Defects in megalin-cubulin-AMN mediated protein endocytosis are responsible for several clinical syndromes, listed below:
- Dent’s disease – is an X-linked defect in a Cl-/H+ exchanger expressed in the proximal tubules and collecting duct intercalated cells. Cl-/H+ knockout mice have very low levels of cubulin and megalin expression, which would explain the LMW proteinuria seen in affected patients. It is less clear how the defect causes PT damage leading to the aminoaciduria, glycosuria, phosphaturia, and hypercalciuria that characterize this disease.
- DB/FOAR syndrome – a genetic defect in LDL receptor protein 2 encoding megalin results in a lack of functional megalin. The syndrome leads to hypertelorism, myopia, hearing loss, and proteinuria, along with many defects in fetal development. If you really wanted to know, DB/FOAR stands for Donnai-Barrow/facio-oculo-acoustico-renal syndromes, described separately but now known to be the same entity.
- Gräsbeck-Imerslund disease – a autosomal recessive defect in either cubulin or AMN synthesis, these patients present with megaloblastic anemia (cubulin deficiency leads to selective B12 malabsorption, as mentioned above) and proteinuria.