title: Deficiency of Sbds in the mouse pancreas leads to features of Shwachman-Diamond syndrome, with loss of zymogen granules.
abstract: OBJECTIVE
  Shwachman-Diamond syndrome (SDS) is the second leading cause of hereditary exocrine pancreatic dysfunction. More than 90% of patients with SDS have biallelic loss-of-function mutations in the Shwachman-Bodian Diamond syndrome (SBDS) gene, which encodes a factor involved in ribosome function. We investigated whether mutations in Sbds lead to similar pancreatic defects in mice.
  
  
  METHODS
  Pancreas-specific knock-out mice were generated using a floxed Sbds allele and bred with mice carrying a null or disease-associated missense Sbds allele. Cre recombinase, regulated by the pancreatic transcription factor 1a promoter, was used to disrupt Sbds specifically in the pancreas. Models were assessed for pancreatic dysfunction and growth impairment.
  
  
  RESULTS
  Disruption of Sbds in the mouse pancreas was sufficient to recapitulate SDS phenotypes. Pancreata of mice with Sbds mutations had decreased mass, fat infiltration, but general preservation of ductal and endocrine compartments. Pancreatic extracts from mutant mice had defects in formation of the 80S ribosomal complex. The exocrine compartment of mutant mice was hypoplastic and individual acini produced few zymogen granules. The null Sbds allele resulted in an earlier onset of phenotypes as well as endocrine impairment. Mutant mice had reduced serum levels of digestive enzymes and overall growth impairment.
  
  
  CONCLUSIONS
  We developed a mouse model of SDS with pancreatic phenotypes similar to those of the human disease. This model could be used to investigate organ-specific consequences of Sbds-associated ribosomopathy. Sbds genotypes correlated with phenotypes. Defects developed specifically in the pancreata of mice, reducing growth of mice and production of digestive enzymes. SBDS therefore appears to be required for normal pancreatic development and function.
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Marina E
authors.initials: ME
authors.lastname: Tourlakis
authors.forename: Jian
authors.initials: J
authors.lastname: Zhong
authors.forename: Rikesh
authors.initials: R
authors.lastname: Gandhi
authors.forename: Siyi
authors.initials: S
authors.lastname: Zhang
authors.forename: Lingling
authors.initials: L
authors.lastname: Chen
authors.forename: Peter R
authors.initials: PR
authors.lastname: Durie
authors.forename: Johanna M
authors.initials: JM
authors.lastname: Rommens
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001855:Bone Marrow Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D004792:Enzyme Precursors / Q000378:metabolism*; D010188:Exocrine Pancreatic Insufficiency / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D056726:Genetic Association Studies; D008068:Lipomatosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D046790:Pancreas, Exocrine / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D022142:Secretory Vesicles / Q000378:metabolism*; D000081003:Shwachman-Diamond Syndrome
chemical_list: D015415:Biomarkers; D004792:Enzyme Precursors; D011506:Proteins; C513661:Sbds protein, mouse