Two new phosphoglycerate kinase mutations associated with chronic haemolytic anaemia and neurological dysfunction in two patients from Spain

SummaryWe report two previously undescribed mutations of the phosphoglyceratekinase gene (PGK1) leading to enzyme deficiency. In both cases, the patientswere of Spanish origin and they exhibited a severe life-long chronichaemolytic anaemia associated with progressive neurological impairment.Sequence analysis of the first patient’s entire PGK1 gene found a novelmissense mutation (140T > A). This mutation caused an amino acid changeof 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 originof the patient. In the second patient, a G to A transversion was discovered atnucleotide 958 (958G > A). This caused a Ser319Asn amino acidsubstitution. Since this mutation had not been previously described, theprovisional name of PGK-Murcia was given to this deficient enzyme. Thecrystal structure of porcine PGK was used as a molecular model to investigatehow these mutations may affect enzyme structure and function. In bothcases, the mutations did not modify any of the PGK binding sites for ATP or3PG, so their consequence is related to a loss of enzyme stability rather than adecrease of enzyme catalytic function.Keywords: phosphoglycerate kinase deficiency, haemolytic anaemia, neuro-logical dysfunction.