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Candidate gene mutation analysis in idiopathic acquired sideroblastic anemia (refractory anemia with ringed
David P Steensma1, Kathleen A Hecksel, Julie C Porcher
1Division of Hematology, Department of Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. Steensma.david@mayo.edu
Background:
For most cases of idiopathic acquired sideroblastic anemia (IASA), the molecular pathogenesis is unknown, despite the consistent morphological signature of abundant pathological ringed sideroblasts with their characteristic iron-engorged mitochondria. Moderately elevated free erythrocyte protoporphyrin (FEP) levels have been described in IASA, suggesting that the activity of ferrochelatase, the enzyme that catalyzes the final step in heme biosynthesis (incorporation of ferrous iron into protoporphyrin), might be diminished in erythroid progenitor cells from IASA patients.
Methods:
We confirmed FEP elevation in IASA, then pursued a candidate gene approach that included screening the gene encoding ferrochelatase, FECH, for promoter and coding region mutations and mRNA expression changes in bone marrow from 37 patients with IASA.
Results:
The analytical techniques employed detected mutations in a test cohort of previously undiagnosed patients with biochemical evidence for erythropoietic protoporphyria, a condition resulting from germline mutations in FECH, but somatic missense mutations of FECH and its promoter were not observed in IASA patients. FECH was modestly overexpressed in progenitor cells from patients with IASA, compared with MDS patients without sideroblasts and healthy controls. In addition, we analyzed ABCB7 and PUS1, genes implicated in congenital sideroblastic anemia syndromes, but again found no coding mutations in acquired cases.
Conclusion:
We conclude that acquired mutations in the factors currently known to cause inherited sideroblastic anemias are uncommon in IASA.
Insights
The molecular causes of idiopathic acquired sideroblastic anemia (IASA) remain unclear. This study found no acquired mutations in known inherited sideroblastic anemia genes, suggesting other factors are involved.
Area of Science:
- Hematology
- Molecular Biology
- Genetics
Background:
- Idiopathic acquired sideroblastic anemia (IASA) is characterized by ringed sideroblasts and unknown molecular pathogenesis.
- Elevated free erythrocyte protoporphyrin (FEP) suggests potential ferrochelatase deficiency in IASA.
Purpose of the Study:
- To investigate the molecular basis of IASA by examining genes involved in heme biosynthesis and congenital sideroblastic anemias.
- To screen for mutations and expression changes in the ferrochelatase gene (FECH) in IASA patients.
Main Methods:
- Confirmed elevated FEP levels in IASA patients.
- Screened the FECH gene (promoter and coding regions) for mutations and analyzed mRNA expression in bone marrow from 37 IASA patients.
- Analyzed ABCB7 and PUS1 genes for mutations.
Main Results:
- No somatic missense mutations in FECH or its promoter were found in IASA patients.
- FECH was modestly overexpressed in IASA progenitor cells compared to controls.
- No coding mutations in ABCB7 or PUS1 were identified in acquired cases.
Conclusions:
- Acquired mutations in genes causing inherited sideroblastic anemias are rare in IASA.
- The molecular pathogenesis of IASA likely involves mechanisms beyond mutations in currently identified genes for inherited forms.
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