Mendelian Disorders of Membrane Trafficking: Molecular Mechanisms and Drug Target Identification

The project’s goal is to apply the basic knowledge of membrane trafficking to the study of Mendelian disorders, diseases that arise from defects in membrane trafficking machinery. It aims to clarify the cellular and molecular pathogeneses of these disorders and to identify candidate drug targets. We are presently focusing on two disorders: Lowe syndrome and spondylo-epiphyseal dysplasia (SED) tarda. Oculocerebrorenal syndrome of Lowe (OCRL), or Lowe syndrome, is a rare X-linked genetic disease caused by mutations in the ocrl1 gene that is characterized by congenital cataracts, renal Fanconi’s syndrome (low molecular weight proteinuria, tubular acidosis) and mental retardation. OCRL-1 is a PtdIns(4,5)P2 5-phosphatase localized at the plasma membrane, in endosomal compartments and at the Golgi complex. We have shown that its activity is required for different trafficking pathways that intersect early endosomes.
X-linked SED tarda is caused by mutations in sedlin, a component of the multi-molecular TRAPP complex, which has been conserved from yeast to mammals. SED tarda is characterized by a disproportionately short stature, short trunk and osteoarthritis. The main defect of chondrogenesis is the chondrocytes’ inability to correctly secrete and assemble extracellular matrix components. Indeed, our studies have uncovered a role for sedlin in the trafficking of selective cargoes from the endoplasmic reticulum to the Golgi complex. In particular, we have shown that sedlin is required for the efficient and selective export of procollagen from the endoplasmic reticulum. Derangement of this process due to sedlin mutation may explain the defective chondrogenesis underlying SED tarda.

The "Total Award" amount indicated for this project represents the share of the funding of the Telethon Foundation for research by the Tigem institute from July 2016 until last budget year, calculated based on the size of the research group.