Thesis supervisor: Róbert Sepp
Location of studies (in Hungarian): 2nd Department of Internal Medicine and Cardiology Center, University of Szeged Abbreviation of location of studies: ÁOK
Description of the research topic:
Background: Ion channel diseases, or channelopathies, are diseases arising from genetic mutations affecting ion channels of the heart. These diseases are best exemplified by the long QT syndrome (LQTS), Brugada syndrome (BrS) or catecholaminergic polymorphic ventricular tachycardia (CPVT). The prototype of ion channel diseases is the long QT syndrome (LQTS) which is characterized by an abnormally prolonged QT interval and, usually, by stress-mediated life-threatening ventricular arrhythmias. Since the discovery of the primary LQTS genes of potassium (KCNQ1 and KCNH2) and sodium (SCN5A) channels at least 13 LQTS genes have been reported, all encoding different ion channels or ion channel related proteins.
The Cardiology Center, University of Szeged has a long-standing interest in familial cardiac diseases, in ion channel diseases and cardiomyopathies in particular. With regard to ion channel diseases the group described the first congenital long QT syndrome in Hungary back in 1972. Molecular genetics to investigate ion channel diseases has been first applied at this institution in Hungary. We were also the first group in Hungary in establishing a molecular genetic laboratory for successful identification of disease causing mutations in long QT syndrome (KCNQ1, KCNH2, KCNE1 genes) and Andersen-Tawil syndrome (KCNJ2 gene). Parallel to this, foundations of a biobank have been laid down as we have been collecting blood samples from patients with different forms of ion channel diseases and cardiomyopathies. Up to now, the biobank contains blood samples from about 150 families with LQTS or other ion channel diseases, and the number of biobanked samples are increasing continuously.
Aims: We aim to identify novel causative mutations for ion channel diseases for which we will use next generation sequencing, particularly the targeted resequencing approach and whole exome sequencing. We will use targeted resequencing strategy to screen for known and highly suspicious candidate genes in patients with different ion channel diseases. This step will select out patients with mutations in known causative genes, and will lead to the identification of novel causative mutations. Patients in whom no causative mutations were identified, will be further analyzed by applying whole exome sequencing. By screening the whole exome, this approach will lead to the identification of genetic alteration/s in gene/s previously not associated with ion channel diseases. Causation of a given genetic variant will be assessed using multiples line of evidences including prediction data, familial segregation data and functional analysis. Selected variants, harboring characteristics of a putative causative mutation will be further characterized by functional analysis. The applicability of the following model systems that are at hand will be evaluated, considering the predicted molecular mechanism or the affected cellular process of each mutation on a case-by-case basis: i) Heterologous expression of wild type and mutant variants in CHO cells; ii) Use of patient-derived human cardiac myocytes derived from induced pluripotent stem cells (hiPSC-CM).
Required language skills: English Further requirements: TDK munka
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