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

Koichiro Higasa, Jun Ichi Manabe, Toshitsugu Yubisui, Hideki Sumimoto, Parichat Pung-Amritt, Voravarn S. Tanphaichitr, Yasuyuki Fukumaki

Research output: Contribution to journalArticlepeer-review

30 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)922-930
Number of pages9
JournalBritish Journal of Haematology
Volume103
Issue number4
DOIs
Publication statusPublished - 1998
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Hematology

Fingerprint Dive into the research topics of 'Molecular basis of hereditary methaemoglobinaemia, types I and II: Two novel mutations in the NADH-cytochrome b<sub>5</sub> reductase gene'. Together they form a unique fingerprint.

Cite this