Acinar cell apoptosis in Serpini2-deficient mice models pancreatic insufficiency.
Pancreatic insufficiency (PI) when left untreated results in a state of malnutrition due to an inability to absorb nutrients. Frequently, PI is diagnosed as part of a larger clinical presentation in cystic fibrosis or Shwachman-Diamond syndrome. In this study, a mouse model for isolated exocrine PI...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2005-09-01
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| Series: | PLoS Genetics |
| Online Access: | http://europepmc.org/articles/PMC1231717?pdf=render |
| _version_ | 1811261772849479680 |
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| author | Stacie K Loftus Jennifer L Cannons Arturo Incao Evgenia Pak Amy Chen Patricia M Zerfas Mark A Bryant Leslie G Biesecker Pamela L Schwartzberg William J Pavan |
| author_facet | Stacie K Loftus Jennifer L Cannons Arturo Incao Evgenia Pak Amy Chen Patricia M Zerfas Mark A Bryant Leslie G Biesecker Pamela L Schwartzberg William J Pavan |
| author_sort | Stacie K Loftus |
| collection | DOAJ |
| description | Pancreatic insufficiency (PI) when left untreated results in a state of malnutrition due to an inability to absorb nutrients. Frequently, PI is diagnosed as part of a larger clinical presentation in cystic fibrosis or Shwachman-Diamond syndrome. In this study, a mouse model for isolated exocrine PI was identified in a mouse line generated by a transgene insertion. The trait is inherited in an autosomal recessive pattern, and homozygous animals are growth retarded, have abnormal immunity, and have reduced life span. Mice with the disease locus, named pequeño (pq), exhibit progressive apoptosis of pancreatic acinar cells with severe exocrine acinar cell loss by 8 wk of age, while the islets and ductal tissue persist. The mutation in pq/pq mice results from a random transgene insertion. Molecular characterization of the transgene insertion site by fluorescent in situ hybridization and genomic deletion mapping identified an approximately 210-kb deletion on Chromosome 3, deleting two genes. One of these genes, Serpini2, encodes a protein that is a member of the serpin family of protease inhibitors. Reintroduction of only the Serpini2 gene by bacterial artificial chromosome transgenic complementation corrected the acinar cell defect as well as body weight and immune phenotypes, showing that deletion of Serpini2 causes the pequeño phenotype. Dietary supplementation of pancreatic enzymes also corrected body size, body weight, and immunodeficiency, and increased the life span of Serpini2-deficient mice, despite continued acinar cell loss. To our knowledge, this study describes the first characterized genetic animal model for isolated PI. Genetic complementation of the transgene insertion mutant demonstrates that Serpini2 deficiency directly results in the acinar cell apoptosis, malabsorption, and malnutrition observed in pq/pq mice. The rescue of growth retardation, immunodeficiency, and mortality by either Serpini2 bacterial artificial chromosome transgenic expression or by pancreatic enzyme supplementation demonstrates that these phenotypes are secondary to malnutrition in pq/pq mice. |
| first_indexed | 2024-04-12T19:11:52Z |
| format | Article |
| id | doaj.art-f13be4f3d65346edb621ed972debd48e |
| institution | Directory Open Access Journal |
| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-04-12T19:11:52Z |
| publishDate | 2005-09-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj.art-f13be4f3d65346edb621ed972debd48e2022-12-22T03:19:52ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042005-09-0113e3810.1371/journal.pgen.0010038Acinar cell apoptosis in Serpini2-deficient mice models pancreatic insufficiency.Stacie K LoftusJennifer L CannonsArturo IncaoEvgenia PakAmy ChenPatricia M ZerfasMark A BryantLeslie G BieseckerPamela L SchwartzbergWilliam J PavanPancreatic insufficiency (PI) when left untreated results in a state of malnutrition due to an inability to absorb nutrients. Frequently, PI is diagnosed as part of a larger clinical presentation in cystic fibrosis or Shwachman-Diamond syndrome. In this study, a mouse model for isolated exocrine PI was identified in a mouse line generated by a transgene insertion. The trait is inherited in an autosomal recessive pattern, and homozygous animals are growth retarded, have abnormal immunity, and have reduced life span. Mice with the disease locus, named pequeño (pq), exhibit progressive apoptosis of pancreatic acinar cells with severe exocrine acinar cell loss by 8 wk of age, while the islets and ductal tissue persist. The mutation in pq/pq mice results from a random transgene insertion. Molecular characterization of the transgene insertion site by fluorescent in situ hybridization and genomic deletion mapping identified an approximately 210-kb deletion on Chromosome 3, deleting two genes. One of these genes, Serpini2, encodes a protein that is a member of the serpin family of protease inhibitors. Reintroduction of only the Serpini2 gene by bacterial artificial chromosome transgenic complementation corrected the acinar cell defect as well as body weight and immune phenotypes, showing that deletion of Serpini2 causes the pequeño phenotype. Dietary supplementation of pancreatic enzymes also corrected body size, body weight, and immunodeficiency, and increased the life span of Serpini2-deficient mice, despite continued acinar cell loss. To our knowledge, this study describes the first characterized genetic animal model for isolated PI. Genetic complementation of the transgene insertion mutant demonstrates that Serpini2 deficiency directly results in the acinar cell apoptosis, malabsorption, and malnutrition observed in pq/pq mice. The rescue of growth retardation, immunodeficiency, and mortality by either Serpini2 bacterial artificial chromosome transgenic expression or by pancreatic enzyme supplementation demonstrates that these phenotypes are secondary to malnutrition in pq/pq mice.http://europepmc.org/articles/PMC1231717?pdf=render |
| spellingShingle | Stacie K Loftus Jennifer L Cannons Arturo Incao Evgenia Pak Amy Chen Patricia M Zerfas Mark A Bryant Leslie G Biesecker Pamela L Schwartzberg William J Pavan Acinar cell apoptosis in Serpini2-deficient mice models pancreatic insufficiency. PLoS Genetics |
| title | Acinar cell apoptosis in Serpini2-deficient mice models pancreatic insufficiency. |
| title_full | Acinar cell apoptosis in Serpini2-deficient mice models pancreatic insufficiency. |
| title_fullStr | Acinar cell apoptosis in Serpini2-deficient mice models pancreatic insufficiency. |
| title_full_unstemmed | Acinar cell apoptosis in Serpini2-deficient mice models pancreatic insufficiency. |
| title_short | Acinar cell apoptosis in Serpini2-deficient mice models pancreatic insufficiency. |
| title_sort | acinar cell apoptosis in serpini2 deficient mice models pancreatic insufficiency |
| url | http://europepmc.org/articles/PMC1231717?pdf=render |
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