Hereditary hemochromatosis (HH) is the main genetic cause of iron overload and is regarded as metal-related human toxicosis. HH may result from HFE and non-HFE gene mutations causing hepcidin deficiency or hepcidin resistance. The disorder has a high biochemical penetrance, but a low clinical prevalence. Unfortunately, the majority of patients with HH remain undiagnosed at their disease-curable stage. The main aim of HH therapy is to prevent iron overload in the early-phase disease and elimination of excess iron from the body by phlebotomy in its late stage. Raising global awareness of HH among health professionals, their training to pay attention to early HH signs and symptoms, and strict patient monitoring are critical management strategies for preventing treatment delays, upgrading its efficacy, and improving patient prognosis.

PCSK9 is implicated in familial hypercholesterolemia via targeting the cell surface PCSK9-LDLR complex toward lysosomal degradation. The M2 repeat in the PCSK9's C-terminal domain is essential for its extracellular function, potentially through its interaction with an unidentified “protein X”. The M2 repeat was recently shown to bind an R-x-E motif in MHC-class-I proteins (implicated in the immune system), like HLA-C, and causing their lysosomal degradation. These findings suggested a new role of PCSK9 in the immune system and that HLA-like proteins could be “protein X” candidates. However, the participation of each member of the MHC-I protein family in this process and their regulation of PCSK9's function have yet to be determined. Herein, we compared the implication of MHC-I-like proteins such as HFE (involved in iron homeostasis) and HLA-C on the extracellular function of PCSK9. Our data revealed that the M2 domain regulates the intracellular sorting of the PCSK9-LDLR complex to lysosomes, and that HFE is a new target of PCSK9 that inhibits its activity on the LDLR, whereas HLA-C enhances its function. This work suggests the potential modulation of the PCSK9 functions through interactions of HFE and HLA-C.

Hereditary hemochromatosis (HH) is an inherited iron metabolism disorder. It is caused by an autosomal recessive disorder resulting from a C28Y8 HFE gene mutation. Mutations in the HFE gene may result in iron accumulation and oxidative stress in the retina, resulting in macular degeneration. This article describes two patients with HH who developed vision difficulties. Both patients were subjected to a retinal exam, multimodal imaging, and electrodiagnostic techniques, which revealed structural and functional degeneration of the central macula. Fundus photography, fluorescein angiography (FA), and fundus autofluorescence (FAF) revealed changes at the level of the retinal pigment epithelium (RPE) in the center of the macula, while optical coherence tomography (OCT) revealed subfoveal accumulation of hyperreflective material at and below the RPE. The multifocal electroretinogram (mfERG) confirmed a decreased cone response, whereas the full-field electroretinogram (ERG) revealed no pathological findings. In addition, patients underwent genetic testing, which ruled out the possibility of hereditary macular dystrophy. Considering macula findings and the nature of the patients' primary illness, we believe that the higher concentration and accumulation of iron and photoreceptor metabolic products have led to dysfunction in the RPE, which has led to morphological and functional changes in the macula.