Recessive congenital methaemoglobinaemia: cytochrome b5 reductase deficiency

• Published in: British journal of haematology 2008-05, Vol.141 (3), p.298-308
• Main Authors: Percy, Melanie J., Lappin, Terry R.
• Format: Article
• Language: English
• Subjects: Anemias. Hemoglobinopathies; Biological and medical sciences; cyanosis; cytochrome b5 reductase; Diseases of red blood cells; Hematologic and hematopoietic diseases; Medical sciences; microencephaly; neurological development; recessive congenital methaemoglobinaemia
• ISSN: 0007-1048; 1365-2141
• DOI: 10.1111/j.1365-2141.2008.07017.x

Summary Some 60 years ago, Quentin Gibson reported the first hereditary disorder involving an enzyme when he deduced that familial methaemoglobinaemia was caused by an enzymatic lesion associated with the glycolysis pathway in red blood cells. This disorder, now known as recessive congenital methaemoglobinaemia (RCM), is caused by NADH‐cytochrome b5 reductase (cb5r) deficiency. Two distinct clinical forms, types I and II, have been recognized, both characterized by cyanosis from birth. In type II, the cyanosis is accompanied by neurological impairment and reduced life expectancy. Cytochrome b5 reductase is composed of one FAD and one NADH binding domain linked by a hinge region. It is encoded by the CYB5R3 (previously known as DIA1) gene and more than 40 mutations have been described, some of which are common to both types of RCM. Mutations associated with type II tend to cause incorrect splicing, disruption of the active site or truncation of the protein. At present the description of the sequence variants of cb5r in the literature is confusing, due to the use of two conventions which differ by one codon position. Herein we propose a new system for nomenclature of cb5r based on recommendations of the Human Genome Variation Society. The development of a heterologous expression system has allowed the impact of naturally occurring variants of cb5r to be assessed and has provided insight into the function of cb5r.