Normal Function
The CYB5R3 gene provides instruction for making an enzyme called cytochrome b5 reductase 3. This enzyme is involved in transferring negatively charged particles called electrons from one molecule to another. Two versions (isoforms) of this enzyme are produced from the CYB5R3 gene. The soluble isoform is present only in red blood cells, and the membrane-bound isoform is found in all other cell types.
Normal red blood cells contain molecules of iron-containing hemoglobin, which deliver oxygen to the body's tissues. The iron in hemoglobin is ferrous (Fe2+), but it can spontaneously become ferric (Fe3+). Hemoglobin that contains ferric iron is called methemoglobin, and it cannot deliver oxygen. The soluble isoform of cytochrome b5 reductase 3 changes ferric iron back to ferrous iron so hemoglobin can function. Normally, red blood cells contain less than 2 percent methemoglobin.
The membrane-bound isoform is embedded in the membranes of various cellular compartments and is widely used in the body. This isoform is necessary for many chemical reactions, including the breakdown and formation of fatty acids, the formation of cholesterol, and the breakdown of various molecules and drugs.
Health Conditions Related to Genetic Changes
Autosomal recessive congenital methemoglobinemia
More than 65 mutations in the CYB5R3 gene have been found to cause autosomal recessive congenital methemoglobinemia types I and II. Most of these CYB5R3 gene mutations cause autosomal recessive congenital methemoglobinemia type I, which is characterized by a lack of oxygen in the body's tissues and bluish appearance of the skin, lips, and nails (cyanosis). The mutations that cause type I usually reduce enzyme activity or stability. As a result, the enzyme cannot efficiently change ferric iron to ferrous iron, leading to a 10 to 50 percent increase in methemoglobin within red blood cells. This increase in methemoglobin and corresponding decrease in normal hemoglobin reduces the amount of oxygen delivered to tissues. The altered enzyme activity affects only red blood cells because other cells can compensate for a decrease in enzyme activity, but red blood cells cannot.
The CYB5R3 gene mutations that cause autosomal recessive congenital methemoglobinemia type II result in the more severe form of the two types. In addition to cyanosis, people with this form have neurological problems. The mutations that cause type II typically result in a complete loss of enzyme activity. Cells cannot compensate for a complete loss of cytochrome b5 reductase 3, which results in a 10 to 70 percent increase in methemoglobin within red blood cells. This increase in methemoglobin and corresponding decrease in normal hemoglobin leads to cyanosis. The lack of enzyme activity in other cells leads to the neurological features associated with type II. Researchers suspect that the neurological problems are caused by impaired fatty acid and cholesterol formation, which reduces the production of a fatty substance called myelin. Myelin insulates nerve cells and promotes the rapid transmission of nerve impulses. This reduced ability to form myelin (hypomyelination) leads to a loss of nerve cells, particularly in the brain. The loss of these cells likely contributes to the encephalopathy and movement disorders characteristic of autosomal recessive congenital methemoglobinemia type II.
More About This Health ConditionOther disorders
A normal variant (polymorphism) in the CYB5R3 gene has been associated with low methemoglobin levels in infants who were born prematurely and treated with nitric oxide to prevent chronic lung disease. The lungs of premature infants are often underdeveloped and need support after birth. Nitric oxide widens the blood vessels of the lungs, allowing for more oxygen to get to the blood flowing through the vessels of the lungs. However, nitric oxide attaches (binds) to hemoglobin in red blood cells, which converts the hemoglobin into methemoglobin. If too much nitric oxide is administered to premature infants, more hemoglobin is turned into methemoglobin, and red blood cells cannot carry enough oxygen to the body's cells and tissues. This complication is known as methemoglobin toxicity. The polymorphism associated with low methemoglobin levels replaces the DNA building block (nucleotide) guanine with the nucleotide adenine at a specific place in the CYB5R3 gene (written as 9015G>A). As a result, cytochrome b5 reductase 3 activity is increased, leading to an increased ability to convert methemoglobin back to hemoglobin, a rise in oxygen delivery, and a reduced risk of methemoglobin toxicity.
