A novel G143D mutation in the NADH-cytochrome b5 reductase gene in an Indian patient with type I recessive hereditary methemoglobinemia

We report a novel homozygous mutation responsible for NADH-b5R deficiency in a family from Ratnagiri district in western India with recessive congenital methemoglobinemia (RCM) type I. The propositus was a 20-year-old female with a history of increasing cyanosis exacerbated by fever and weakness. There was no history of cardiac illness or exposure to drugs and chemicals. The methemoglobin level was 38.0% in the propositus with 70% reduction in NADH-b5R activity. Spectroscopic analysis of the hemolysate showed normal peaks suggesting absence of Hb-M. There was no hemoglobin instability and G6PD activity was normal. This novel G → A homozygous mutation at codon 143 in exon 5 was identified by SSCP followed by DNA sequencing and results in a glycine to aspartic acid substitution in the cytochrome b5 reductase protein. This mutation, which is located outside the FAD and NADH binding domain, leads to mild cyanosis. Investigations of the family members revealed that both the parents and a brother of the propositus were heterozygous for the G143D mutation.