GLUCOSE-6-PHOSPHATE-DEHYDROGENASE MUTATIONS CAUSING ENZYME DEFICIENCYIN A MODEL OF THE TERTIARY STRUCTURE OF THE HUMAN ENZYME

Human glucose 6-phosphate dehydrogenase (G6PD) has a particularly larg e number of variants resulting from point mutations; some 60 mutations have been sequenced to date. Many variants, some polymorphic, are ass ociated with enzyme deficiency. Certain variants have severe clinical manifestations; for such variants, the mutant enzyme almost always dis plays a reduced thermal stability. A homology model of human G6PD has been built, based on the three-dimensional structure of the enzyme fro m Leuconostoc mesenteroides. The model has suggested structural reason s for the diminished enzyme stability and hence for deficiency. It has shown that a cluster of mutations in exon 10, resulting in severe cli nical symptoms, occurs at or near the dimer interface of the enzyme, t hat the eight-residue deletion in the variant Nara is at a surface loo p, and that the two mutations in the A- variant are close together in the three-dimensional structure. (C) 1996 by The American Society of H ematology.