Another polymorphism in the CYB5R3 gene has been found to increase the risk of breast cancer in African American women who smoke cigarettes. Cigarette smoke contains chemicals that can cause errors in DNA. These errors prevent cells from controlling their own growth and division, which can lead to the formation of a cancerous tumor. Normally, the cytochrome b5 reductase 3 enzyme can break down these chemicals into nontoxic substances, specifically targeting chemicals that have been shown to be involved in breast cancer. However, women who have a specific CYB5R3 gene polymorphism that changes the way the gene's instructions are used to make the protein (written as I1M+6C>T) have reduced enzyme activity. As a result, the chemicals from cigarette smoke are not broken down. They cause errors in DNA that allow cells to grow without control or order, leading to breast cancer. Studies show that the CYB5R3 gene polymorphism associated with breast cancer occurs at a 90-fold higher rate in African American women than in white women.
Other Names for This Gene
- B5R
- DIA1
- diaphorase-1
- NADH-cytochrome b5 reductase 3
- NADH-diaphorase 1
- NB5R3_HUMAN
Additional Information & Resources
Tests Listed in the Genetic Testing Registry
Scientific Articles on PubMed
Catalog of Genes and Diseases from OMIM
References
- Arikoglu T, Yarali N, Kara A, Bay A, Bozkaya IO, Tunc B, Percy MJ. A novel L218P mutation in NADH-cytochrome b5 reductase associated with type I recessive congenital methemoglobinemia. Pediatr Hematol Oncol. 2009 Jul-Aug;26(5):381-5. doi: 10.1080/08880010902979233. Citation on PubMed
- Blanke KL, Sacco JC, Millikan RC, Olshan AF, Luo J, Trepanier LA. Polymorphisms in the carcinogen detoxification genes CYB5A and CYB5R3 and breast cancer risk in African American women. Cancer Causes Control. 2014 Nov;25(11):1513-21. doi: 10.1007/s10552-014-0454-7. Epub 2014 Sep 16. Citation on PubMed or Free article on PubMed Central
- Fermo E, Bianchi P, Vercellati C, Marcello AP, Garatti M, Marangoni O, Barcellini W, Zanella A. Recessive hereditary methemoglobinemia: two novel mutations in the NADH-cytochrome b5 reductase gene. Blood Cells Mol Dis. 2008 Jul-Aug;41(1):50-5. doi: 10.1016/j.bcmd.2008.02.002. Epub 2008 Mar 17. Citation on PubMed
- Fuller TD, Spracklen CN, Ryckman KK, Knake LA, Busch TD, Momany AM, Murray JC, Dagle JM. Genetic variation in CYB5R3 is associated with methemoglobin levels in preterm infants receiving nitric oxide therapy. Pediatr Res. 2015 Mar;77(3):472-6. doi: 10.1038/pr.2014.206. Epub 2014 Dec 18. Citation on PubMed or Free article on PubMed Central
- Hudspeth MP, Joseph S, Holden KR. A novel mutation in type II methemoglobinemia. J Child Neurol. 2010 Jan;25(1):91-3. doi: 10.1177/0883073809336136. Epub 2009 May 26. Citation on PubMed
- Lorenzo FR 5th, Phillips JD, Nussenzveig R, Lingam B, Koul PA, Schrier SL, Prchal JT. Molecular basis of two novel mutations found in type I methemoglobinemia. Blood Cells Mol Dis. 2011 Apr 15;46(4):277-81. doi: 10.1016/j.bcmd.2011.01.005. Epub 2011 Feb 24. Citation on PubMed or Free article on PubMed Central
- Warang PP, Kedar PS, Shanmukaiah C, Ghosh K, Colah RB. Clinical spectrum and molecular basis of recessive congenital methemoglobinemia in India. Clin Genet. 2015;87(1):62-7. doi: 10.1111/cge.12326. Epub 2013 Dec 20. Citation on PubMed
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