International Mammalian Genome Society

The 16th International Mouse Genome Conference (2002)


Oral Presentation

Monday 18 November

10:45 - 11:00 HRS

A NOVEL TRANSGENIC LINE OF MICE EXHIBITING AUTOSOMAL RECESSIVE MALE-SPECIFIC LETHALITY AND NAFLD

A Buchberg
Kimmel Cancer Center

Co-Authors: Sollars V, McEntee B, Engiles J, Rothstein J
Institutions: Kimmel Cancer Center, Thomas Jefferson University

We have isolated a Meis1a transgenic mouse line exhibiting recessive male-specific lethality and non-alcoholic fatty liver disease (NAFLD), which coincides with pubescence and is androgen-dependent.  The phenotype is due to disruption of an endogenous locus, since other Meis1a transgenic lines do not exhibit these phenotypes.  Necropsy analysis revealed hepatic microvesicular steatosis in pubescent male homozygous mice, which is absent in transgenic females.  The average age of death in the males is 39.5 days post partum.  Rendering the homozygous male mice testosterone insensitive via introducing the ArTfm mutation, resulted in the rescue of both the fatty liver and lethal phenotypes.  The transgene insertion site was cloned by both genomic library and PCR technologies.  The insertion site is located on proximal mouse chromosome 1 in a region syntenic with Human chromosome 8.  Sequence analysis and comparison with the public Mouse genomic sequence database reveals that the integration site disrupts a novel metallo-b-lactamase gene (Lactb2) of unknown function.  The transgene insertion results in a 21.3 kb deletion which includes exons 5-7 of Lactb2.  The insertion results in a fusion transcript between the Lactb2 gene and the transgene.  Work is in progress to determine the genetic cause of the varied phenotypes observed in these mice as well as the underlying biochemical defects that results in the fatty liver and male specific lethality.


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