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Acquired somatic mutations in ATRX, an X-linked gene encoding a chromatin-associated protein, were recently identified in 4 patients with the rare subtype of myelodysplastic syndrome (MDS) associated with thalassemia (ATMDS). Here we describe a series of novel point mutations in ATRX detected in archival DNA samples from marrow and/or blood of patients with ATMDS by use of denaturing high-performance liquid chromatography (DHPLC), a technique sensitive to low-level mosaicism. Two of the new mutations result in changes in amino acids altered in previously described pedigrees with germ line ATRX mutations (ATR-X syndrome), but the hematologic abnormalities were much more severe in the patients with ATMDS than in the corresponding constitutional cases. In one ATMDS case where DNA samples from several time points were available, the proportion of ATRX-mutant subclones correlated with changes in the amount of hemoglobin H. This study strengthens the link between acquired, somatic ATRX mutations and ATMDS, illustrates how molecular defects associated with MDS and other hematologic malignancies masked by somatic mosaicism may be detected by DHPLC, and shows that additional factors increase the severity of the hematologic phenotype of ATRX mutations in ATMDS.

Original publication

DOI

10.1182/blood-2003-09-3360

Type

Journal article

Journal

Blood

Publication Date

15/03/2004

Volume

103

Pages

2019 - 2026

Keywords

Aged, Aged, 80 and over, DNA Helicases, DNA Mutational Analysis, Erythroid Precursor Cells, Female, Germ-Line Mutation, Humans, Male, Middle Aged, Mosaicism, Myelodysplastic Syndromes, Nuclear Proteins, Phenotype, RNA Splicing, Severity of Illness Index, alpha-Thalassemia