Submission Details

The FTH1 gene codes for the ferritin heavy chain. Synthesis of both heavy H- type and light L- type ferritin subunits is controlled by a common cytosolic protein known as iron regulatory protein (IRP), which binds to the iron-responsive element (IRE) in the 5′-UTR of the H- and L-ferritin mRNAs (PMID:11389486). The H subunit is known to generate a ferroxidase activity that is essential for the incorporation of iron into the ferritin molecule, contributing to the maintenance of the redox status of the cells by removing Fe (II). Improperly coordinated Fe (II) has the potential to convert hydrogen peroxide and superoxide into the highly toxic hydroxyl radical, which can attack proteins, lipids, and DNA causing oxidation, fragmentation and crosslinking leading to their loss of function. Variants in FTH1 have been reported in individuals with the following disease entities: Hemochromatosis type 5 (HFE5) (MIM#0014225) and Neurodegeneration with brain iron accumulation 9(NBIA9) (MIM#0958012). As per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found the two disease entities do not exhibit phenotypic overlap and are inconsistent with a single spectrum of disease while both being autosomal dominantly inherited. Summary of case- based evidence: One variant in the IRE region of H-subunit mRNA has been reported in association with hemochromatosis type 5 in three members of a Japanese family affected with dominantly inherited iron overload (PMID:11389486). Summary of experimental evidence: This gene-disease association is supported by experimental evidence from the study on an iron-uptake assay using the COS-1 transfectants, which suggests the A49U mutation of H subunit would affect not only its own translation but also that of the L subunit and that the decrease in H subunit not only impaired iron uptake into the ferritin molecule but also caused iron accumulation in the cytosol, possibly because of the decrease in ferroxidase activity (PMID:11389486). The iron storage function of ferritin plays a major role in preventing iron-mediated cell and tissue damage. (PMID: 19492434). Study on H-ferritin gene–knockout mice showed early embryonic lethality due to massive iron deposition (PMID: 11468145). The studies on kinetics of iron oxidation and uptake of ferritin purified from human liver and of the engineered mutant H-chain observed that the deletion at the carboxyl terminus prevents the formation of a stable iron core suggesting that the ferritin H-chain has an iron oxidation site which is separated from the sites of iron transfer and hydrolysis (PMID:3192527). A study on Hydroxyl radical spin-trapping experiments showed that H-chain ferritin greatly attenuates hydroxyl radical generation from the Fenton reaction and that the ferroxidase site is responsible for this activity. The presence of wild-type human H-chain ferritin HuHF during Fe2+ oxidation by H2O2 greatly decreases the amount of OH- radical produced from Fenton chemistry whereas the ferroxidase site mutant 222 (H62K + H65G) and human L-chain ferritin (HuLF) lack this activity. This data relates to the pathogenesis mechanism in the patients as well where the ferroxidase activity of H-ferritin is lost and there is increase in the serum iron levels (PMID:16519538). In summary, there is limited evidence supporting the relationship between FTH1 and susceptibility to Hemochromatosis type 5. This classification was approved by the ClinGen IEM GCEP at the meeting on August 8, 2025 (SOP Version 11).