International Mammalian Genome Society

logo18th International Mouse Genome Conference

17-22 October 2004, Seattle, USA


POSTER 175 - DIETARY RESCUE AND POSITIONAL CLONING OF PEQUEÑO: A SECOND LOCUS FOR SHWACHMAN DIAMOND SYNDROME?

Loftus SK, Cannons J, Incao A, Chen A, Zerfas P, Bryant MA, Schwartzberg P, Biesecker LG, Pavan WJ

1 National Human Genome Research Institute, NIH, Bethesda, United States, 2 Diagnostic and Research Services Branch, Veterinary Resources Program, NIH, Bethesda, United States

Pequeño is inherited in an autosomal recessive pattern and is a mouse model for exocrine pancreatic insufficiency.  The pequeño phenotype is caused by a transgene insertion and 210kb deletion mutation on chromosome 3.  Pequeño mice exhibit progressive postnatal apoptosis of pancreatic acinar cells with nearly complete exocrine acinar cell loss at 8 weeks, while islets and ductal tissue remain present.  Homozygous animals are about 1/3 smaller than heterozygous or wildtype littermates at weaning, have an average lifespan of 4 months under standard housing conditions and have immunodeficiency.  Dietary supplementation pancreatic enzymes can correct the body size, weight, immunodeficiency, and increase the lifespan of pq/pq mice, suggesting that malnutrition is a major cause of the phenotype.  BAC transgenic rescue crosses have identified a single transcript present in the deletion that is responsible for the pancreatic insufficiency.  The pequeño phenotype is similar to that of Shwachman Diamond syndrome (SDS) in humans. SDS is characterized by short stature, pancreatic lipomatosis, neutropenia, and increased risk of myelodysplastic syndrome with progression to acute myeloid leukemia.  The major genetic locus for SDS has recently been identified (Boocock et al., 2003) and is distinct from that of the pequeño locus.  As only 89% of patients with SDS have mutations at the SDS locus, we are currently testing if the pequeño locus may contribute to the genetic heterogeneity found in humans

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