PMID: 9542324May 16, 1998Paper

The molecular biology and pyridoxine responsiveness of X-linked sideroblastic anaemia

Haematologica
A May, David F Bishop

Abstract

Pyridoxine-responsive, X-linked sideroblastic anaemia (XLSA) has been shown to be caused by missense mutations in the erythroid-specific ALA synthase gene, ALAS2. These are scattered widely across the part of the gene encoding the catalytic domain and in half the cases affect residues conserved throughout evolution. Only a loose correlation has been found between the in vitro kinetics and stability of the catalytic activity of the recombinant variant enzymes and the in vivo severity and pyridoxine-responsiveness of the anaemia. Enhanced instability in the absence of pyridoxal phosphate (PLP) or decreased PLP and substrate binding have been noted. A detailed explanation of the anaemia and its response to pyridoxine, however, requires greater insight into the structure-function relationships of this protein than we have at present. Knowledge of its tertiary structure and further knowledge of intracellular factors which impinge on the ability of normal and variant ALAS2 to contribute to haemoglobin production are also required. Mutations in the same gene which affect mitochondrial processing, terminate translation prematurely, or are thought to abolish function altogether cause an XLSA that is refractory to treatment with pyridoxi...Continue Reading

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