HFE H63D gene mutation

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The HFE H63D is a single-nucleotide polymorphism in the HFE gene (c.187C>G, rs1799945), which results in the substitution of an aspartic acid for a histidine at amino acid position 63 of the HPE protein (p.His63Asp). HFE participates in the regulation of iron absorption.[1][2][3]

Homozygous H63D variant can occasionally be the cause of hemochromatosis. It is also associated with the occurrence of other conditions like hypotransferrinemia,[4][5] liver dysfunction,[6][7] bone and joint issues, diabetes mellitus, heart disease, hormone imbalances, porphyria cutanea tarda (PCT), infertility, stroke,[8] neurodegenerative and brain damages,[9] some cancers, venous and peripheral artery disease.[10][11]

Health impacts[edit]

The primary risk associated with the H63D mutation is brain damage, as iron accumulation can cause oxidation within affected cells, ultimately leading to cell death and scarring of the brain tissue.[12][13] Another potential consequence is abnormal levels of tau proteins and alpha-synuclein, which play a role in conditions like Alzheimer's,[14] Lewy body dementia, and Parkinson’s;[15][16][17][18] patients homozygous for the H63D mutation show a higher risk of earlier signs of cognitive impairment and earlier onset of dementias compared to individuals with normal or heterozygous genotypes.

A study in 2020 predicted that the H63D variant may be a risk factor for incidental amyotrophic lateral sclerosis in a Han Chinese population.[19]

Some individuals with the homozygous H63D variant may show signs of heart disease, cardiomyopathies, and disturbances in the calcium channels in particular.[20][21]

The homozygous H63D variant is an indicator of the iron metabolism disorder hemochromatosis, which may increase the risk of developing a fatty liver.[22] In patients with a cirrhotic liver, the mutation can increase the rate of liver cancer.[6][23][24]

Athletic advantage[edit]

A 2020 study revealed that the homozygous H63D variant (as well as the heterozygous one) is significantly higher in elite endurance athletes comparing to ethnically-matched controls in Russian and Japanese populations, and is associated with high V̇O2max in male athletes.[25]


