The Classical Human Phosphoglucomutase (PGM1) Isozyme Polymorphism is Generated by Intragenic Recombination

The molecular basis of the classical human phosphoglucomutase 1 (PGM1) isozyme polymorphism has been established. In 1964, when this genetic polymorphism was first described, two common allelozymes PGM1 1 and PGM1 2 were identified by starch gel electrophoresis. The PGM1 2 isozyme showed a greater a...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 1993-11, Vol.90 (22), p.10730-10733
Main Authors: March, R. E., Putt, W., Hollyoake, M., Ives, J. H., Lovegrove, J. U., Hopkinson, D. A., Edwards, Y. H., Whitehouse, D. B.
Format: Article
Language:English
Subjects:
550400 - Genetics
Alleles
Base Sequence
BASIC BIOLOGICAL SCIENCES
Biological and medical sciences
BIOLOGICAL EVOLUTION
Blotting, Western
DNA
DNA Primers - chemistry
ENZYMES
Exons
Fundamental and applied biological sciences. Psychology
Gels
GENE MUTATIONS
GENE RECOMBINATION
GENES
Genes. Genome
Genetic mutation
Genetic polymorphism
Genetics
Humans
Intragenic recombination
Isoenzymes - genetics
Molecular and cellular biology
Molecular genetics
Molecular Sequence Data
Mutation
MUTATIONS
ORGANIC COMPOUNDS
Phenotypes
Phosphoglucomutase - genetics
Point Mutation
Polymerase chain reaction
Polymorphism, Genetic
Polymorphism, Restriction Fragment Length
PROTEINS
Recombination, Genetic
RFLPS
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Summary:The molecular basis of the classical human phosphoglucomutase 1 (PGM1) isozyme polymorphism has been established. In 1964, when this genetic polymorphism was first described, two common allelozymes PGM1 1 and PGM1 2 were identified by starch gel electrophoresis. The PGM1 2 isozyme showed a greater anodal electrophoretic mobility than PGM1 1. Subsequently, it was found that each of these allelozymes could be split, by isoelectric focusing, into two subtypes; the acidic isozymes were given the suffix + and the basic isozymes were given the suffix -. Hence, four genetically distinct isozymes 1+, 1-, 2+, and 2- were identified. We have now analyzed the whole of the coding region of the human PGM1 gene by DNA sequencing in individuals of known PGM1 protein phenotype. Only two mutations have been found, both C to T transitions, at nt 723 and 1320. The mutation at position 723, which changes the amino acid sequence from Arg to Cys at residue 220, showed complete association with the PGM1 2/1 protein polymorphism: DNA from individuals showing the PGM1 1 isozyme carried the Arg codon CGT, whereas individuals showing the PGM1 2 isozyme carried the Cys codon TGT. Similarly, the mutation at position 1320, which leads to a Tyr to His substitution at residue 419, showed complete association with the PGM1+/- protein polymorphism: individuals with the + isozyme carried the Tyr codon TAT, whereas individuals with the - isozyme carried the His codon CAT. The charge changes predicted by these amino acid substitutions are entirely consistent with the charge intervals calculated from the isoelectric profiles of these four PGM1 isozymes. We therefore conclude that the mutations are solely responsible for the classical PGM1 protein polymorphism. Thus, our findings strongly support the view that only two point mutations are involved in the generation of the four common alleles and that one allele must have arisen by homologous intragenic recombination between these mutation sites.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.90.22.10730