Molecular and cellular defects of cystatin B – from cell to population.

Investigador: Ana Joana Duarte
Instituição: Departamento de Genética – INSA, Porto

Abstract

Cystatin B (Cstb) is a protein involved in several cellular processes including interaction with cysteine proteases, or cathepsins, which leak from lysosomes leading to a state of cellular dysfunction. It is also known that Cstb deficiency in mice can induce a secondary enhancement of tryptophan metabolism in the Central Nervous System, contributing to the epilepsy phenotype. Mutations on cystatin B gene (CSTB) are causal of Unverricht-Lundborg disease (EPM1) the most common cause of Progressive Myoclonic Epilepsy (PME). EPM1 is estimated to be underdiagnosed worldwide and the Portuguese population is no exception. Population characterization is important for genetic counseling and development of new therapeutic strategies in these diseases. The objectives of this work will be mutational characterization of CSTB lesions in the Portuguese population and identification of subcellular distribution of Cstb in patients and normal controls cell lines, in order to better understand the pathophysiology of disease. Along with the potential identification of new EPM1 patients, the concerted action with neurologists will help confirm putative diagnosis of this rare disease and provide their molecular analysis and subsequently allow genetic counseling in the appropriate cases. Cellular and molecular studies concerning the mechanism of Cstb involvement will be major objectives of this study.