Moleculaire en functionele analyse van nieuwe Brugada syndroom kanditaatgenen

Abstract

The Brugada syndrome is diagnosed as an abnormality in the electric activity of the heart. This primary heart condition occurs in a structurally normal heart and is characterized by an abnormal electrocardiogram with a ST-elevation due to a right bundle branch block in the electrical conduction system of the heart. The syndrome is autosomal dominant inherited. It is suspected that it is responsible for a big part of the victims of an unsuspected cardiac arrest. The Brugada syndrome has been known before its description in South-East Asia as SUDS (sudden unexplained death syndrome) before the Brugada syndrome was described.
The main objective of this study was the optimization of a procedure to sequence several genes that are possibly involved in Brugada syndrome. The genetic basis of Brugada syndrome is probably a defect in an ion channel or in one of its regulatory proteins. To date mutations in the alpha-subnunit of the sodium channel can be related to Brugada syndrome. However, they account for only 15 to 30% of patients. Therefore mutational research in other candidate genes is needed. This work focuses at first instance on genes coding for the beta-subunits of sodium channel (SCN1B, SCN2B, SCN3B, SCN4B), and on the potassium channels (KCNA4 en KCNC4). After the optimization of the PCR and sequencing procedure, patients with the syndrome could be tested for mutations in the target genes. Undescribed variants were detected In several of the of the Brugada syndrome patients. In-silico analysis revealed that the variations did not have an effect on splicing. Furthermore, their influence on the mRNA secondary structures was rather limited. An unknown variant in SCN4B requested further research. Due to the lack of family members to investigate the variants segregation, a control group of 200 persons was checked for the presence of the SCN4B variant. The variant was absent in all of the control persons. Subsequently, an experiment was started in which the effect of the SCN4B variant was measured on the transcription level. But by a lack of time only the optimization of the relative quantification of SCN4B mRNA by an RT-PCR assay could be started up.

Date of Award	2011
Original language	English
Supervisor	Sonia Van Dooren (Promotor)