title: Impaired ribosomal subunit association in Shwachman-Diamond syndrome.
abstract: Shwachman-Diamond syndrome (SDS) is an autosomal-recessive marrow failure syndrome with a predisposition to leukemia. SDS patients harbor biallelic mutations in the SBDS gene, resulting in low levels of SBDS protein. Data from nonhuman models demonstrate that the SBDS protein facilitates the release of eIF6, a factor that prevents ribosome joining. The complete abrogation of Sbds expression in these models results in severe cellular and lethal physiologic abnormalities that differ from the human disease phenotype. Because human SDS cells are characterized by partial rather than complete loss of SBDS expression, we interrogated SDS patient cells for defects in ribosomal assembly. SDS patient cells exhibit altered ribosomal profiles and impaired association of the 40S and 60S subunits. Introduction of a wild-type SBDS cDNA into SDS patient cells corrected the ribosomal association defect, while patient-derived SBDS point mutants only partially improved subunit association. Knockdown of eIF6 expression improved ribosomal subunit association but did not correct the hematopoietic defect of SBDS-deficient cells. In summary, we demonstrate an SBDS-dependent ribosome maturation defect in SDS patient cells. The role of ribosomal subunit joining in marrow failure warrants further investigation.
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Burwick
authors.forename: Scott A
authors.initials: SA
authors.lastname: Coats
authors.forename: Tomoka
authors.initials: T
authors.lastname: Nakamura
authors.forename: Akiko
authors.initials: A
authors.lastname: Shimamura
mesh_terms: D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001855:Bone Marrow Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D039642:Eukaryotic Initiation Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D010188:Exocrine Pancreatic Insufficiency / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D055785:Gene Knockdown Techniques; D006410:Hematopoiesis / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D006801:Humans; D007231:Infant, Newborn; D008068:Lipomatosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D055503:Protein Multimerization / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D011506:Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D034741:RNA, Small Interfering / Q000494:pharmacology; D054657:Ribosome Subunits / Q000378:metabolism*; D000081003:Shwachman-Diamond Syndrome; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014162:Transfection
chemical_list: C109284:EIF6 protein, human; D039642:Eukaryotic Initiation Factors; D011506:Proteins; D034741:RNA, Small Interfering; C470521:SBDS protein, human