhibit loss of function with a decrease in the inward sodium current or a decrease in the inward calcium current.
This observation supports the hypothesis that inadequate depolarizing current in the epicardium of the right ventricular is primarily responsible for the echocardiogram phenotype. It is believed that the transient outward repolarizing current causes premature repolarization current to occur. This results in ST-segment elevation on the ECG, giving rise to reentry arrhythmias.
Mutation found
In the present study by London et al, a mutation was identified in Glycerol-3-Phosphate Dehydrogenase 1-Like gene which causes Brugada syndrome. This is the first gene to be identified that encodes for a protein other than an ion channel. However, it does appear that this particular protein (GPD1-L) interacts with the sodium ion channel, decreasing the inward sodium current, which further supports the hypothesis previously stated to account for the findings on the echocardiogram and the reentry arrhythmias.
In this study, the investigators, analyzing the DNA from a multi-generation family, identified the mutation. The mutation segregates in the family with affected individuals and is not present in normal controls. In previous studies, the investigators genetically linked the defect to a locus on chromosome 3p22-24 with a LOD score of 4.0. Since the gene encoding for the cardiac sodium channel is at chromosome 3p21, this excluded the sodium channel gene as the responsible gene.
On further analysis, the investigators were able to clone and sequence the gene and show the defect is a single nucleotide substitution in exon 6 at position 899 of GPD1-L gene showing a C/T change resulting in (C899T) substitution of valine for alanine amino acid 280 (A280V) of the protein. There were 16 affected individuals, all of whom had the mutation while 27 other family members carried the mutation but did not have clinical disease, indicating a penetrance of approximately 37%.
The human GPD1-L mRNA is 3,954 base pairs long and encodes a protein predicted to be 351 amino acids in length. The alanine at position 280 is conserved in all organisms including human, orangutan, mouse, rat, dog, cow, pig and salmon. It is also of note that this new cause for Brugada syndrome involves a DNA restriction site that can be used to rapidly and cheaply screen individuals for this particular mutation. GPD1-L is highly expressed in heart tissue with lesser expression in skeletal muscle, kidney, lung and other organs. Following transient co-transfection in HGK cells, the investigators showed that over expression of the mutant GPD1-L gene significantly decreased the inward sodium current similar to previous mutations that occur in the sodium channel gene.
Over 350,000 cardiac deaths occur annually in the United States alone. Those occurring in people older than 36 years are due mostly to ischemic heart disease. In contrast, virtually all sudden cardiac deaths occurring in people younger than 36 years is due to hereditable disease, predominantly familial hypertrophic cardiomyopathy, Long QT syndrome, familial WPW and others. Identifying the mutations responsible for these arrhythmias are paving the way for ultimate screening and also adding abundantly to our pathogenetic understanding of these arrhythmias. The number of new targets made available by these rare inherited disorders for novel therapy is only now being exploited.
For more information:
- Robert Roberts, MD, is President and CEO of the University of Ottawa Heart Institute and Section Editor of the Molecular Cardiology Section of the Cardiology Today Editorial Board.
- London B, Michalec M, Mehdi H, et al. Mutation in glycerol-3-phosphate dehydrogenase 1-Like gene (GPD1-L) decreases cardiac Na+ current and causes inherited arrhythmais. Circulation. 2007;116:2260-2268.