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.
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Research Article|
December 21 2011
Iron-mediated retinal degeneration in haemojuvelin-knockout mice
Jaya P. Gnana-Prakasam;
Jaya P. Gnana-Prakasam
*Department of Biochemistry and Molecular Biology, Georgia Health Sciences University, Augusta, GA 30912, U.S.A.
‡Vision Discovery Institute, Georgia Health Sciences University, Augusta, GA 30912, U.S.A.
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Amany Tawfik;
Amany Tawfik
†Department of Cellular Biology and Anatomy, Georgia Health Sciences University, Augusta, GA 30912, U.S.A.
‡Vision Discovery Institute, Georgia Health Sciences University, Augusta, GA 30912, U.S.A.
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Michelle Romej;
Michelle Romej
*Department of Biochemistry and Molecular Biology, Georgia Health Sciences University, Augusta, GA 30912, U.S.A.
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Sudha Ananth;
Sudha Ananth
*Department of Biochemistry and Molecular Biology, Georgia Health Sciences University, Augusta, GA 30912, U.S.A.
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Pamela M. Martin;
Pamela M. Martin
*Department of Biochemistry and Molecular Biology, Georgia Health Sciences University, Augusta, GA 30912, U.S.A.
‡Vision Discovery Institute, Georgia Health Sciences University, Augusta, GA 30912, U.S.A.
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Sylvia B. Smith;
Sylvia B. Smith
†Department of Cellular Biology and Anatomy, Georgia Health Sciences University, Augusta, GA 30912, U.S.A.
‡Vision Discovery Institute, Georgia Health Sciences University, Augusta, GA 30912, U.S.A.
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Vadivel Ganapathy
Vadivel Ganapathy
1
*Department of Biochemistry and Molecular Biology, Georgia Health Sciences University, Augusta, GA 30912, U.S.A.
‡Vision Discovery Institute, Georgia Health Sciences University, Augusta, GA 30912, U.S.A.
1To whom correspondence should be addressed (email vganapat@georgiahealth.edu).
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Publisher: Portland Press Ltd
Received:
June 27 2011
Revision Received:
September 23 2011
Accepted:
September 26 2011
Accepted Manuscript online:
September 26 2011
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2012 Biochemical Society
2012
Biochem J (2012) 441 (2): 599–608.
Article history
Received:
June 27 2011
Revision Received:
September 23 2011
Accepted:
September 26 2011
Accepted Manuscript online:
September 26 2011
Citation
Jaya P. Gnana-Prakasam, Amany Tawfik, Michelle Romej, Sudha Ananth, Pamela M. Martin, Sylvia B. Smith, Vadivel Ganapathy; Iron-mediated retinal degeneration in haemojuvelin-knockout mice. Biochem J 15 January 2012; 441 (2): 599–608. doi: https://doi.org/10.1042/BJ20111148
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