HFE H63D gene mutation

Homozygous mutations of HFE gene H63D are rarely the cause of hemochromatosis, however it is also associated with the occurrence of other conditions like hypotransferrinemia, liver dysfunction,[1] bone and joint issues, diabetes mellitus, heart disease, hormone imbalances, porphyria cutanea tarda (PCT), infertility, stroke, neurodegenerative and brain damages, some cancers, venous and peripheral artery disease.[2][3][4][5][6][7][8]

HFE

Brain iron accumulation

The most relevant risk associated with a H63D mutation is for brain damage due to iron accumulation which causes oxidation processes within the affected cells (chronic oxidative stress) and, as a consequence, leading to cell death (scarring of brain tissue) with severely disturbed neurotransmitter activity. These incurable processes include increased cellular iron, oxidative stress (free radical activity), brain glutamate dysbalance, and abnormal levels of tau proteins and alpha-synuclein which both may result in dementias and parkinson’s disease, or similar conditions. Scientists found that patients homozygous for H63D show a higher risk of earlier signs of cognitive impairment and earlier onset of dementias compared to individuals with normal HFE genes or H63D heterozygous mutation.[9][10][11][12][13][14][15]

Cardiac iron accumulation

Some individuals with a homozygous H63D mutation may show signs of heart disease, cardiomyopathies and disturbances in the calcium channels in particular.[16][17]

Liver disorders

A homozygous mutation of HFE gene H63D is an indication of an Iron Metabolism Disorder known as Hemochromatosis (Iron Overload) and may increase the risk to develop a fatty liver, cryptic (nonspecific) liver dysfunctions, metabolic syndrome[18] and, in patients with a cirrhotic or a liver damaged due to alcohol also the rates of liver cancer.[2][19][20]

References
  1. 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.
  2. 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.
  3. 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. PMID 19931264.
  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.
  5. 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.
  6. "H63D - The Other Mutation" (PDF). Iron Disorders Institute nanograms. 2010.
  7. 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.
  8. 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.
  9. 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. PMID 20164577.
  10. 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.
  11. 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.
  12. 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): 1–8. doi:10.1186/1471-2377-6-24. PMID 16824219.
  13. 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.
  14. 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.
  15. 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.
  16. 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.
  17. 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.
  18. 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.
  19. 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.
  20. 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.

External sources
  • "H63D - The Other Mutation" (PDF). Iron Disorders Institute nanograms. 2010.
  • Nandar W, Connor JR (2011). "HFE Gene Variants Affect Iron in the Brain". The Journal of Nutrition. 141 (4): 729S–739S. doi:10.3945/jn.110.130351. PMID 21346098.
  • Adams P, Brissot P, Powell LW (2000). "EASL International Consensus Conference on Haemochromatosis". Journal of Hepatology. 33 (3): 496–504. doi:10.1016/S0168-8278(01)80875-8.
  • Bridle K, Cheung TK, Murphy T, et al. (2006). "Hepcidin is down-regulated in alcoholic liver injury: implications for the pathogenesis of alcoholic liver disease". Alcoholism, Clinical and Experimental Research. 30 (1): 106–12. doi:10.1111/j.1530-0277.2006.00002.x. PMID 16433737.
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