STUDY OF THE MOLECULAR DEFECTS IN PYRUVATE-KINASE DEFICIENT PATIENTS AFFECTED BY NONSPHEROCYTIC HEMOLYTIC-ANEMIA

We have examined DNA from fifteen unrelated pyruvate kinase deficient patients with hereditary nonspherocytic hemolytic anemia (HNSHA) for t he molecular alterations responsible for the enzyme deficiency. All bu t 3 of the 30 putative mutations were identified. Fourteen different m utations were found. Nine were missense mutations: 320 T-->C, 823 G-C, 1276 C-->T, 1376 C-->T, 1378 G-->A, 1484 C-->T, 1529 G-->A, 1654 G--> A, 1675 C-->G; three were nonsense mutations: 603 G-->A, 721 G-->T, 15 01 C-->T; one was an insertion at 1574 GGG-->GGGG and the other a thre e nucleotide in-frame deletion 391-392-393 ATC. Eight of these mutatio ns have not been previously described. We also investigated all of the patients for the C/A polymorphism at nt 1705 and the microsatellite A TT repeat in intron 11. All of the mutations that had previously been reported by us (391-393del, 721T, 1484T, 1529A) were found in the cont ext of the same haplotype as the earlier cases, supporting the concept that each may have a single origin.