Ribosomal Protein L5 and L11 Mutations Are Associated with Cleft Palate and Abnormal Thumbs in Diamond-Blacktan Anemia Patients

Diamond-Blackfan anemia (DBA), a congenital bone-marrow-failure syndrome, is characterized by red blood cell aplasia, macrocytic anemia, clinical heterogeneity, and increased risk of malignancy. Although anemia is the most prominent feature of DBA, the disease is also characterized by growth retarda...

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Published in:American journal of human genetics 2008-12, Vol.83 (6), p.769
Main Authors: Gazda, Hanna T, Sheen, Mee Rie, Vlachos, Adrianna, Choesmel, Valerie, O'Donohue, Marie-Françoise, Schneider, Hal, Darras, Natasha, Hasman, Catherine, Sieff, Colin A, Newburger, Peter E, Ball, Sarah E, Niewiadomska, Edyta, Matysiak, Michal, Zaucha, Jan M, Glader, Bertil, Niemeyer, Charlotte, Meerpohl, Joerg J, Atsidaftos, Eva, Lipton, Jeffrey M, Gleizes, Pierre-Emmanuel, Beggs, Alan H
Format: Article
Language:English
Subjects:
Anemia
Cells
Gene expression
Mutation
Proteins
Ribonucleic acid
RNA
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Summary:Diamond-Blackfan anemia (DBA), a congenital bone-marrow-failure syndrome, is characterized by red blood cell aplasia, macrocytic anemia, clinical heterogeneity, and increased risk of malignancy. Although anemia is the most prominent feature of DBA, the disease is also characterized by growth retardation and congenital anomalies that are present in ~30%-50% of patients. The disease has been associated with mutations in four ribosomal protein (RP) genes, RPS19, RPS24, RPS17, and RPL35A, in about 30% of patients. However, the genetic basis of the remaining 70% of cases is still unknown. Here, we report the second known mutation in RPS17 and probable pathogenic mutations in three more RP genes, RPL5, RPL11, and RPS7. In addition, we identified rare variants of unknown significance in three other genes, RPL36, RPS15, and RPS27A. Remarkably, careful review of the clinical data showed that mutations in RPL5 are associated with multiple physical abnormalities, including craniofacial, thumb, and heart anomalies, whereas isolated thumb malformations are predominantly present in patients carrying mutations in RPL11. We also demonstrate that mutations of RPL5, RPL11, or RPS7 in DBA cells is associated with diverse defects in the maturation of ribosomal RNAs in the large or the small ribosomal subunit production pathway, expanding the repertoire of ribosomal RNA processing defects associated with DBA. [PUBLICATION ABSTRACT]
ISSN:0002-9297
1537-6605