Defective targeting of hemojuvelin to plasma membrane is a common pathogenetic mechanism in juvenile hemochromatosis

摘要: Hemojuvelin (HJV) positively modulates the iron regulator hepcidin, and its mutations are major cause of juvenile hemochromatosis (JH), a recessive disease leading to overload. Defective HJV reduces hepcidin up-regulation both in humans Hjv-deficient mice. To investigate JH pathogenesis functional properties human we studied biosynthesis maturation 6 pathogenic mutants HeLa HepG2 cells. We show that proteolytic processing is defective F170S, W191C, G320V, but not G99V C119F. Moreover, C119F targeted cell surface, while R326X (lacking glycosilphosphatidylinositol [GPI] anchor) mainly retained endoplasmic reticulum, although all released as soluble forms (s-HJV) proportion modulated by supplementation. Membrane (m-HJV) composed cleaved protein, level increased wild-type (WT) mice mutants. Altogether, data demonstrate loss membrane export central JH, cleavage essential for export. The results support dual function s- m-HJV deficiency overload, respectively.