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Blood, Vol. 95 No. 10 (May 15), 2000:
pp. 3250-3255
A novel mutation in the NADH-cytochrome b5 reductase gene of a
Chinese patient with recessive congenital methemoglobinemia
Yao Wang,
Yu-Shui Wu,
Pei-Zhen Zheng,
Wen-Xi Yang,
Guo-An Fang,
Yu-Chai Tang,
Fei Xie,
Feng-Hua Lan, and
Zhong-Yong Zhu
From Research Laboratories, Center for Laboratory Medicine, Fuzhou
General Hospital, Fuzhou City, Fujian Province, China; and Zhousan
People's Hospital, Zhousan City, Zhejiang Province, China.
Recessive congenital methemoglobinemia due to nicotinamide adenine
dinucleotide (NADH)-cytochrome b5 reductase (b5R) deficiency is
classified into 2 clinical types: type 1 (erythrocyte type) and type 2 (generalized type). We found a Chinese family with type 1 recessive
congenital methemoglobinemia, the patients from which were diagnosed
according to clinical symptoms and b5R enzyme activity in the blood
cells. To learn the molecular basis of type 1 recessive congenital
methemoglobinemia in this Chinese family, we isolated total RNA from
the peripheral leukocytes of the propositus and b5R complementary
DNA (cDNA) by reverse transcription- polymerase chain reaction
(RT-PCR). The coding region of the b5R cDNA was analyzed by sequencing
the cloned PCR products. The results showed that the propositus was
homozygous for a G A transition at codon 203 in exon 7, changing a cysteine to a tyrosine (Cys203Tyr). To characterize the
mutant enzyme, both glutathione S-transferase (GST)-fused wild-type b5R
and GST-fused mutant Cys203Tyr b5R were expressed in Escherichia
coli and affinity purified. The results showed that the catalytic
activity of the enzyme was not much affected by this amino acid
substitution, but the mutant enzyme exhibited decreased heat stability
and increased susceptibility to trypsin. These properties of the mutant
enzyme would account for the restricted b5R deficiency and mild
clinical manifestations of these type 1 patients. The finding of
this novel mutation makes codon 203 the only position within the b5R
gene at which more than 1 mutation has been found.
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