Published online 24 September 2008
Haematologica, Vol 93, Issue 11, 1617-1626 doi:10.3324/haematol.13359
Copyright © 2008 by Ferrata Storti Foundation
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Original Articles

Enhanced alternative splicing of the FLVCR1 gene in Diamond Blackfan anemia disrupts FLVCR1 expression and function that are critical for erythropoiesis

Michelle A. Rey1,2, Simon P. Duffy1,2, Jennifer K. Brown1,2, James A. Kennedy2,3, John E. Dick2,3, Yigal Dror1, Chetankumar S. Tailor1,2

1 Program in Cell Biology, The Hospital for Sick Children, Toronto, ON
2 Department of Molecular Genetics, University of Toronto, Toronto, ON
3 Division of Cell and Molecular Biology, University Health Network, Suite 8-355 Toronto Medical Discovery Tower, Toronto, ON, Canada

Correspondence: Chetankumar S. Tailor, The Hospital for Sick Children, Program in Cell Biology, Room 7129 Elm Wing, 555 University Avenue, Toronto, ON, M5G 1X8, Canada. E-mail:chetankumar.tailor{at}sickkids.ca

Background: Diamond-Blackfan anemia is a fatal congenital anemia characterized by a specific disruption in erythroid progenitor cell development. Approximately 25% of patients have mutations in the ribosomal protein RPS19 suggesting that Diamond-Blackfan anemia may be caused by a defect in ribosome biogenesis and translation. However, it is unclear how these defects specifically disrupt early erythropoiesis. Recent studies have shown that the retroviral receptor/heme exporter FLVCR1 is critical for early erythropoiesis. FLVCR1 null mice, despite dying in utero and having reduced myeloid and lymphoid cell growth, show a disruption in early erythropoiesis and have craniofacial and limb deformities similar to those found in some Diamond-Blackfan anemia patients.

Design and Methods: In this study, we recapitulated the Diamond-Blackfan anemia hematologic features of reduced erythropoiesis but normal myelopoiesis by disrupting FLVCR1 in human hematopoietic stem cells.

Results: We found that CD71high cells, which are enriched for immature erythroid cells, from Diamond-Blackfan anemia patients negative for RPS19 gene mutations express alternatively spliced isoforms of FLVCR1 transcript which encode proteins whose expression and function are disrupted. More importantly, our results suggest alternative splicing of FLVCR1 is significantly enhanced in Diamond-Blackfan anemia immature erythroid cells. Furthermore, we also observed enhanced FLVCR1 alternative splicing and a dramatic reduction of FLVCR1 protein expression in RPS19 down-regulated human K562 cells, which were used as a model to represent RPS19 gene mutated Diamond-Blackfan anemia.

Conclusions: Taken together, our results suggest enhanced alternative splicing of FLVCR1 transcripts and subsequent FLVCR1 insufficiency as an additional contributing factor to the erythropoietic defect observed in Diamond-Blackfan anemia.

Key words: Diamond-Blackfan anemia, FLVCR1, retroviral receptor, heme exporter, alternative splicing.


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