6 PREVIOUSLY UNDESCRIBED PYRUVATE-KINASE MUTATIONS CAUSING ENZYME DEFICIENCY

Erythrocyte pyruvate kinase deficiency is the most common cause of her editary nonspherocytic hemolytic anemia. We present 6 previously undes cribed mutations of the PKLR gene associated with enzyme deficiency lo cated at cDNA nt 476 G --> T ((159)Gly --> Val), 884 C --> T ((295)Ala --> Val), 943 G --> A ((315)Glu --> Lys), 1022 G --> A ((341)Gly --> Asp), 1511 G --> T ((504)Arg --> Leu), and 1528 C --> T ((510)Arg --> Ter). Two of these mutations are near the substrate binding site: the (315)Glu --> Lys (943A) mutation may be involved in Mg2+ binding and ( 159)Gly --> Val (476T) mutation has a possible effect on ADP binding, Four of six mutations produce deduced changes in the shape of the mole cule. Two of these mutations, (504)Arg --> Leu (1511T) and (510)Arg -- > Ter (1528T), are located at the interface of domains A and C. One of them ((510)Arg --> Ter) is a deletion of the C-terminal residues affe cting the integrity of the protein. The (504)Arg --> Leu mutation elim inates a stabilizing interaction between domains A and C. Changes in a mino acid 341(nt 1022) from Gly to Asp cause local perturbations. The mutation (295)Ala --> Val (884T) might affect the way pyruvate kinase interacts with other molecules, We review previously described mutatio ns and conclude that there is not yet sufficient data to allow us to d raw conclusions regarding genotype/phenotype relationship. (C) 1998 by The American Society of Hematology.