<p>Ribosomal proteins are components of the ribosome, the protein synthesis machinery. The ribosomal protein S19 gene (<i>RPS19</i>) 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.</p><p>A genetic analysis of <i>RPS19</i> in 24 DBA cases was performed. Four novel <i>RPS19</i> mutations were identified with evidence of wide clinical expression of the disease.</p><p>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 <i>RPS19</i> gene region. Coding exons of <i>RPS19</i> 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 <i>RPS19</i> and TEC. </p><p>To investigate the role of RPS19 in erythropoiesis in a mammal, we created a mouse model for the targeted disruption of the homologue <i>Rps19</i> on the C57BL/6J genetic background. Null mutants are embryonic lethal prior to implantation. The <i>Rps19</i><sup>+/-</sup> mice, however, are viable with normal development including the hematopoietic system. The <i>Rps19</i> transcript level in <i>Rps19</i><sup>+/-</sup> mice is normal. Accordingly, RPS19 protein levels are similar in <i>Rps19</i><sup>+/-</sup> and <i>Rps19</i><sup>+/+</sup> mice. This argues for a transcriptional up-regulation to compensate for the loss of one <i>Rps19</i> allele. </p><p>Peripheral blood is normal in <i>Rps19</i><sup>+/-</sup> mice also on the FVB/NJ strain which argues against strain-specific effects of the <i>Rps19</i> disruption. Preliminary results indicate a reduced erythroid proliferation in response to erythropoietin in <i>Rps19</i><sup>+/-</sup> mice, suggesting the requirement of both <i>Rps19</i> alleles for normal erythroid proliferation under stress. This would support a mechanism by which haplo-insufficiency for RPS19 causes DBA.</p>
| Identifer | oai:union.ndltd.org:UPSALLA/oai:DiVA.org:uu-4283 |
| Date | January 2004 |
| Creators | Matsson, Hans |
| Publisher | Uppsala University, Department of Genetics and Pathology, Uppsala : Acta Universitatis Upsaliensis |
| Source Sets | DiVA Archive at Upsalla University |
| Language | English |
| Detected Language | English |
| Type | Doctoral thesis, comprehensive summary, text |
| Relation | Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, 0282-7476 ; 1356 |
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