Loss-of-function mutations in
HJV cause juvenile hemochromatosis. This represents fewer than 5% of cases of hemochromatosis, but it is a rapidly progressive disorder with clinical symptoms arising from excessive iron accumulation in tissues appearing before the age of 30, with the clinical findings including cirrhosis, diabetes, cardiomyopathy, and nephropathy.
10–12 Again, as in the case of HFE mutations, retinal involvement has not been investigated in patients with HJV mutations. We have used
Hjv−/− mice as a model for juvenile hemochromatosis and demonstrated iron overload and significant morphological alterations in retina in these mice.
13–15 A distinct difference between
Hfe−/− and
Hjv−/− mice is the occurrence of abnormal vascularization in the retina of
Hjv−/− mice visualized as angiomas.
15 This abnormal phenotype occurs very rarely, if at all, in
Hfe−/− mice despite excessive iron accumulation. Hemojuvelin is expressed in various retinal cell types, including retinal ganglion cells (RGCs), RPE, Muller cells, and photoreceptor cells.
13 Even though HFE and HJV are both membrane proteins, the former is expressed in the basal membrane and the latter in the apical membrane in RPE.
13,16 However, unlike HFE, which is an integral membrane protein with a transmembrane domain, HJV is anchored to the membrane via glycosylphosphatidylinositol.
17 As such, HJV can be cleaved from the membrane by specific phospholipases and the intact protein can be released in a soluble form. The membrane-anchored HJV is a coreceptor for bone morphogenetic proteins (BMPs) and potentiates BMP signaling.
18 The soluble form of HJV binds BMPs and prevents BMP signaling.
17 This suggests that the relative abundance of the two forms of HJV in a given tissue would determine the final outcome of BMP signaling. Hemojuvelin facilitates the expression of the iron-regulatory hormone hepcidin via BMP signaling.
18 Although BMP2, BMP4, and BMP6 all induce hepcidin expression in vitro in an HJV-dependent manner,
18 BMP6 seems to be solely responsible in vivo.
19 However, HJV does not mediate BMP signaling on its own but requires BMP receptors. Bone morphogenetic protein signaling involves phosphorylation of Smad protein complex resulting in its nuclear translocation to induce the target genes.