Polarized protein trafficking and disease: Towards understanding the traffic jams in microvillus inclusion- and Wilson disease

It is essential for the function of cells that proteins are transported to the correct intracellular locations. Disruption of these transport routes can lead to terrible diseases. Two examples are microvillus inclusion disease (MVID), and Wilson disease (WD). In MVID patients, mutations in the motor-protein Myosin Vb disrupt the transport of other proteins. In the case of WD, mutations in the copper transporter ATP7B cause the ectopic localization of this protein.
It is not clear why MVID patients develop cholestasis. To investigate this, we have developed new Myosin Vb deficient disease models, which include knock-out mice, hepatic cell lines (HepG2) and stem cell-derived hepatocytes. Using these, we show that is not the lack of myosin Vb protein, but the presence of mutant myosin Vb that disrupts transport in the liver.
The most prevalent mutation in Wilson disease is the H1069Q mutations. Despite its high prevalence, the effect of the mutation is still poorly understood. To elucidate this, we developed a new model based on the differentiation of hepatocytes from the stem cells of WD patients. This allowed us to study the behavior of endogenous ATP7B mutant protein, and yieded new insights in the pathogenesis of this disease.