Impaired ribosomal subunit association in Shwachman-Diamond syndrome

Blood. 2012 Dec 20;120(26):5143-52. doi: 10.1182/blood-2012-04-420166. Epub 2012 Oct 31.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bone Marrow Cells / drug effects
  • Bone Marrow Cells / metabolism
  • Bone Marrow Cells / pathology
  • Bone Marrow Diseases / genetics
  • Bone Marrow Diseases / metabolism*
  • Bone Marrow Diseases / pathology
  • Cells, Cultured
  • Eukaryotic Initiation Factors / genetics
  • Eukaryotic Initiation Factors / metabolism
  • Eukaryotic Initiation Factors / physiology
  • Exocrine Pancreatic Insufficiency / genetics
  • Exocrine Pancreatic Insufficiency / metabolism*
  • Exocrine Pancreatic Insufficiency / pathology
  • Gene Knockdown Techniques
  • Hematopoiesis / drug effects
  • Hematopoiesis / genetics
  • Hematopoiesis / physiology
  • Humans
  • Infant, Newborn
  • Lipomatosis / genetics
  • Lipomatosis / metabolism*
  • Lipomatosis / pathology
  • Protein Binding / drug effects
  • Protein Binding / genetics
  • Protein Multimerization / drug effects
  • Protein Multimerization / genetics
  • Protein Multimerization / physiology
  • Proteins / genetics
  • Proteins / metabolism
  • Proteins / physiology
  • RNA, Small Interfering / pharmacology
  • Ribosome Subunits / metabolism*
  • Shwachman-Diamond Syndrome
  • Stromal Cells / drug effects
  • Stromal Cells / metabolism
  • Stromal Cells / pathology
  • Transfection

Substances

  • EIF6 protein, human
  • Eukaryotic Initiation Factors
  • Proteins
  • RNA, Small Interfering
  • SBDS protein, human