Compound heterozygosity of two missense mutations in the NADH‐cytochrome b5 reductase gene of a Polish patient with type I recessive congenital methaemoglobinaemia

A case of type I methaemoglobinaemia observed in a Polish subject with compound heterozygosity for two mutations in the reduced nicotinamide adenine dinucleotide (NADH) cytochrome b5 reductase (b5R) gene is described. One is a novel mutation 647T→C which leads to substitution of isoleucine by threonine at position 215 (I215T). This maternal mutation was found in several family members. A previously known mutation, 757G→A, leads to the replacement of valine by methionine at position 252 (V252M). The latter mutation was found also in the father and one of the two brothers. The effects of these mutations were analysed on a model of the human b5R protein obtained by homology modelling. Although both amino acid substitutions are located in the NADH‐binding domain, the whole protein structure, especially the region between the flavin adenine dinucleotide and NADH‐binding domains, is disturbed. The structural changes in the I215T mutant are less prominent than those in the V252M mutant. We presume that the 647T→C mutation is a type I mutation, however, it has not been observed in the homozygous state.