Pathogenic mechanisms in microvillus inclusion disease

Eating is the most natural thing in the world. This does not apply to children with microvillus inclusion disease (MVID). MVID is a very rare and severe malfunctioning of the gut preventing absorption of food and leading to persistent diarrhea and dehydration. Without treatment the children die shortly after birth. The prognosis depends on lifelong intravenous feeding and eventual intestinal transplantation.
Recently, mutations in the MYO5B gene have been identified as the underlying genetic cause of MVID. Each child/family with MVID displays unique MYO5B mutations. Despite the identification of the defective gene, it is unknown how the genetic defect results in the disease. Currently there is no cure.
The studies described in this thesis unravel in detail the cellular and molecular mechanisms through which the loss of MYO5B function leads to abnormalities in the structure of the cells in the intestinal wall. The protein encoded by the MYO5B gene, myosin Vb, appears to play a key role in organizing the infrastructure within the intestinal cell. The deregulated infrastructure in the intestinal cells from children with MVID leads to a decrease of the available cell surface where nutrients are absorbed, and prevents that the in the intestinal cells synthesized enzymes for the digestion of nutrients reach the cell surface. These new insights into the pathogenesis of MVID, together with the founded International MVID patient registry and database of MYO5B gene mutations, are an important step towards more effective treatments to combat this devastating disease.