MOLECULAR DEFECT OF A PHOSPHOGLYCERATE KINASE VARIANT ASSOCIATED WITHHEMOLYTIC-ANEMIA AND NEUROLOGICAL DISORDERS IN A LARGE KINDRED

The X-chromosome-linked phosphoglycerate kinase (PGK) deficiency assoc iated with severe chronic and acute haemolytic anaemia and mental diso rders was first described in a large Chinese kindred in 1969. The mole cular abnormality of this original variant remained to be identified, The red cell PGK activity was only about 5%, but the activity of the p atients' lymphoblastoid cells was about 15% of normal, The PGK mRNA co ntent of the patients' lymphoblastoid cells were normal, Analysis of t he 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 p osition 163 of the enzyme. The replacement of the acidic aspartic acid by a hydrophobic valine is expected to induce drastic structural inst ability 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 gen omic DNA samples. 13/24 females examined were found to be variant hete rozygous. In this large family, affected males over three generations have died at a pre-adult age. Post- and pre-natal genotyping of the fa mily members may prevent future problems.