The Proteomics Study of Compounded HFE/TF/TfR2/HJV Genetic Variations in a Thai Family with Iron Overload, Chronic Anemi
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The Proteomics Study of Compounded HFE/TF/TfR2/HJV Genetic Variations in a Thai Family with Iron Overload, Chronic Anemia, and Motor Neuron Disorder Torsak Tippairote 1,2
&
Geir Bjørklund 3
&
Massimiliano Peana 4
&
Sittiruk Roytrakul 5
Received: 30 April 2020 / Accepted: 31 July 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract The mutation of the homeostatic iron regulatory genes (HFE) impaired the hepatic hepcidin transcription leading to the chronic excess of the iron pool, with the adverse consequences of free radical oxidative damages. We herein reported the findings of Thai family members who had the compound of uncommon HFE rs2794719, together with transferrin (TF) rs1867504, transferrin receptor 2 (TfR2) rs7385804, and hemojuvelin (HJV) rs16827043 genetic variants involved in the hepcidin transcriptional pathway. These compounded genetic variants could produce the spectrum of clinical phenotypes that spanned from mild to moderate symptoms of chronic anemia to an established motor neuron disorder. The feasible pathophysiologies were the impairment of the transferrin receptor functions, which affected the endocytic uptake of halo-transferrin into the erythroblast precursors. Such a defect left the erythropoiesis depleted of their iron supply. These alterations also promoted the TfRindependent uptake of iron into other target tissues and left the TrF2/BMP-dependent-hepcidin activation pathway unattended. We used the predicted molecular interactive proteomes to support our speculated dysregulated iron metabolism. During the early stage of an elevated ferritin level, there was no inhibition of ferroportin activities from hepcidin. These pathophysiological processes went on to the point of an iron overload threshold. After that, the hepcidin transcription started to kick in with the resulting decreased serum iron levels and deterioration of clinical symptoms. Keywords Iron regulatory genes . Transferrin . Ferroportin . Iron overload . Anemia . Motor neuron disorder
Abbreviation ALP Alkaline phosphatase levels ASL Amyotrophic lateral sclerosis BMI Body mass index BMP Bone morphogenetic proteins CPK Creatine phosphokinase
* Geir Bjørklund [email protected] 1
Doctor of Philosophy Program in Nutrition, Faculty of Medicine, Ramathibodi Hospital and Institute of Nutrition, Mahidol University, Bangkok, Thailand
2
BBH Hospital, Bangkok, Thailand
3
Council for Nutritional and Environmental Medicine, Toften 24, 8610 Mo i Rana, Norway
4
Department of Chemistry and Pharmacy, University of Sassari, Sassari, Italy
5
Proteomics Research Laboratory, National Center for Genetic Engineering and Biotechnology (BIOTEC), Pathum Thani, Thailand
ESR HAMP HBA1C HFE HJV HH hs-CRP SMAD SNPs TF TfR2 ZFP
Erythrocytes sedimentary rate Hepcidin antimicrobial peptide Glycated hemoglobin Homeostatic iron regulatory genes Hemojuvelin Hereditary hemochromatosis High-sensitivity C-reactive protein Mothers against decapentaplegic homolog Single nucleotide polymorphisms Transferrin Transferrin
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