Molecular defect of a phosphoglycerate kinase variant associated with haemolytic anaemia and neurological disorders in a large kindred.

The X-chromosome-linked phosphoglycerate kinase (PGK) deficiency associated with severe chronic and acute haemolytic anaemia and mental disorders was first described in a large Chinese kindred in 1969. The molecular abnormality of this original variant remained to be identified. The red cell PGK activity was only about 5%, but the activity of the patients' lymphoblastoid cells was about 15% of normal. The PGK mRNA content of the patients' lymphoblastoid cells were normal. Analysis of the patients' mRNA showed the existence of a nucleotide transversion A-->T at position 491 (counting from adenine of the initiation codon). The mutation should cause an amino acid substitution Asp-->Val at position 163 of the enzyme. The replacement of the acidic aspartic acid by a hydrophobic valine is expected to induce drastic structural instability resulting in severe enzyme deficiency in the patients' tissues. The genotypes of two affected males, their mothers and 22 females of the family were identified by the PCR-mediated method using their genomic DNA samples. 13/24 females examined were found to be variant heterozygous. In this large family, affected males over three generations have died at a pre-adult age. Post- and pre-natal genotyping of the family members may prevent future problems.