Kleyn, Patrick W.; (1990) The isolation of the human 6 phosphogluconate dehydrogenase gene, a genetic marker in man. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

6-Phosphogluconate dehydgogenase (PGD) is an NADP-dependent dehydrogenase involved in the metabolism of glucose-6-phosphate via the pentose pathway. The enzyme is a dimer which displays an electrophoretic polymorphism which has been widely used in genetic mapping and which allowed its initial assignment to chromosome 1p. This thesis describes the isolation of human PGD cDNAs. Their identity was established by a combination of genetic and physical mapping studies which indicated their close genetic linkage to the PGD protein polymorphism in the p36 region of chromosome 1. Sequence analysis of the human cDNAs revealed extensive homology with the E.Coli 6-phosphogluconate dehydrogenase gene at the nucleotide level and with the sheep PGD protein at the amino acid level. However, the latter homology required some rearrangement of the cyanogen bromide peptides in the published sequence. The presence of at least two PGD-related loci in humans is described which are probably processed pseudogenes; one of these was assigned to chromosome 18q. The human PGD cDNA was shown to detect a restriction fragment length polymorphism (RFLP) in BamHI-cleaved human DNA. This RFLP yielded a polymorphism information content (PIC) of 0.30 compared to 0.04 for the protein polymorphism, a useful increase in genetic variation detectable at this locus. The genomic organisation of the human PGD gene was established in outline and a region enriched in hypo- methylated CpG dimers was identified at the 5' end. Physical linkage to the ENOl locus, which is genetically linked to PGD at a distance of 1.5cM was investigated by pulsed-field gel electrophoresis. Preliminary evidence was obtained suggesting that ENOl and PGD are separated by less than 350kb, providing a provisional estimate for the relationship between genetic and physical distance in the distal region of the short arm of chromosome 1.

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