title: Six previously undescribed pyruvate kinase mutations causing enzyme deficiency.
abstract: Erythrocyte pyruvate kinase deficiency is the most common cause of hereditary nonspherocytic hemolytic anemia. We present 6 previously undescribed mutations of the PKLR gene associated with enzyme deficiency located at cDNA nt 476 G-->T (159Gly-->Val), 884 C-->T (295Ala-->Val), 943 G-->A (315Glu-->Lys), 1022 G-->A (341Gly-->Asp), 1511 G-->T (504Arg-->Leu), and 1528 C-->T (510Arg-->Ter). Two of these mutations are near the substrate binding site: the 315Glu-->Lys (943A) mutation may be involved in Mg2+ binding and 159Gly-->Val (476T) mutation has a possible effect on ADP binding. Four of six mutations produce deduced changes in the shape of the molecule. Two of these mutations, 504Arg-->Leu (1511T) and 510Arg-->Ter (1528T), are located at the interface of domains A and C. One of them (510Arg-->Ter) is a deletion of the C-terminal residues affecting the integrity of the protein. The 504Arg-->Leu mutation eliminates a stabilizing interaction between domains A and C. Changes in amino acid 341(nt 1022) from Gly to Asp cause local perturbations. The mutation 295Ala-->Val (884T) might affect the way pyruvate kinase interacts with other molecules. We review previously described mutations and conclude that there is not yet sufficient data to allow us to draw conclusions regarding genotype/phenotype relationship.
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: A
authors.initials: A
authors.lastname: Demina
authors.forename: K I
authors.initials: KI
authors.lastname: Varughese
authors.forename: J
authors.initials: J
authors.lastname: Barbot
authors.forename: L
authors.initials: L
authors.lastname: Forman
authors.forename: E
authors.initials: E
authors.lastname: Beutler
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism; D000595:Amino Acid Sequence; D004912:Erythrocytes / Q000201:enzymology*; D005260:Female; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D011770:Pyruvate Kinase / Q000172:deficiency* / Q000235:genetics*; D017421:Sequence Analysis
chemical_list: D000244:Adenosine Diphosphate; D011770:Pyruvate Kinase