Nucleotidase deficiency

This enzyme deficiency, known for some 30 years, is of interest for several reasons. Firstly, it is probably the third most common red cell enzymopathy (trailing G6PD deficiency and PK deficiency). Secondly, the diagnosis can be suspected from red cell morphology because it is associated with basophilic stippling (accounted for by persistence of RNA in mature red cells). Thirdly, although we do not really understand the precise mechanism, 5' nucleotidase (5'N) deficiency is a

The molecular basis of anemia 147

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©Mahidol; ©Chatham; ©Coimbra; ©Seattle; ©Santamaria; ©Aures; ©Cosenza; @A-(968C). Fig. 12.9 Distribution of mutations along the human G6PD gene

(a) Genomic structure of the human G6PD gene. Exons are shown as numbered rectangles (black rectangles represent coding sequences; shaded rectangles represent non-coding sequences). (b) The locations of amino acid substitutions are shown along the coding sequence of the gene, in which the exons are shown as open boxes. Substitutions giving rise to the more severe (class I) variants are shown as filled circles below. Small deletions, a nonsense mutation, and a splice site mutation are shown as filled rectangle, a cross and a J, respectively. The milder class II and class Ill variants are shown as open circles above: polymorphic variants are shown as a letter in a colored circle . Class IV variants are shown as open ellipses. From Luzzatto L, Mehta A, Vulliamy T. (2001) Glucose-6-phosphate dehydrogenase deficiency. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds). The Metabolic and Molecular Basis of Inherited Disease, 8th edn. New York: McGraw-Hill, pp. 4517-4553.

good example of how the red cell has virtually only one way to manifest its suffering: thus, almost any metabolic abnormality will lead to accelerated destruction; that is, hemolysis. Fourthly, the anemia of chronic lead poisoning (which had been known for a long time to be associated with basophilic stippling) turns out to be the consequence of the fact that lead is a powerful inhibitor of 5'N; thus, in terms of its hematological effects, lead poisoning is a phenocopy of 5'N deficiency.

In 2001 a gene corresponding to a previously published 5'N cDNA was mapped to chromosome 7, and three different mutations in this gene were discovered in homozygosity in four subjects with 5'N deficiency. One was a missense mutation, one was a nonsense mutation, and one was a splicing mutation causing the loss of exon 9 from the mature mRNA. This important advance makes it now possible to carry out a molecular diagnosis of 5'N deficiency. Moreover, it will be possible to explore the implications of heterozygous 5'N deficiency, which is of special interest in view of previous suggestions that it may interact with Hb E disease to make its clinical expression more severe.

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