Deficiency of Sbds in the Mouse Pancreas Leads to Features of Shwachman–Diamond Syndrome, With Loss of Zymogen Granules
| Autor: | Peter R. Durie, Siyi Zhang, Jian Zhong, Rikesh Gandhi, Marina E. Tourlakis, Lingling Chen, Johanna M. Rommens |
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| Rok vydání: | 2012 |
| Předmět: |
Ribosomopathy
Pancreatic Extracts Cre recombinase Biology Real-Time Polymerase Chain Reaction Mice medicine Animals Lipomatosis Allele Bone Marrow Diseases Genetic Association Studies Mice Knockout Enzyme Precursors Shwachman–Diamond syndrome Hepatology Secretory Vesicles Gastroenterology Proteins SBDS medicine.disease Zymogen granule Molecular biology Pancreas Exocrine Shwachman-Diamond Syndrome Disease Models Animal medicine.anatomical_structure Cancer research Exocrine Pancreatic Insufficiency Pancreas Biomarkers |
| Zdroj: | Gastroenterology. 143:481-492 |
| ISSN: | 0016-5085 |
| DOI: | 10.1053/j.gastro.2012.04.012 |
| Popis: | Background & Aims 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. |
| Databáze: | OpenAIRE |
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