Transferrin receptor levels and polymorphism of its gene in age-related macular degeneration

Abstract

The aim of the present study was to investigate the association of age related macular degeneration (AMD) risk with some aspects of iron homeostasis: iron concentration in serum, level of soluble transferrin receptor (sTfR), and transferrin receptor (TFRC) genetic variability. Four hundred and ninety one AMD patients and 171 controls were enrolled in the study. Restriction fragment length polymorphism PCR was employed to genotype polymorphisms of the TFRC gene, and colorimetric assays were used to determine the level of iron and sTfR. Multiple logistic regression was applied for all genotype/allele-related analyses and the ANOVA test for iron and sTfR serum level comparison. We found that the genotypes and alleles of the c.-253G > A polymorphism of the TFRC gene were associated with AMD risk and this association was modulated by smoking status, AMD family history, living environment (rural/urban), body mass index and age. The levels of sTfR was higher in AMD patients than controls, whereas concentrations of iron did not differ in these two groups. No association was found between AMD occurrence and the p.Gly142Ser polymorphism of the TRFC gene. The results obtained suggest that transferrin receptor and variability of its gene may influence AMD risk.

X-ray fluorescence microscopic measurement of elemental distribution in the mouse retina with age

“…7 Moreover, polymorphisms in Fe transport and regulatory genes, including transferrin receptor and iron regulatory proteins 1 and 2 are associated with AMD risk. 8,9 These studies suggest an important role for biometal homeostasis in aging and retinal disease.…”

“Manganese-induced neurotoxicity: a review of its behavioral consequences and neuroprotective strategies”

“…DAT knockout mice exposed to Mn accumulate significantly less Mn in the striatum compared to WT[50, 232]Ca channelsPlasma membraneVoltage-regulated, store-operated Ca 2+ channels as well as ionotropic glutamate receptors also facilitate Mn uptake into the brainThe number of known ion channel diseases (channelopathies) has increased dramatically and include cystic fibrosis, Bartter syndrome and epilepsy[233, 234]Choline transporterPlasma membraneCholine uptake was found to be significantly inhibited in the presence of Cd and Mn, but not Cu or AlPrenatal choline deficiency is associated with increased choline transporter mRNA expression in the septum and hippocampus of rats as a compensatory mechanism for acetylcholine synthesis[235, 236]Citrate transporterPlasma membraneMn citrate represents the major non-protein-bound species of Mn to enter the brain at the BBB. The influx transfer coefficient for Mn citrate was shown to be greater than that of Mn 2 + alone and Tf–Mn 3+ Defects in SLC25A1, a mitochondrial citrate carrier, were identified to cause combined D-2- and L-2-hydroxyglutaric aciduria[237, 238]Tf/TfRTf in plasma and TfR in the membrane of neurons, microglia, astrocytes and the endothelial cells of the BBBTf/TfR facilitates Mn 3+ influx into the CNS from the blood streamPolymorphisms in TfR gene have been correlated with increased risk of age related macular degeneration (AMD)[57, 237, 239, 240]Mn exportersFpnTransmembrane, expressed in the duodenum, liver, spleen, intestine, endothelial cells of the BBB, neurons, oligodendrocytes, astrocytes, choroid plexus and ependymal cellsIncreased Fpn expression in HEK293 cells is associated with decreased intracellular Mn concentration and attenuated cytotoxicityMutations in Fpn cause type IV hemochromatosis, commonly known as Fpn disease, characterized by Fe accumulation in reticuloendothelial macrophages[50, 62, 63]SLC30A10Cell surface-localized. Present in basal ganglia and liverMediates Mn efflux from cellsMutations in SLC30A10 that impair Mn export induce hypermanganesemia, dystonia, and polycythemia with a variable degree of hepatic dysfunction[22, 23]SPCA1Mainly in Golgi membrane of keratinocytes, liver and brainImports Mn 2+ from the cytosol to the Golgi lumenMonoallelic mutations in SPCA1 are known to cause Hailey-Hailey disease, a blistering skin disorder.…”

Transferrin Non-Viral Gene Therapy for Treatment of Retinal Degeneration

“…Similarly, increased expression of TF was shown in the retinas of AMD patients relative to those of healthy control patients, which suggests that iron regulation is impaired [14]. Finally, several polymorphisms in iron homeostasis genes have been identified as risk factors for AMD, such as the TF receptors (TFR1 and TFR2) genes [15], IRP1 and IRP2 genes [16], and the heme oxygenase-1 and -2 (HMOX1/2) genes [17]. We and others have characterized the role of iron homeostasis dysregulation and associated oxidative injury in the pathogenesis of RP.…”