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Molecular characterization of PK-LR gene in pyruvate kinase-deficient
Italian patients
A Zanella, P Bianchi, L Baronciani, M Zappa, E Bredi, C Vercellati, F Alfinito, G Pelissero and G Sirchia
Divisione di Ematologia and Centro Trasfusionale e di Immunologia dei
Trapianti, Instituto di Ricovero Cura a Carattere Scientifico (IRCCS)
Ospedale Maggiore, Milano, Italy.
We studied the PK-LR gene in 15 unrelated Italian patients with congenital
hemolytic anemia associated with erythrocyte pyruvate kinase (PK)
deficiency. Fourteen different mutations were detected among 26 mutated
alleles identified: a five-nucleotide (nt) deletion (227 to 231), two
splice-site (1269C and IVS3(-2)c), 10 missense (514C, 787T, 823A, 993A,
994A, 1168A, 1456T, 1529A, 1552A, and 1594T) and one nonsense mutation(s)
(721T). Eight of these (deletion 227-231, 1269C, IVS3(-2)c, 514C, 787T,
823A, 1168A, and 1552A) were novel. Moreover, a new polymorphic site was
detected in the 3' untranslated region of the mRNA (C/T, nucleotide 1738).
The deletion 227-231 causes a stop codon after amino acid 77, probably
resulting in an unstable gene product. Mutations 1269C and IVS3(-2)c lead
to an alteration of the 5' and 3' splice-site consensus sequence,
respectively; cDNA analysis failed to reveal any abnormal transcript,
suggesting that these mutations generate an unstable mRNA that is rapidly
degraded. Of the five new missense mutations, 823A (Gly275-Arg) and 1168A
(Asp390-Asn) involve highly conserved amino acids, 514C (Glu172-Gln) and
1552A (Arg518-Ser), although found in less conserved regions, affect the
balance of the electric charges of the protein. Mutation 787T (Gly263-Trp)
is likely to determine strong modifications in the local structure of the
molecule. The most frequent mutation in Italy appears to be 1456T (seven of
30 alleles), followed by 1529A (three of 30) and 994A (three of 30). A
correlation was found between mutations, biochemical characteristics of the
enzyme, and clinical course of the disease.
Volume 89,
Issue 10,
pp. 3847-3852,
05/15/1997
Copyright © 1997 by The American Society of Hematology
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