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Serine-proline replacement at residue 127 of NADH-cytochrome b5 reductase
causes hereditary methemoglobinemia, generalized type
Y Kobayashi, Y Fukumaki, T Yubisui, J Inoue and Y Sakaki
Research Laboratory for Genetic Information, Kyushu University, Fukuoka,
Japan.
Hereditary methemoglobinemia is an autosomal recessive disorder
characterized by NADH-cytochrome b5 reductase (b5R) deficiency. In an
attempt to clarify the molecular mechanisms involved in the enzyme
deficiency, we isolated the b5R gene from a patient homozygous for
hereditary methemoglobinemia, generalized type, and compared its nucleotide
sequence with that of the normal NADH-cytochrome b5R gene. Only one
difference was observed; a thymidine at the first position of codon 127
(TCT) was altered to a cytidine in the b5R gene of the patient, resulting
in replacement of serine with proline. Dot blot hybridization of the
amplified DNA samples with allele-specific oligonucleotide probes showed
that the proband and her brothers were homozygous for this mutation and
that their father was heterozygous. Although the activity of b5R in
lymphoblastoid cells from homozygotes was reduced to 10% of the normal
level, RNA blot and protein blot analyses of the lymphoblastoid cells
showed that synthesis of b5R messenger RNA and the b5R polypeptide were
normal. Serine at residue 127 is presumed to be in an alpha-helix structure
that is part of a nucleotide-binding domain. These observations suggest
that replacement of Pro-127 causes a significant conformation change in the
nucleotide- binding domain that affects electron transport from NADH to
cytochrome b5. Functional enzyme deficiency results in a generalized type
of hereditary methemoglobinemia.
Volume 75,
Issue 7,
pp. 1408-1413,
04/01/1990
Copyright © 1990 by The American Society of Hematology
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