  1. ^ Olynyk JK, Trinder D, Ramm GA, Britton RS, Bacon BR (September 2008). "Hereditary hemochromatosis in the post-HFE era". Hepatology. 48 (3): 991–1001. doi:10.1002/hep.22507. PMC 2548289. PMID 18752323.
  2. ^ "Hemochromatosis: Causes". Mayo Foundation for Medical Education and Research (MFMER).
  3. ^ den Dunnen JT, Dalgleish R, Maglott DR, Hart RK, Greenblatt MS, McGowan-Jordan J, Roux AF, Smith T, Antonarakis SE, Taschner PE (June 2016). "HGVS Recommendations for the Description of Sequence Variants: 2016 Update". Human Mutation. 37 (6): 564–9. doi:10.1002/humu.22981. PMID 26931183.
  4. ^ Fujii H, Takagaki N, Yoh T, et al. (2008). "Non-prescription supplement-induced hepatitis with hyperferritinemia and mutation (H63D) in the HFE gene". Hepatology Research. 38 (3): 319–23. doi:10.1111/j.1872-034X.2007.00266.x. PMID 17944940. S2CID 30008466.
  5. ^ Castiella A, Urreta I, Zapata E, et al. (2019). "H63/H63D genotype and the H63D allele are associated in patients with hyperferritinemia to the development of metabolic syndrome". Eur. J. Intern. Med. (Letter to the Editor). 72: 106–107. doi:10.1016/j.ejim.2019.11.021. PMID 31796245.
  6. ^ a b Raszeja-Wyszomirska J, Kurzawski G, Zawada I, et al. (2010). "HFE gene mutations in patients with alcoholic liver disease. A prospective study from northwestern Poland". Polish Archives of Internal Medicine. 120 (4): 127–31. doi:10.20452/pamw.905. PMID 20424537.
  7. ^ Valenti L, Fracanzani AL, Bugianesi E, et al. (2010). "HFE Genotype, Parenchymal Iron Accumulation, and Liver Fibrosis in Patients With Nonalcoholic Fatty Liver Disease". Gastroenterology. 138 (3): 905–12. doi:10.1053/j.gastro.2009.11.013. hdl:2318/85426. PMID 19931264.
  8. ^ Ellervik C, Tybjaerg-Hansen A, Appleyard M, et al. (2007). "Hereditary hemochromatosis genotypes and risk of ischemic stroke". Neurology. 68 (13): 1025–31. doi:10.1212/01.wnl.0000257814.77115.d6. PMID 17389307. S2CID 43908712.
  9. ^ Liu Y, Lee SY, Neely E, et al. (2011). "Mutant HFE H63D Protein Is Associated with Prolonged Endoplasmic Reticulum Stress and Increased Neuronal Vulnerability". J. Biol. Chem. 286 (15): 13161–70. doi:10.1074/jbc.M110.170944. PMC 3075663. PMID 21349849.
  10. ^ Mitchell RM, Lee SY, Simmons Z, et al. (2011). "HFE polymorphisms affect cellular glutamate regulation". Neurobiol. Aging. 32 (6): 1114–23. doi:10.1016/j.neurobiolaging.2009.05.016. PMID 19560233. S2CID 22440350.
  11. ^ "H63D - The Other Mutation" (PDF). Iron Disorders Institute nanograms. 2010.
  12. ^ Nandar W, Connor JR (2011). "HFE Gene Variants Affect Iron in the Brain". J. Nutr. 141 (4): 729S–739S. doi:10.3945/jn.110.130351. PMID 21346098.
  13. ^ Hall EC 2nd, Lee SY, Simmons Z, et al. (2010). "Prolyl-peptidyl isomerase, Pin1, phosphorylation is compromised in association with the expression of the HFE polymorphic allele, H63D" (PDF). Biochim. Biophys. Acta. 1802 (4): 389–95. doi:10.1016/j.bbadis.2010.01.004. PMID 20060900.
  14. ^ Bartzokis G, Lu PH, Tishler TA, et al. (2010). "Prevalent Iron Metabolism Gene Variants Associated with Increased Brain Ferritin Iron in Healthy Older Men". J. Alzheimer's Dis. 20 (1): 333–41. doi:10.3233/JAD-2010-1368. PMC 3119253. PMID 20164577.
  15. ^ Guerreiro RJ, Bras JM, Santana I, et al. (2006). "Association of HFE common mutations with Parkinson's disease, Alzheimer's disease and mild cognitive impairment in a Portuguese cohort". BMC Neurology. 6 (24): 24. doi:10.1186/1471-2377-6-24. PMC 1534050. PMID 16824219.
  16. ^ Dekker MC, Giesbergen PC, Njajou OT, et al. (2003). "Mutations in the hemochromatosis gene (HFE), Parkinson's disease and parkinsonism". Neurosci. Lett. 348 (2): 117–9. doi:10.1016/S0304-3940(03)00713-4. PMID 12902032. S2CID 32076298.
  17. ^ Borie C, Gasparini F, Verpillat P, et al. (2002). "Association study between iron-related genes polymorphisms and Parkinson's disease". J. Neurol. 249 (7): 801–4. doi:10.1007/s00415-002-0704-6. PMID 12140659. S2CID 22293375.
  18. ^ Akbas N, Hochstrasser H, Deplazes J, et al. (2006). "Screening for mutations of the HFE gene in Parkinson's disease patients with hyperechogenicity of the substantia nigra". Neurosci. Lett. 407 (1): 16–9. doi:10.1016/j.neulet.2006.07.070. PMID 16935420. S2CID 45492253.
  19. ^ Zhang QQ, Jiang H, Li CY, Liu YL, Tian XY (September 2020). "H63D CG genotype of HFE is associated with increased risk of sporadic amyotrophic lateral sclerosis in a single population". Journal of Integrative Neuroscience. 19 (3): 495–499. doi:10.31083/j.jin.2020.03.131. PMID 33070529.
  20. ^ Adams PC, Pankow JS, Barton JC, et al. (2009). "HFE C282Y Homozygosity Is Associated With Lower Total and Low-Density Lipoprotein Cholesterol: The Hemochromatosis and Iron Overload Screening Study". Circ. Cardiovasc. Genet. 2 (1): 34–7. doi:10.1161/CIRCGENETICS.108.813089. PMID 20031565.
  21. ^ Franchini M (2006). "Hereditary iron overload: Update on pathophysiology, diagnosis, and treatment". Am. J. Hematol. 81 (3): 202–9. doi:10.1002/ajh.20493. PMID 16493621.
  22. ^ Castiella A, Zapata E, Zubiaurre L, et al. (2015). "Impact of H63D mutations, magnetic resonance and metabolic syndrome among outpatient referrals for elevated serum ferritin in the Basque Country". Annals of Hepatology. 14 (3): 333–9. doi:10.1016/S1665-2681(19)31272-4. PMID 25864213.
  23. ^ Jin F, Qu L, Shen X (2010). "Association between C282Y and H63D mutations of the HFE gene with hepatocellular carcinoma in European populations: a meta-analysis". J. Exp. Clin. Cancer Res. 29 (1): 18. doi:10.1186/1756-9966-29-18. PMC 2845109. PMID 20196837.
  24. ^ Machado MV, Ravasco P, Martins A, et al. (2009). "Iron homeostasis and H63D mutations in alcoholics with and without liver disease". World Journal of Gastroenterology. 15 (1): 106–11. doi:10.3748/wjg.15.106. PMC 2653287. PMID 19115475.
  25. ^ Semenova EA, Miyamoto-Mikami E, Akimov EB, Al-Khelaifi F, Murakami H, Zempo H, Kostryukova ES, Kulemin NA, Larin AK, Borisov OV, Miyachi M, Popov DV, Boulygina EA, Takaragawa M, Kumagai H, Naito H, Pushkarev VP, Dyatlov DA, Lekontsev EV, Pushkareva YE, Andryushchenko LB, Elrayess MA, Generozov EV, Fuku N, Ahmetov II (March 2020). "The association of HFE gene H63D polymorphism with endurance athlete status and aerobic capacity: novel findings and a meta-analysis". European Journal of Applied Physiology. 120 (3): 665–673. doi:10.1007/s00421-020-04306-8. PMC 7042188. PMID 31970519.

External sources[edit]