title: HK Utrecht: missense mutation in the active site of human hexokinase associated with hexokinase deficiency and severe nonspherocytic hemolytic anemia.
abstract: Hexokinase deficiency is a rare autosomal recessive disease with a clinical phenotype of severe hemolysis. We report a novel homozygous missense mutation in exon 15 (c.2039C>G, HK [hexokinase] Utrecht) of HK1, the gene that encodes red blood cell-specific hexokinase-R, in a patient previously diagnosed with hexokinase deficiency. The Thr680Ser substitution predicted by this mutation affects a highly conserved residue in the enzyme's active site that interacts with phosphate moieties of adenosine diphosphate, adenosine triphosphate (ATP), and inhibitor glucose-6-phosphate. We correlated the molecular data to the severe clinical phenotype of the patient by means of altered enzymatic properties of partially purified hexokinase from the patient, notably with respect to Mg(2+)-ATP binding. These kinetic properties contradict those obtained from a recombinant mutant brain hexokinase-I with the same Thr680Ser substitution. This contradiction thereby stresses the valuable contribution of studying patients with hexokinase deficiency to achieve a better understanding of hexokinase's key role in glycolysis.
authors.affiliation: Department of Clinical Chemistry and the Department of Hematology, University Medical Center Utrecht, The Netherlands.
authors.forename: Richard
authors.initials: R
authors.lastname: van Wijk
authors.forename: Gert
authors.initials: G
authors.lastname: Rijksen
authors.forename: Eric G
authors.initials: EG
authors.lastname: Huizinga
authors.forename: Hendrik K
authors.initials: HK
authors.lastname: Nieuwenhuis
authors.forename: Wouter W
authors.initials: WW
authors.lastname: van Solinge
mesh_terms: D000746:Anemia, Hemolytic, Congenital Nonspherocytic / Q000201:enzymology* / Q000235:genetics; D001665:Binding Sites / Q000235:genetics; D017124:Conserved Sequence; D004912:Erythrocytes / Q000201:enzymology; D005260:Female; D006593:Hexokinase / Q000172:deficiency / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D007700:Kinetics; D020125:Mutation, Missense; D010375:Pedigree; D016415:Sequence Alignment
chemical_list: C472074:HK1 protein, human; D006593:Hexokinase