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Acinar cell apoptosis in Serpini2-deficient mice models pancreatic insufficiency.

PLoS genetics | Sep 9, 2005

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.

Pubmed ID: 16184191 RIS Download

Mesh terms: Animals | Apoptosis | Growth Disorders | In Situ Hybridization, Fluorescence | Malnutrition | Mice | Mice, Knockout | Mice, Transgenic | Pancreatic Diseases | Promoter Regions, Genetic | Serpins

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  • Agency: Intramural NIH HHS, Id:

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MapViewer

Database that provides special browsing capabilities for a subset of organisms in Entrez Genomes. Map Viewer allows users to view and search an organism's complete genome, display chromosome maps, and zoom into progressively greater levels of detail, down to the sequence data for a region of interest. If multiple maps are available for a chromosome, it displays them aligned to each other based on shared marker and gene names, and, for the sequence maps, based on a common sequence coordinate system.

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UCSC Genome Browser

A collection of genomes which include reference sequences and working draft assemblies, as well as a variety of tools to explore these sequences. The Genome Browser zooms and scrolls over chromosomes, showing the work of annotators worldwide. The Gene Sorter shows expression, homology and other information on groups of genes that can be related in many ways. Blat quickly maps your sequence to the genome. The Table Browser provides access to the underlying database. VisiGene lets you browse through a large collection of in situ mouse and frog images to examine expression patterns. Genome Graphs allows you to upload and display genome-wide data sets. Also provided is a portal to the Encyclopedia of DNA Elements (ENCODE) and Neandertal projects.

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A portal to biomedical and genomic information. NCBI creates public databases, conducts research in computational biology, develops software tools for analyzing genome data, and disseminates biomedical information for the better understanding of molecular processes affecting human health and disease.

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MGD

An integrated data resource for mouse genetic, genomic, and biological information. MGD includes a variety of data, ranging from gene characterization and genomic structures, to orthologous relationships between mouse genes and those of other mammalian species, to maps (genetic, cytogenetic, physical), to descriptions of mutant phenotypes, to characteristics of inbred strains, to information about biological reagents such as clones and primers. Data are accessed via search/retrieval Web forms and displayed as tables, text, and graphical maps, with supporting primary data. A rich set of hypertext links is provided, such as those from gene and clone information to DNA and protein sequence databases (GenBank, EMBL, DDBJ, SWISS-PROT), from bibliographic data to PubMed, from phenotypes to OMIM (Online Mendelian Inheritance in Man), and from gene homology records to the genomic databases of other species. MGD's data integration process places disparate data in contextual relationship, bringing together information from electronic downloads, the mouse Chromosome Committees, submissions from individual researchers, and actively curated data from the published literature. MGD encourages community participation via contributions of data and the development of consensus representations of the mouse genome. The resource's electronic bulletin boards are maintained to facilitate communication and collaboration among interested scientists. These Bulletin Boards provide a forum for community discussions and an excellent communication vehicle for MGD news. For more on the Mouse Genome Database follow the link, http://www.informatics.jax.org/mgihome/projects/overview.shtml.

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