title: Iron-mediated retinal degeneration in haemojuvelin-knockout mice.
abstract: Haemochromatosis is a genetic disorder of iron overload resulting from loss-of-function mutations in genes coding for the iron-regulatory proteins HFE (human leucocyte antigen-like protein involved in iron homoeostasis), transferrin receptor 2, ferroportin, hepcidin and HJV (haemojuvelin). Recent studies have established the expression of all of the five genes in the retina, indicating their importance in retinal iron homoeostasis. Previously, we demonstrated that HJV is expressed in RPE (retinal pigment epithelium), the outer and inner nuclear layers and the ganglion cell layer. In the present paper, we report on the consequences of Hjv deletion on the retina in mice. Hjv-/- mice at ≥18 months of age had increased iron accumulation in the retina with marked morphological damage compared with age-matched controls; these changes were not found in younger mice. The retinal phenotype in Hjv-/- mice included hyperplasia of RPE. We isolated RPE cells from wild-type and Hjv-/- mice and examined their growth patterns. Hjv-/- RPE cells were less senescent and exhibited a hyperproliferative phenotype. Hjv-/- RPE cells also showed up-regulation of Slc7a11 (solute carrier family 7 member 11 gene), which encodes the 'transporter proper' subunit xCT in the heterodimeric amino acid transporter xCT/4F2hc (cystine/glutamate exchanger). BMP6 (bone morphogenetic protein 6) could not induce hepcidin expression in Hjv-/- RPE cells, confirming that retinal cells require HJV for induction of hepcidin via BMP6 signalling. HJV is a glycosylphosphatidylinositol-anchored protein, and the membrane-associated HJV is necessary for BMP6-mediated activation of hepcidin promoter in RPE cells. Taken together, these results confirm the biological importance of HJV in the regulation of iron homoeostasis in the retina and in RPE.
authors.affiliation: Department of Biochemistry and Molecular Biology, Georgia Health Sciences University, Augusta, GA 30912, USA.
authors.forename: Jaya P
authors.initials: JP
authors.lastname: Gnana-Prakasam
authors.forename: Amany
authors.initials: A
authors.lastname: Tawfik
authors.forename: Michelle
authors.initials: M
authors.lastname: Romej
authors.forename: Sudha
authors.initials: S
authors.lastname: Ananth
authors.forename: Pamela M
authors.initials: PM
authors.lastname: Martin
authors.forename: Sylvia B
authors.initials: SB
authors.lastname: Smith
authors.forename: Vadivel
authors.initials: V
authors.lastname: Ganapathy
mesh_terms: D000375:Aging / Q000502:physiology; D027182:Amino Acid Transport System y+ / Q000096:biosynthesis; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000096:biosynthesis; D055418:Bone Morphogenetic Protein 6 / Q000494:pharmacology; D058851:GPI-Linked Proteins; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D015395:Histocompatibility Antigens Class I / Q000235:genetics; D007501:Iron / Q000378:metabolism / Q000494:pharmacology*; D035925:Iron-Regulatory Proteins / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D012160:Retina / Q000378:metabolism*; D012162:Retinal Degeneration / Q000139:chemically induced* / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000378:metabolism* / Q000473:pathology
chemical_list: D027182:Amino Acid Transport System y+; D023181:Antimicrobial Cationic Peptides; C525816:BMP6 protein, human; D055418:Bone Morphogenetic Protein 6; D058851:GPI-Linked Proteins; C578702:HAMP protein, human; C504414:HJV protein, mouse; C579599:Hamp protein, mouse; D000071020:Hemochromatosis Protein; D064451:Hepcidins; C499535:Hfe protein, mouse; D015395:Histocompatibility Antigens Class I; D035925:Iron-Regulatory Proteins; D008565:Membrane Proteins; C492255:Slc7a11 protein, mouse; D007501:Iron