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Molecular analysis of 29 pyruvate kinase-deficient patients from central
Europe with hereditary hemolytic anemia
C Lenzner, P Nurnberg, G Jacobasch, C Gerth and BJ Thiele
Institute of Biochemistry, Faculty of Medicine, Humboldt-University Berlin
(Charite), Germany.
We investigated the DNA of 29 unrelated pyruvate kinase (PK) deficiency
(PKD) patients from Central Europe with hereditary nonspherocytic hemolytic
anemia for mutations in the PK-L/R gene. Among 58 potentially affected
alleles, 53 mutations were identified, of which 17 were different from each
other. Of these 17 mutations, 13 were single- nucleotide (nt) substitutions
resulting in amino acid exchanges, G787A (Gly263-Arg), G994A (Gly332-Ser),
G1006T (Ala336-Ser), G1010A (Arg337- Gln), A1081G (Asn361-Asp), G1127T
(Ser376-Ile), G1174A (Ala392-Thr), G1281T (Glu427-Asp), C1454T
(Ser485-Phe), C1456T (Arg486-Trp), G1493A (Arg498-His), G1529A
(Arg510-Gin), and C1594T (Arg532-Trp); 1 in-frame triplet deletion,
1060delAAG (delLys354); 1 in-frame triplet insertion, 1203insAGC (insSer
after Cys401); 1 splicesite mutation, 101-1G-A; and 1 frameshift deletion,
628delGT. Six mutations, 628delGT, G787A, G1010A, G1127T, G1281T, and
C1454T, are described for the first time. To test the hypothesis of a
single origin of the most common PK mutation in the European population,
G1529A, we investigated all patients at four polymorphic sites in the
PK-L/R gene: C/A at nt 1705, C/T at nt 1992, the (ATT)n microsatellite in
intron J, and a polymorphism (T)10/(T)19 in intron I. Nine patients
homozygous for mutation G1529A were consistent in all four markers. In the
group of patients homozygous for mutation G1529A, the hematologic
parameters and clinical manifestations have been studied in detail.
Although having an identical mutation in the PK-L/R gene, the patients are
affected differently. Their appearance ranges from a very mild compensated
hemolysis to a severe anemia. Possible molecular explanations are
discussed.
Volume 89,
Issue 5,
pp. 1793-1799,
03/01/1997
Copyright © 1997 by The American Society of Hematology
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