Veronika Harmat

Biography

Researcher is working as a professor at Semmelweis University

Research Interest

The steroid-resistant nephrotic syndrome (SRNS) is one of the main causes of chronic kidney failure in childhood. 12-18 percent of the SRNS cases derive from the mutations of the podocin coding gene, NPHS2. Podocin is the component of the podocyte filtration slits, and as the member of the stomatin family, it forms dimer oligomers. We have previously demonstrated that the polymorphism of R229Q, which is considered to be the hypomorphic variant of NPHS2, is pathogenetic only if is paired with certain 3’ missense mutations on the other parent allele. These trans-associations lead to pathological dimer formations and the intracellular dislocation of podocin. Based on epidemiological data, a 3’ truncating mutation (F344Lfs*4) also forms a pathogenetic structure with the R229Q variant. The aim of our current research is to understand the impact of this truncating mutation on podocin localisation compared with that of other 3’ truncating mutations. The impact of truncating mutations and their associations on podocin localisation is studied by transient expression on podocyte culture. The structure of podocin is simulated based on the crystal structure of the Pyrococcus horikoshii stomatin and theoretical methods are used for the study of the structure and dimerization ability of different variations. In order to support our hypothesis, we aim to investigate the behaviour of the different variations’ segments responsible for dimerization, in solution by chromatographic methods and CD and NMR spectroscopy. We plan the complete expression and cleaning of the C-terminal intracellular domain of podocin in order to obtain a sufficient amount of protein for the crystallization and structure definition of podocin. Based on the above we aim to understand the connection between dimerization, intracellular delocalisation and clinical practice.