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Point mutations in the L-type pyruvate kinase gene of two children with
hemolytic anemia caused by pyruvate kinase deficiency [see comments]
B Neubauer, M Lakomek, H Winkler, M Parke, S Hofferbert and W Schroter
Universitats-Kinderklinik, Gottingen, Germany.
The molecular alterations responsible for the characteristic enzyme
abnormalities in pyruvate kinase (PK) deficiency were investigated in two
unrelated children homozygous for PK deficiency. Both variant enzymes were
characterized according to the recommendations of the International
Committee for Standardization in Haematology. Genomic DNA was specifically
amplified by the polymerase chain reaction. Normal and mutant alleles of
the L-type PK gene were analyzed by nucleotide sequencing. Heterozygosity
of the parents was confirmed by allele- specific oligonucleotide
hybridization. In PK Linz a C to T base exchange at position 394 of the
L-type PK gene was found. As a result, the 132nd amino acid of the mutant
enzyme, arginine (CGC), is replaced by cysteine (TGC). The affected amino
acid residue is located within the deduced active site of the protein and
the enzyme variant shows strongly altered allosteric properties. PK Beirut
shows a C for T substitution at position 1058, changing the 353 amino acid
from threonine (ACG) to methionine (ATG). In contrast to PK Linz, this
amino acid lies outside the deduced substrate binding site and kinetic
parameters of PK Beirut are close to normal. Both enzyme variants show a
markedly reduced specific activity and thermolability.
Volume 77,
Issue 9,
pp. 1871-1875,
05/01/1991
Copyright © 1991 by The American Society of Hematology
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