The brush border surface of intestinal epithelial cells is a highly polarized subcellular structure with a unique protein composition. The brush border is crucial for the absorption of dietary nutrients as well as oral medication, and acts as a tumour-supressing subcellular unit. The brush border shows an aging-associated functional decline which is not understood. We aim to understand the molecular mechanisms that control brush border function. Our approach is to identify and study inherited diseases that are clinically characterized by severe congenital diarrhoea and generalized malabsorption of dietary nutrients, indicative of brush border defects. We identified novel genes that cooperate in molecular pathways that secure the unique protein composition and integrity of the brush border and prevent aging-related cellular damage. Furthermore, mutations in these genes also affect protein trafficking and cell polarity in other organs (e.g., the liver and, during prenatal life, the placenta), which is an often-overlooked co-determinant in disease development and organismal health. Current work focusses on 1) unravelling the function of these genes in intracellular protein trafficking and cell polarity in relevant organ systems, 2) revealing the pathogenic mechanisms of mutations in these genes and 3) identifying leads for therapeutic intervention.