uu.seUppsala University Publications
Change search
ReferencesLink to record
Permanent link

Direct link
Ribosomal protein S19 binds to its own mRNA with reduced affinity in Diamond-Blackfan anemia
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.ORCID iD: 0000-0002-4383-9880
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
Show others and affiliations
2010 (English)In: Blood Cells, Molecules & Diseases, ISSN 1079-9796, E-ISSN 1096-0961, Vol. 45, no 1, 23-28 p.Article in journal (Refereed) Published
Abstract [en]

Heterozygous mutations in the ribosomal protein S19 (RPS19) gene are associated with Diamond-Blackfan anemia (DBA). The mechanism by which RPS19 mediates anemia are still unclear, as well as the regulation of RPS19 expression. We show herein that RPS19 binds specifically to the 5' untranslated region of its own mRNA with an equilibrium binding constant (K(D)) of 4.1+/-1.9 nM. We investigated the mRNA binding properties of two mutant RPS19 proteins (W52R and R62W) identified in DBA patients. We observed a significant increase in K(D) for both proteins (16.1+/-2.1 and 14.5+/-4.9 nM, respectively), indicating a reduced RNA binding capability (p<0.05). We suggest that the binding of RPS19 to its mRNA has a regulatory function and hypothesize that the weaker RNA binding of mutant rRPS19 may have implications for the pathophysiological mechanisms in DBA.

Place, publisher, year, edition, pages
Elsevier , 2010. Vol. 45, no 1, 23-28 p.
National Category
Medical Genetics Biochemistry and Molecular Biology
URN: urn:nbn:se:uu:diva-127207DOI: 10.1016/j.bcmd.2010.03.007ISI: 000278480600004PubMedID: 20395159OAI: oai:DiVA.org:uu-127207DiVA: diva2:329218
Available from: 2010-07-08 Created: 2010-07-08 Last updated: 2016-09-09Bibliographically approved
In thesis
1. Molecular Studies of Diamond-Blackfan Anemia and Congenital Nail Dysplasia
Open this publication in new window or tab >>Molecular Studies of Diamond-Blackfan Anemia and Congenital Nail Dysplasia
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The aim of this thesis is to investigate the effect of genetic mutations on the pathophysiology of two human disorders: Diamond-Blackfan Anemia (DBA) and isolated congenital nail dysplasia.

The first part of this thesis (Paper I-III) investigates the mechanism associated with DBA. DBA is a rare bone marrow failure syndrome characterized by the absence or decrease of erythroid precursor cells. The disease is further associated with growth retardation, malformations, predisposition to malignant disease and heterozygous mutations in ribosomal protein (RP) genes. The second part of this thesis (Paper IV) investigates the genetic basis of isolated autosomal recessive nail dysplasia characterized by pachyonychia and onycholysis of both finger- and toenails. It further dissects the molecular mechanisms regulating nail development.

In the first study, we investigated the previously reported RPS19/PIM-1 interaction by generating a combined Rps19/Pim-1 knockout mouse model. We found that allelic Rps19 insufficiency and Pim-1 deficiency have a cooperative effect on murine hematopoiesis resulting in increased myeloid cellularity associated with cell cycle alterations and reduced apoptosis. In the second study, we analyzed primary fibroblasts from DBA patients with truncating mutations in RPS19 or RPS24 and observed a marked delay in cellular growth associated with specific cell cycle defects. In the third study, we discovered that recombinant RPS19 binds its own mRNA and that the binding is altered when two DBA-associated RPS19 mutations are introduced. In the fourth study, we identified mutations in the WNT signaling receptor Frizzled 6 (FZD6). We observed that the nonsense mutant fails to interact with the first downstream effector Dishevelled. Fzd6 mutant mice displayed claw malformations and we detected a transient Fzd6 expression in the distal digits at the embryonic time point for nail development.

In summary, this thesis elucidates several mechanisms in the etiology of DBA and congenital nail dysplasia and mechanisms regulating nail development.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsalaiensis, 2010. 65 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 579
Diamond-Blackfan Anemia, RPS19, RPS24, PIM-1, Erythropoiesis, Cell cycle, Apoptosis, Nail dysplasia, FZD6, WNT signaling
National Category
Medical Genetics
urn:nbn:se:uu:diva-128067 (URN)978-91-554-7849-0 (ISBN)
Public defence
2010-09-17, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjöldsv. 20, Uppsala, 09:15 (English)
Available from: 2010-08-27 Created: 2010-07-19 Last updated: 2010-08-30

Open Access in DiVA

No full text

Other links

Publisher's full textPubMed

Search in DiVA

By author/editor
Schuster, Jens
By organisation
Department of Genetics and PathologyDepartment of Cell and Molecular Biology
In the same journal
Blood Cells, Molecules & Diseases
Medical GeneticsBiochemistry and Molecular Biology

Search outside of DiVA

GoogleGoogle Scholar
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Altmetric score

Total: 192 hits
ReferencesLink to record
Permanent link

Direct link