An X-chromosome linked phosphoglycerate kinase deficiency in erythrocytes and leucocytes was discovered in a large German kindred. Seven males of two generations were found to have only 21% of the normal enzyme activity in their erythrocytes, and twelve females of three generations showed various degrees of this defect. The differences in the expression of the deficiency in heterozygote females are explained by the Lyon hypothesis. The deficiency is caused by a variant enzyme, named phosphoglycerate kinase München. Although it differs from the normal enzyme electrophoretically, the two enzymes resemble one another closely in many respects. They have essentially the same Km for the substrates of the backward reaction, identical pH optima and similar rates of thermal inactivation. In contrast to the nine previously described phosphoglycerate kinase deficiencies, all of which are associated with haemolytic anaemia, the carriers of phosphoglycerate kinase München show no overt clinical symptoms. The erythrocyte concentrations of adenine nucleotides and 2,3-diphosphoglycerate are normal.

During a heterozygote screening of nearly 3000 persons, triosephosphate isomerase (TPI) deficiencies in erythrocytes were discovered in 11 unrelated persons, showing a residual activity between 39 and 76% of normal activity. Extensive genealogic studies were performed to confirm that these persons with TPI deficiency were heterozygous carriers. The total heterozygote frequency of triosephosphate isomerase deficiencies was 3.7/1000. The persons with heterozygous deficiency could be divided into two categories. Subjects of category I had a mean residual activity of 49% of the expected normal activity and were represented by a frequency of 1.3/1000. Subjects of category II had a mean residual activity of 67% of the expected normal activity and were represented by a frequency of 2.4/1000. None of the heterozygous persons showed an electrophoretic variant. The immunologic specific activity was normal with one exception. Therefore, we assume that in many cases of our heterozygous TPI-deficiencies a TPI protein with a normal specific activity is synthesized to a diminished degree.

Triosephosphate isomerase deficiencies in erythrocytes and leucocytes were discovered in three unrelated families by a heterozygote screening of 3000 blood samples. In addition, a family found by Schroter et al. [not published] was studied. In these four families, only heterozygote carriers were found. In the family described by Freycon et al. with hetero- and homozygote carriers of triosephosphate isomerase deficiency, the heterozygotes were reinvestigated. There was 51% of normal enzyme activity in three of the families. In the other two families the enzyme activity was 64% and 71% of normal. Two of the eleven heterozygotes, both children, were diseased, but it seems unlikely that the disorders resulted from the deficiencies. The activities of thirteen enzymes, the Km of triosephosphate isomerase for glyceraldehyde phosphate and the concentrations of metabolites were normal. Antibody titration showed normal specific activities in four families and 50% of normal in one family. No electrophoretic variant was detected. From the proved heredity, a heterozygous frequency of at least 1/1000 is indicated. A maximal frequency of 5/1000 is estimated by using further instances of triosephosphate isomerase deficiency where heredity has not yet been investigated. An explanation for the small number of known cases is that this enzyme is not routinely assayed.

SummaryThe effect of the Xce (x-chromosome controlling element) genotype on the randomness of X-chromosome inactivation in the mouse was studied by monitoring the expression of the X-linked locus pgk-1. The main aim was to test whether the Xce genotype modified the preferential expression of the maternally derived X-chromosome in the yolk sac endoderm. Quantitative electrophoresis of phosphoglycerate kinase (PGK-1) was used to study Pgk-1 expression in the foetus, yolk sac mesoderm and yolk sac endoderm at 13½ days post coitum. The Xcea/Xcec genotype caused non-random X-chromosome expression in the foetus and yolk sac mesoderm. However, there was no evidence that the Xce genotype moderates the preferential expression of the maternally derived X-chromosome in the yolk sac endoderm, as reported by Rastan & Cattanach (1983).

The stability of allelic gene expression of X-linked phosphoglycerate kinase was studied in seven carriers of a rare genetic variant named PGK München. The enzymatic activities in erythrocytes of five heterozygous females and three hemizygous males were determined repeatedly over a period of 10 years (1975-1984) and shown to remain constant. As the phosphoglycerate kinase activity is lower in cells expressing the PGK München allele, the ratio of the two cell types in all heterozygous females of the PGK München kindred could be calculated from the PGK activity and from the known allozyme activities in erythrocytes of homozygous wild type or hemizygous PGK München carriers. Since the maternal or paternal origin of both alleles is known from the pedigree, the quantitative expression of the maternally derived allozyme in heterozygous women could be determined. In heterozygous carriers the cell pool expressing the maternally inherited allele was significantly increased, independently, of the PGK allele linked to the maternal X chromosome (P less than 0.001). Our data show that inactivation of one of the two X chromosomes in human female erythropoietic stem cell precursors may be non-random, at least in the kindred and cell populations described here. The results are discussed in the context of random X chromosome inactivation (Lyon hypothesis).