Recent advances in molecular pathology of microvillus inclusion disease (MVID)

Abstract

MVID, first reported in 1972 as a familial enteropathy is a congenital disorder of intestinal mucosa characterized by villous atrophy with marked abnormalities of enterocytes which on electron microscopy (EM) show loss of apical microvilli, intracytoplasmic microvillous inclusions as well as vesicular inclusion bodies and subapical secretory-like granules. The clinical manifestations include severe malabsorption and intractable watery diarrhea starting at birth (classical MVID) or at few days or weeks of age (variant MVID). Recent studies have identified loss-of-function mutations in the MYO5B gene as the major cause of MVID. We will review the histopathology, immunomarkers and EM features of MVID with emphasis on genetic analysis and molecular mechanisms of a non-functional myosin Vb motor in enterocytes investigated in a MYO5B RNAi CaCo2 cell model and in duodenal biopsies from MVID patients harboring loss-of-function mutations in the MYO5B gene. Our findings suggest that MVID is a disease of defective intracellular traffic and disrupted epithelial cell polarity. A non-functional myosin Vb motor in mature enterocytes disrupts intracellular vesicle trafficking with redistribution of Rab GTPases (Rab11, Rab9 and Rab8), mislocalization of cell organelles (EEA1 and LAMP2) and transporter proteins (CD36, TfR and Na/K ATPase) leading to impaired intestinal barrier formation and loss of cell polarity.