Institut Cochin, département GDPM, faculté de médecine Cochin, 24 rue du faubourg St-Jacques, 75014 Paris
- Key words: α-thalassemia, ATRX, gene
- Page(s) : 229-38
- Published in: 2006
The word ATRX was initially used in 1990 to characterize a mental retardation syndrome including α-thalassemia among various other features. Both α-globin locus were found normal, and troubles were referred to mutations of a gene located on the long arm of the X chromosome, and called therefore ATRX. The gene, covering 300 kb and composed of 36 exons is encoding a protein belonging to the SNF2 family, with two functionally important domains: at the N-terminal a zinc finger domain, in the central part a helicase domain. Several isoforms and alternative splicings have been demonstrated for the wild protein as well as in variants. This likely explains why nul mutants have never been found, they could be lethal. The mechanism of action is only partially understood. The ATRX protein is involved in multimolecular complexes and chromatin remodeling, the precision of which could be critical. In entirely different circumstances an acquired α-thalassemia has been described in elderly people during malignancies. In 1978 the ATMDS was systematically described as an association of α-thalassemia and myelodysplasia, without mutations of the α-globin locus. Mutations of the ATRX gene were described in 1993, and other such somatic mutations found since then. It is remarkable that the site of these clonal mutations is similar to those of the innate ATRX syndrome, clustered in the two important functional PHD and helicase domains. In few cases the same mutation was found in both series. The observed hematologic phenotype is always more severe in the acquired form than in the innate one, suggesting that a myelodysplastic context could amplify the deleterious effect of the ATRX gene mutations. The mechanisms involved are presently hypothetical and require further investigation.