Genetic variants in the noncoding region of RPS19 gene in Diamond‐Blackfan anemia: Potential implications for phenotypic heterogeneity |
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| Authors: | Aurore Crétien Alexis Proust Jean Delaunay Patricia Rincé Thierry Leblanc Rolande Ducrocq Maud Simansour Isabelle Marie Hannah Tamary Jörg Meerpohl Charlotte Niemeyer Hanna Gazda Colin Sieff Sarah Ball Gil Tchernia Narla Mohandas Lydie Da Costa |
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| Affiliation: | 1. INSERM U790, Villejuif, France;2. AP‐HP, Le Kremlin‐Bicêtre, France;3. INSERM U779, Faculté de médecine Paris‐Sud, Univ Paris‐sud, Kremlin‐Bic?tre, France;4. AP‐HP, H?pital Saint‐Louis, Paris, France;5. AP‐HP, H?pital Robert Debré, Paris, France;6. Department of Hematology and Oncology, Schneider Children's Medical Center of Israel, Petah Tikva, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel;7. Division of Pediatric Hematology & Oncology, Department of Pediatrics, University Medical Center, and German Cochrane Center, Institute Medical Biometry and Medical Informatics, University Medical Center, Freiburg, Germany;8. Division of Genetics, Children's Hospital Boston, Boston, Massachusetts;9. Harvard Medical School, Boston, Massachusetts;10. St. Georges University of London, London, England;11. Centre d'information et de dépistage de la drépanocytose, Paris, France;12. Red Cell Physiology laboratory, New York Blood Center, New York, New York;13. Univ Paris VII, Denis Diderot, Paris, France |
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| Abstract: | Mutations in the RPS19 gene have been identified in 25% of individuals affected by Diamond‐Blackfan anemia (DBA), a congenital erythroblastopenia characterized by an aregenerative anemia and a variety of malformations. More than 60 mutations in the five coding exons of RPS19 have been described to date. We previously reported a mutation (c.‐1 + 26G>T) and an insertion at ?631 upstream of ATG (c.‐147_‐146insGCCA) in the noncoding region. Because DBA phenotype is extremely heterogeneous from silent to severe and because haploinsufficiency seems to play a role in this process, it is likely that genetic variations in the noncoding regions affecting translation of RPS19 can modulate the phenotypic expression of DBA. However, to date, very few studies have addressed this question comprehensively. In this study, we performed detailed sequence analysis of the RPS19 gene in 239 patients with DBA and 110 of their relatives. We found that 6.2% of the patients with DBA carried allelic variations upstream of ATG: 3.3% with c.‐1 + 26G>T; 2.5% with c.‐147_‐146insGCCA; and 0.4% with c.‐174G>A. Interestingly, the c.‐147_‐146insGCCA, which has been found in a black American and French Caribbean control population, was not found in 500 Caucasian control chromosomes we studied. However, it was found in association with the same haplotype distribution of four intronic polymorphisms in our patients with DBA. Although a polymorphism, the frequency of this variant in the patients with DBA and its association with the same haplotype raises the possibility that this polymorphism and the other genetic variations in the noncoding region could play a role in DBA pathogenesis. Am. J. Hematol., 2010. © 2009 Wiley‐Liss, Inc. |
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