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Mutations in the pyruvate kinase L gene in patients with hereditary
hemolytic anemia
C Lenzner, P Nurnberg, BJ Thiele, A Reis, V Brabec, A Sakalova and G Jacobasch
Institute for Medical Genetics, Faculty of Medicine, Humboldt- University
Berlin (Charite), Germany.
We have completely sequenced the introns of the human L-type pyruvate
kinase (PK) gene using the published cDNA sequence. Subsequently, DNA from
12 unrelated PK deficiency (PKD) patients of Central European origin was
investigated for mutations in this gene by solid-phase sequencing. We
detected 10 different mutations, 9 of which result in single amino acid
alterations, whereas the tenth destroys a splice site. Eight of the 10
mutations have not been described before. We found 7 missense mutations:
G994-->A (Gly-332-->Ser), G1006-->T (Ala- 336-->Ser),
A1081-->G (Asn-361-->Asp), G1174-->A (Ala-392-->Thr), G1493-
->A (Arg-498-->His), G1529-->A (Arg-510-->Gln), C1594-->T
(Arg-532-- >Trp), one in-frame triplet deletion (del) as well as one
insertion (ins): del AAG1060-62 (del Lys-354), ins AGC after C1203 (ins Ser
after Cys-401), and one splice-site mutation at the border of intron A to
exon 3: g/G283-->a/G. Although the enzymatic properties are
substantially changed in all PK mutations, only two affected amino acid
positions are in or close to the active site. Mutations C1594-->T, G994-
->A, del AAG1060-62 and the splice-site mutation g/G283-->a/G have
been detected in two different patients each. Mutation G1529-->A was
found in five different alleles. Haplotype analysis with the A/C
polymorphism at position 1705 gave evidence for a single origin of this
most frequent mutation in PKD as suggested by Baronciani and Beutler (Proc
Natl Acad Sci USA 90:4324, 1993). Carrier detection and prenatal diagnosis
are now feasible for the affected families.
Volume 83,
Issue 10,
pp. 2817-2822,
05/15/1994
Copyright © 1994 by The American Society of Hematology
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