Alpha-Thalassemia Myelodysplasia Syndrome

A number sign (#) is used with this entry because of evidence that this phenotype is caused in many cases by mutation in the chromatin-remodeling factor ATRX (300032), which is mutant in the alpha-thalassemia/mental retardation syndrome (301040) and in certain other X-linked mental retardation syndromes.

Clinical Features

Alpha-thalassemia is a common inherited form of anemia that usually results from deletion of 1 or more of the duplicated alpha-globin genes on chromosome 16 (Higgs et al., 1989). A mild form of alpha-thalassemia is also associated with a variety of developmental abnormalities in a rare, severe form of X-linked mental retardation (301040).

In the alpha-thalassemia myelodysplasia syndrome, alpha-thalassemia occurs as an acquired abnormality in association with a multilineage myelodysplasia. Gibbons et al. (2003) stated that 71 such individuals had been identified, of whom 62 (87%) were males who had a de novo, acquired form of alpha-thalassemia with hypochromic microcytic anemia. A reduction in alpha-globin expression leads to an excess of beta-globin chains, which form an abnormal hemoglobin, HbH (beta-4), which is readily detectable in peripheral blood.

Gibbons et al. (2003) demonstrated by gene expression studies using a microarray technique and RT-PCR that ATRX (300032) expression in granulocytes was 3 to 4% of that in normal controls.

Molecular Genetics

Inherited mutations of specific genes have elucidated the normal roles of the proteins they encode by relating specific mutations to particular phenotypes. However, many potentially informative mutations in such genes are lethal early in development. Consequently, inherited mutations may not reflect all the functional roles of such proteins. Acquired, somatic defects reflect a wider spectrum of mutations because they are not prone to negative selection in development. It had been difficult to identify such mutations; microarray analysis provided a new opportunity to identify mutations and was the method used by Gibbons et al. (2003) in studying the relationship to the large (300 kb) ATRX gene in myelodysplasia associated with alpha-thalassemia (ATMDS). The ATRX gene encodes a member of the SWI2/SNF2 family of proteins. Like other members of this group, multiprotein complexes isolated by ATRX antibodies have ATP-dependent nucleosome-remodeling and DNA translocase activities in vitro. ATRX is a nuclear protein that localizes to nuclear subcompartments called PML bodies and to pericentromeric heterochromatin, where it interacts with a component of heterochromatin, HP1. Sequence analysis identified specific somatic mutations in the ATRX gene in granulocytes or bone marrow cells that were absent in buccal cells and a lymphoblastoid cell line.