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Am J Hematol. 1996 Feb;51(2):122-32.

Molecular basis of erythroenzymopathies associated with hereditary hemolytic anemia: tabulation of mutant enzymes.

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Okinawa Memorial Institute for Medical Research, Tokyo Women's Medical College, Japan.


Molecular abnormalities of erythroenzymopathies associated with hereditary hemolytic anemia have been determined by means of molecular biology. Pyruvate kinase (PK) deficiency is the most common and well-characterized enzyme deficiency in the glycolytic pathway, and it causes hereditary hemolytic anemia. To date, 47 gene mutations have been identified. We identified one base deletion, one splicing mutation, and six distinct missense mutations in 12 unrelated families with a homozygous PK deficiency. Mutations located near the substrate or fructose-1,6- diphosphate binding site may change the conformation of the active site, resulting in a drastic loss of activity and severe clinical symptoms. Glucose-6-phosphate dehydrogenase (G6PD)deficiency is the most common metabolic disorder, and it is associated with chronic hemolytic anemia and/or drug- or infection-induced acute hemolytic attack. An estimated 400 million people are affected worldwide. The mutations responsible for about 78 variants have been determined. Some have polymorphic frequencies in different populations. Most variants are produced by one or two nucleotide substitutions. Molecular studies have disclosed that most of the class 1 G6PD variants associated with chronic hemolysis have the mutations surrounding either the substrate or the NADP binding site. Among rare enzymopathies, missense mutations have been determined in deficiencies of glucosephosphate isomerase, (TPI), phosphoglycerate kinase, and adenylate kinase. Compound heterozygosity with missense mutation and base deletion has been determined in deficiencies of hexokinase and diphosphoglyceromutase. Compound heterozygosity with missense and nonsense mutations has been identified in TPI deficiency. One base junction mutations resulting in abnormally spliced PFK-M mRNA have been identified in homozygous PFK deficiency. An exception is hemolytic anemia due to increased adenosine deaminase activity. The basic abnormality appears to result from the overproduction of a structurally normal enzyme.

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