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Truncating ribosomal protein S19 mutations and variable clinical expression in Diamond-Blackfan anemia
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
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1999 In: Human Genetics, ISSN 0340-6717, Vol. 105, 496-500 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
1999. Vol. 105, 496-500 p.
URN: urn:nbn:se:uu:diva-91836OAI: oai:DiVA.org:uu-91836DiVA: diva2:164695
Available from: 2004-05-14 Created: 2004-05-14Bibliographically approved
In thesis
1. Studies of the Ribosomal Protein S19 in Erythropoiesis
Open this publication in new window or tab >>Studies of the Ribosomal Protein S19 in Erythropoiesis
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Studier av Ribosom-protein S19 i erytropoesen
Abstract [en]

Ribosomal proteins are components of the ribosome, the protein synthesis machinery. The ribosomal protein S19 gene (RPS19) is mutated in Diamond-Blackfan anemia, DBA, which is a rare congenital anemia with absence or reduction of erythroid precursors in bone marrow. In this thesis, the role of RPS19 in erythropoiesis is investigated.

A genetic analysis of RPS19 in 24 DBA cases was performed. Four novel RPS19 mutations were identified with evidence of wide clinical expression of the disease.

Due to the clinical overlap in Transient Erythroblastopenia of Childhood, TEC, and DBA, the two diseases may be caused by a common genetic factor. In a study of seven TEC families, all affected shared at least one parental haplotype in the RPS19 gene region. Coding exons of RPS19 were normal for all affected, although mutations in intronic and regulatory sequences are not excluded. This indicates a genetic factor behind TEC and a possible association between RPS19 and TEC.

To investigate the role of RPS19 in erythropoiesis in a mammal, we created a mouse model for the targeted disruption of the homologue Rps19 on the C57BL/6J genetic background. Null mutants are embryonic lethal prior to implantation. The Rps19+/- mice, however, are viable with normal development including the hematopoietic system. The Rps19 transcript level in Rps19+/- mice is normal. Accordingly, RPS19 protein levels are similar in Rps19+/- and Rps19+/+ mice. This argues for a transcriptional up-regulation to compensate for the loss of one Rps19 allele.

Peripheral blood is normal in Rps19+/- mice also on the FVB/NJ strain which argues against strain-specific effects of the Rps19 disruption. Preliminary results indicate a reduced erythroid proliferation in response to erythropoietin in Rps19+/- mice, suggesting the requirement of both Rps19 alleles for normal erythroid proliferation under stress. This would support a mechanism by which haplo-insufficiency for RPS19 causes DBA.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2004. 39 p.
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1356
Molecular genetics, RPS19, Rps19, erythropoiesis, erythroblastopenia, Diamond-Blackfan, anemia, Genetik
National Category
urn:nbn:se:uu:diva-4283 (URN)91-554-5983-8 (ISBN)
Public defence
2004-06-04, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, 751 85, Uppsala, 09:15
Available from: 2004-05-14 Created: 2004-05-14Bibliographically approved

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