A novel 5′ ATRX mutation with splicing consequences in acquired α thalassemia-myelodysplastic syndrome

Maria E. Nelson, Paul J. Thurmes, James D. Hoyer, David P. Steensma

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


Background and Objectives. Acquired α thalassemia (hemoglobin H (HbH) disease) is a rare complication of neoplastic chronic myeloid disorders, especially myelodysplastic syndrome. Acquired HbH has recently been associated with mutations in an X-linked gene, ATRX, previously linked to inherited ATR-X syndrome (α thalassemia-retardation-X linked). Design and Methods. A Swiss man with chronic myelomonocytic leukemia complicated by various autoimmune disorders and by strikingly microcytic, hypochromic anemia was analyzed for the presence of acquired HbH. After HbH detection, we sought an underlying genetic cause. We used denaturing high-performance liquid chromatography to screen for an ATRX mutation, and measured ATRX expression by reverse transcriptase polymerase chain reaction. Results. The patient had 50% HbH-containing cells on supravital staining. Marrow karyotype and the α globin cluster were normal. A clonally-restricted ATRX point mutation was detected in the conserved splice donor motif in intron 4 (IVS 4 +2 T→C). Plasmid vector cloning of patient ATRX cDNA demonstrated both exon 4 skipping and partial intron retention with activation of a cryptic splice site, both outcomes resulting in frameshifts with premature stop codon generation in exon 5 and near-decimation of ATRX expression in myeloid cells. Normal exon 6 alternative splicing was retained. Interpretation and Conclusions, Intronic ATRX mutations with splicing consequences, uncommon in inherited ATR-X syndrome because of their devastating effect on expression of functional protein, should be routinely sought when undertaking molecular analysis of acquired HbH disease. Detection of an acquired ATRX mutation can help support clonality in karyotypically normal ambiguous myeloid disorders with HbH.

Original languageEnglish (US)
Pages (from-to)1463-1470
Number of pages8
Issue number11
StatePublished - Nov 2005


  • Acquired hemoglobinopathy
  • Myelodysplastic syndrome
  • Splicing
  • α thalassemia

ASJC Scopus subject areas

  • Hematology


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