oxidation and reduction reactions, such as the reduction of methemoglobin to hemoglobin. Of the two forms of NADH-cytochrome b5 reductase, the membrane-bound form exists mainly on the cytoplasmic side of the endoplasmic reticulum and functions in desaturation and elongation of fatty acids, in cholesterol biosynthesis, and in drug metabolism. The erythrocyte form is located in a soluble fraction of circulating erythrocytes and is involved in methemoglobin reduction. Clinical significance Mutations in the CYB5R3 gene cause methemoglobinemia types I and II. This is a rare autosomal recessive disease due to a deficiency of isoform of NADH-cytochrome b5 reductase. Many mutations of this gene and the subsequent disease manifestation have been described. The disease manifests as the accumulation of oxidized Fe+3 in humans. Type I recessive congenital methemoglobinemia (RCM) is characterized by a deficiency of the soluble isoform and manifests as the cyanosis of skin and mucous membranes. In type II, the defect affects both isoforms and thus affects more general tissues such as red blood cells, leukocytes, and all body tissues. This type is associated with mental deficiency and other neurologic symptoms, which may be because the cytochrome b5 system plays a crucial role in the desaturation of fatty acids in the body. Recently, it was reported that abnormal lipid metabolism related with the desaturation of fatty acids is likely to be a secondary phenotype rather than a direct cause of the disease. The authors describe new insights on the aetiology of neurological disorders caused by CYB5R3d deficiency. One patient was described as having a new class of this disorder, type III. This condition was characterized by a deficiency of NADH cytochrome b5 reductase in lymphocytes, platelets, and erythrocytes, but this was not associated with mental retardation. Interactions CYB5R3 is known to interact with CYB5A, ENO1, and SUMO2 among other proteins. References External links Further reading