Molecular basis of hereditary methaemoglobinaemia, types I and II: two novel mutations in the NADH‐cytochrome b5 reductase gene

Hereditary methaemoglobinaemia, caused by deficiency of NADH‐cytochrome b5 reductase (b5R), has been classified into two types, an erythrocyte (type I) and a generalized (type II). We analysed the b5R gene of two Thai patients and found two novel mutations. The patient with type II was homozygous fo...

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Bibliographic Details
Published in:British journal of haematology 1998-12, Vol.103 (4), p.922-930
Main Authors: Higasa, Koichiro, Manabe, Jun‐Ichi, Yubisui, Toshitsuga, Sumimoto, Hideki, Pung‐amritt, Parichat, Tanphaichitr, Varavarn S., Fukumaki, Yasuyuki
Format: Article
Language:English
Subjects:
Amino Acid Substitution
Anemias. Hemoglobinopathies
Biological and medical sciences
Cytochrome Reductases - genetics
Cytochrome-B Reductase
Diseases of red blood cells
enzyme deficiency
enzyme stability
Female
Hematologic and hematopoietic diseases
hereditary methaemoglobinaemia
Hot Temperature
Humans
Male
Medical sciences
Methemoglobinemia - genetics
mutation
Mutation, Missense - genetics
NADH‐cytochrome b5 reductase
Pedigree
Point Mutation - genetics
Sequence Analysis
Spectrum Analysis
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Summary:Hereditary methaemoglobinaemia, caused by deficiency of NADH‐cytochrome b5 reductase (b5R), has been classified into two types, an erythrocyte (type I) and a generalized (type II). We analysed the b5R gene of two Thai patients and found two novel mutations. The patient with type II was homozygous for a C‐to‐T substitution in codon 83 that changes Arg (CGA) to a stop codon (TGA), resulting in a truncated b5R without the catalytic portion. The patient with type I was homozygous for a C‐to‐T substitution in codon 178 causing replacement of Ala (GCG) with Val (GTG). To characterize effects of this missense mutation, we investigated enzymatic properties of mutant b5R (Ala 178 Val). Although the mutant enzyme showed normal catalytic activity, less stability and different spectra were observed. These results suggest that this substitution influenced enzyme stability due to the slight change of structure. In conclusion, the nonsense mutation led to type II because of malfunction of the truncated protein. On the other hand, the missense mutation caused type I, due to degradation of the unstable mutant enzyme with normal activities in patient's erythrocytes, because of the lack of compensation by new protein synthesis during the long life‐span of erythrocytes.
ISSN:0007-1048
1365-2141
DOI:10.1046/j.1365-2141.1998.01123.x