The significance of our discovery is that it offers a different perspective on the disease: a focus on absent MYO5B is replaced with a focus on disordered differentiation of the enterocytes. Since there are already many professional-oriented articles and reviews available for MVID, below is a compiled library of resources and fundamental papers on this rare, pediatric disease. We also present our own research on the pathogenesis of MVID (Kravtsov et al., 2016) which has been the basis for developing the first treatment for the disease. Our drug development has been fully based on existing information and research, including the following:
Overviews and databases
- Medscape MVID provides the most comprehensive description of the disease with information on existing treatment options.
- PubMed lists more than 100 papers on the disease.
- UpToDate (login required) is the premier hospital database, but has only limited information on this rare disease under the section in chronic diarrhea.
- MVID Patient Registry contains the largest database of known mutations within the MYO5B gene.
First MVID report MVID was described as a distinct nosological entity in 1978 and the congenital nature of the disease was confirmed by Davidson and his team (Davidson et al., 1978). Etiology Since the discovery of MVID, the disease was suspected to be autosomal recessive, but the precise data on the gene involved was lacking until 2008. Researchers then confirmed that MVID is, indeed, a genetic disease resulting from mutations in the gene of actin-based motor protein myosin VB (Muller et al., 2008).
This initial discovery was re-confirmed in 2010 when another team of researchers found additional MYO5B mutations in MVID patients and successfully modeled the disease in vitro (Ruemmele et al., 2010). Recently researchers discovered that mutations in other genes may lead to MVID-like symptoms, including the gene of the apical SNARE protein Syntaxin 3 (Wiegerinck et al., 2014). However, there is still no consensus in the field whether mutations of Syntaxin 3 should be incorporated into the current MVID classification, or if they should be classified into a separate category of congenital diarrheas. Epidemiology MVID, an exceedingly rare disease, is tied to the so-called founder effect, in which a normally rare disease increases in frequency in a small and isolated community.
The founder of that community is often a silent carrier of the disease, and the disease spreads within the community over time. The Navajo Nation represents one of the populations with the highest known burden of the disease (Pohl et al., 1999). Japan represents one of the populations with lowest burden of the disease due to the same founder effect (Kaneko et al., 1999).
Pathogenesis
Morphology MVID presents with significant variations in the morphological and ultra-morphological features of intestinal epithelium. The research articles presented by Philips and Schmitz in 1992 and Al-Daraji et al in 2010 represents two of the most comprehensive reviews of the morphological features for MVID (Philips and Schmitz, 1999) (Al-Daraji et al., 1999).
Ion transport defects: Secretory diarrhea In a 1991 report researchers unequivocally confirmed the secretory nature of diarrhea in the MVID patient, and studied the transport of electrolytes across the MVID intestine (Rhoads et al., 1991). Cellular polarity defects It is universally accepted that MVID enterocytes present with severe polarity defects. There is a wealth of literature available on the subject, but the following three papers broadly represent the core ideas of disordered polarity, while also covering human and mouse MVID intestinal tissues and Caco-2 cellular models of the disease. The first paper is by Michaux in which they looked at the abnormalities of polarity molecules in the intestinal cells as a result of the MYO5B deficiency (Michaux et al., 2016). The second paper is by Weis and they performed a thorough analysis on the effects of MYO5B loss in inducible and constitutive mouse models, at different ages for the onset of the disease (Weis et al., 2016). The third paper is by Bijlsma and they found that the abnormal polarity of the cells translates into the abnormalities of the entire organ, such as increased intestinal permeability, due to the paracellular leakiness of intestinal epithelium (Bijlsma et al., 2000).
Differentiation and proliferation defects Proper development of the intestinal epithelial cells depends on the proper polarity of the enterocytes. It is no surprise that MVID is a disorder of differentiation as well as polarity. The abnormalities of life cycle and differentiation of the MVID enterocytes have been known since 2000 (Groisman et al., 2000). While working on the molecular mechanisms of MVID diarrhea at Yale University, we were shocked by how different the process of cellular maturation was in the enterocytes lacking MYO5B compared to the normal controls. This has led us to develop a different point of view on the entire pathogenesis of the disease. We asked ourselves, what if the disordered polarity is only a trigger for the clinical symptoms? What if the devastating diarrhea is a result of the immaturity of the enterocytes, which don’t acquire the proper absorptive machinery during their very limited lifespan? In a paper found in the American Journal of Physiology by our very own, Dmitry Kravtsov, we were able to confirm that the differentiation pathway (HIPPO pathway) is indeed abnormal in MVID (Kravtsov et al., 2016).
The significance of this discovery is that it offers a different perspective on the disease: a focus on absent MYO5B is replaced with a focus on disordered differentiation of the enterocytes. This in turn opens up the possibility to develop a treatment that bypasses the genetic defect without directly addressing it. With this idea in mind, we founded Vanessa Research and we are working on the treatment for MVID .