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Hereditary hemolytic anemia caused by diverse point mutations of pyruvate
kinase gene found in Japan and Hong Kong
H Kanno, DC Wei, LC Chan, H Mizoguchi, M Ando, T Nakahata, K Narisawa, H Fujii and S Miwa
Okinaka Memorial Institute for Medical Research, Tokyo, Japan.
We identified four distinct point mutations in homozygous pyruvate kinase
(PK) variants in Japanese and Chinese patients with chronic nonspherocytic
hemolytic anemia. All gene abnormalities were missense mutations that
caused single amino acid substitutions. 1261A (Q421K) and 1436A (R436H),
which were identified in PK Sendai and PK Shinshu, had been found in
unrelated Japanese and Amish PK variants, respectively. The clinical
severity and extremely low residual erythrocyte PK activity of PK Shinshu
as well as of the Amish PK might be caused partly by aberrant splicing,
because the 1436A mutation changes a nucleotide at the last nucleotide in
the exon 10. Recently, we diagnosed a 42-year-old Japanese woman with
chronic nonspherocytic hemolytic anemia as having a homozygous PK
deficiency. DNA sequencing of the variant PK gene showed a homozygous
missense mutation at 1403GCT- ->GTT, resulting in a single amino acid
substitution from 468la-->Val. The gene mutation is likely to impair the
allostericity of this enzyme, speculated from the tertiary structure. A
homozygous missense mutation in PK Hong Kong, a boy of a non-Han southern
Chinese minority group, was identified in exon 7 of the human L-PK gene,
941ATT-->ACT, resulting in a single amino acid substitution from
314lle-->Thr. The R- PK activity is expected to be severely affected,
because the mutated amino acid residue is located between the 313 Lys and
the 315 Glu, which are very important for acid-base catalysis and magnesium
binding, respectively. Both the R- and M2-type PK were shown by
polyacrylamide gel electrophoresis of the PK Hong Kong erythrocyte lysate,
and this is the first report of a homozygous individual whose erythrocytes
contain the immature (M2)-type isozyme.
Volume 84,
Issue 10,
pp. 3505-3509,
11/15/1994
Copyright © 1994 by The American Society of Hematology
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