title: Two new phosphoglycerate kinase mutations associated with chronic haemolytic anaemia and neurological dysfunction in two patients from Spain.
abstract: We report two previously undescribed mutations of the phosphoglycerate kinase gene (PGK1) leading to enzyme deficiency. In both cases, the patients were of Spanish origin and they exhibited a severe life-long chronic haemolytic anaemia associated with progressive neurological impairment. Sequence analysis of the first patient's entire PGK1 gene found a novel missense mutation (140T > A). This mutation caused an amino acid change of Ile to Asn at 46th position from the NH(2)-terminal serine residue (Ile46Asn), which has been called PGK-Barcelona based on the place of origin of the patient. In the second patient, a G to A transversion was discovered at nucleotide 958 (958G > A). This caused a Ser319Asn amino acid substitution. Since this mutation had not been previously described, the provisional name of PGK-Murcia was given to this deficient enzyme. The crystal structure of porcine PGK was used as a molecular model to investigate how these mutations may affect enzyme structure and function. In both cases, the mutations did not modify any of the PGK binding sites for ATP or 3PG, so their consequence is related to a loss of enzyme stability rather than a decrease of enzyme catalytic function.
authors.affiliation: Red Cell Pathology Unit, Hospital Clinic i Provincial, CDB-IDIBAPS, University of Barcelona, Barcelona, Spain.
authors.forename: Núria
authors.initials: N
authors.lastname: Noel
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Flanagan
authors.forename: John
authors.initials: J
authors.lastname: Flanagan
authors.forename: Maria Jose
authors.initials: MJ
authors.lastname: Ramirez Bajo
authors.forename: Susana G
authors.initials: SG
authors.lastname: Kalko
authors.forename: María del Mar
authors.initials: Mdel M
authors.lastname: Mañú
authors.forename: José Luis
authors.initials: JL
authors.lastname: Garcia Fuster
authors.forename: Pablo
authors.initials: P
authors.lastname: Perez de la Ossa
authors.forename: Josep
authors.initials: J
authors.lastname: Carreras
authors.forename: Ernest
authors.initials: E
authors.lastname: Beutler
authors.forename: Joan-Lluís
authors.initials: JL
authors.lastname: Vives Corrons
mesh_terms: D000743:Anemia, Hemolytic / Q000201:enzymology / Q000235:genetics*; D002908:Chronic Disease; D017809:Fatal Outcome; D006801:Humans; D007231:Infant, Newborn; D008607:Intellectual Disability / Q000201:enzymology / Q000235:genetics; D008297:Male; D009154:Mutation; D009422:Nervous System Diseases / Q000201:enzymology / Q000235:genetics*; D010735:Phosphoglycerate Kinase / Q000235:genetics*; D016133:Polymerase Chain Reaction / Q000379:methods; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D013030:Spain
chemical_list: D010735:Phosphoglycerate Kinase