title: Shwachman-Bodian-Diamond syndrome (SBDS) protein deficiency impairs translation re-initiation from C/EBPα and C/EBPβ mRNAs.
abstract: Mutations in the Shwachman-Bodian-Diamond Syndrome (SBDS) gene cause Shwachman-Diamond Syndrome (SDS), a rare congenital disease characterized by bone marrow failure with neutropenia, exocrine pancreatic dysfunction and skeletal abnormalities. The SBDS protein is important for ribosome maturation and therefore SDS belongs to the ribosomopathies. It is unknown, however, if loss of SBDS functionality affects the translation of specific mRNAs and whether this could play a role in the development of the clinical features of SDS. Here, we report that translation of the C/EBPα and -β mRNAs, that are indispensible regulators of granulocytic differentiation, is altered by SBDS mutations or knockdown. We show that SBDS function is specifically required for efficient translation re-initiation into the protein isoforms C/EBPα-p30 and C/EBPβ-LIP, which is controlled by a single cis-regulatory upstream open reading frame (uORF) in the 5' untranslated regions (5' UTRs) of both mRNAs. Furthermore, we show that as a consequence of the C/EBPα and -β deregulation the expression of MYC is decreased with associated reduction in proliferation, suggesting that failure of progenitor proliferation contributes to the haematological phenotype of SDS. Therefore, our study provides the first indication that disturbance of specific translation by loss of SBDS function may contribute to the development of the SDS phenotype.
authors.affiliation: Leibniz Institute on Aging - Fritz Lipmann Institute, Beutenbergstrasse 11, D-07745 Jena, Germany.
authors.forename: Kyungmin
authors.initials: K
authors.lastname: In
authors.affiliation: Leibniz Institute on Aging - Fritz Lipmann Institute, Beutenbergstrasse 11, D-07745 Jena, Germany European Institute for the Biology of Ageing (ERIBA), University Medical Center Groningen, University of Groningen, 9700 AD, Groningen, The Netherlands.
authors.forename: Mohamad A
authors.initials: MA
authors.lastname: Zaini
authors.affiliation: Leibniz Institute on Aging - Fritz Lipmann Institute, Beutenbergstrasse 11, D-07745 Jena, Germany European Institute for the Biology of Ageing (ERIBA), University Medical Center Groningen, University of Groningen, 9700 AD, Groningen, The Netherlands.
authors.forename: Christine
authors.initials: C
authors.lastname: Müller
authors.affiliation: Cambridge Institute for Medical Research, Wellcome Trust-Medical Research Council Stem Cell Institute, the Department of Haematology, University of Cambridge, CB2 0XY, Cambridge, UK.
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Warren
authors.affiliation: Sanquin Research and Landsteiner Laboratory, Department of Hematopoiesis, 1066 CX Amsterdam, The Netherlands.
authors.forename: Marieke
authors.initials: M
authors.lastname: von Lindern
authors.affiliation: Leibniz Institute on Aging - Fritz Lipmann Institute, Beutenbergstrasse 11, D-07745 Jena, Germany European Institute for the Biology of Ageing (ERIBA), University Medical Center Groningen, University of Groningen, 9700 AD, Groningen, The Netherlands c.f.calkhoven@umcg.nl.
authors.forename: Cornelis F
authors.identifier: 0000-0001-6318-7210
authors.initials: CF
authors.lastname: Calkhoven
mesh_terms: D020121:5' Untranslated Regions; D001855:Bone Marrow Diseases / Q000235:genetics / Q000378:metabolism*; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics* / Q000378:metabolism; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D010188:Exocrine Pancreatic Insufficiency / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D005786:Gene Expression Regulation; D006801:Humans; D008068:Lipomatosis / Q000235:genetics / Q000378:metabolism*; D009504:Neutrophils / Q000502:physiology; D010442:Peptide Chain Initiation, Translational; D011506:Proteins / Q000502:physiology*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D000081003:Shwachman-Diamond Syndrome
chemical_list: D020121:5' Untranslated Regions; D022782:CCAAT-Enhancer-Binding Protein-beta; D022762:CCAAT-Enhancer-Binding Proteins; C515848:CEBPA protein, human; C545012:CEBPB protein, human; C489427:MYC protein, human; D011506:Proteins; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; C470521:SBDS protein, human