Genetic and Biochemical Studies of Hereditary Methemoglobinemia (NADH-Cytochrome b5 Reductase Deficiency

Hereditary methemoglobinemia is an autosomal recessive disorder caused by a deficiency of NADH-cytochrome b5 reductase. In most cases enzyme deficiency occurs in red cells and symptom is only cyanosis due to elevated methemoglobin (type I). In about 10% of the cases deficiency is demonstrated in all the examined tissues and is accompanied by methemoglobinemia and severe neurological disorders (type II). Gene analyses of five independent families with I disease showed that point mutations leading to amino acid substitutions occur in all cases. Mutations found in three patients of type II disease were a point mutation, a deletion of 3 bases that leads to one amino acid deletion, and a mutation of splicing acceptor site of exon 9. Charasterization of recombinant type I and type II mutant enzymes syowed that type Ienzymes retained high enzyme activity but were unstable, wherews type II enzymes had low catalytic ability. Mutations in type I disease on three dimensional styucture of the enzyme residein the marginal portion of the enzyme that seem to participate in maintaining the enzyme structure, explain low catalytic efficiency of mutants.

hereditary methemoglobinemia

NADH-cytochrome b5 reductase

genetic diagnosis

x-ray structure

catalytic mechanism