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. 1992 May 1;89(9):4028–4032. doi: 10.1073/pnas.89.9.4028

Enzymatic defect in "X-linked" sideroblastic anemia: molecular evidence for erythroid delta-aminolevulinate synthase deficiency.

P D Cotter 1, M Baumann 1, D F Bishop 1
PMCID: PMC525625  PMID: 1570328

Abstract

Recently, the human gene encoding erythroid-specific delta-aminolevulinate synthase was localized to the chromosomal region Xp21-Xq21, identifying this gene as the logical candidate for the enzymatic defect causing "X-linked" sideroblastic anemia. To investigate this hypothesis, the 11 exonic coding regions of the delta-aminolevulinate synthase gene were amplified and sequenced from a 30-year-old Chinese male with a pyridoxine-responsive form of X-linked sideroblastic anemia. A single T----A transition was found in codon 471 in a highly conserved region of exon 9, resulting in an Ile----Asn substitution. This mutation interrupted contiguous hydrophobic residues and was predicted to transform a region of beta-sheet structure to a random-coil structure. Prokaryotic expression of the normal and mutant cDNAs revealed that the mutant construct expressed low levels of enzymatic activity that required higher concentrations of pyridoxal 5'-phosphate to achieve maximal activation than did the normal enzyme. The amino acid substitution occurred in the exon containing the putative pyridoxal 5'-phosphate binding site and may account for the reduced ability of the cofactor to catalyze the formation of delta-aminolevulinic acid.

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Selected References

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