International Mammalian Genome Society

17th International Mouse Genome Conference

9-12 November 2003, Braunschweig, Germany


POSTER 127 - INADVERTANT INACTIVATION OF A NEARBY GENE IDENTIFIED BY ANALYSIS OF SEVERAL PLANH2 KNOCKOUT MOUSE LINES

Westrick R J
University of Michigan

Co-Authors: 2) Mohlke K L, 1) Korepta L M, 1) Manning S L, 3) Aiyagari A, 4) Dougherty K M, 1,3) Ginsburg D
Institutions: 1) University of Michigan, 2) National Institutes of Health, 3) Howard Hughes Medical Institute, 4) Pfizer Global Research

In characterizing gene targeted mice deficient in Planh2, we observed mice which were small at birth, exhibited delayed growth and had decreased lifespan. We initially attributed this growth abnormality to deficiency of Planh2, an intracellular serpin hypothesized to play roles in apoptosis and tumor growth. Subsequent analysis of mice derived from two additional independent ES cell clones yielded Planh2 deficient mice that displayed no growth abnormalities. Upon further analysis of the original Planh2 deficient mouse line, we observed recombination between the small phenotype and the Planh2 locus in approximately 10% of the offspring from a Planh2 heterozygote intercross. An intercross with CASA/RK mice mapped the location of the locus responsible for the small phenotype to a less than 2 cM interval ~12 cM proximal to Planh2 on mouse chromosome 1, bounded by markers rh114877 and rh114812. Mice homozygous deficient for a known gene in the candidate interval, Irs1, have been reported to display delayed growth. Sequencing of Irs1 from Planh2small mice revealed a nonsense mutation at serine 57, which would be predicted to result in complete loss of Irs1 function. This substitution appears to have arisen as a spontaneous mutation in a precursor ES cell. Coincidental occurrence of similar mutations in regions tightly linked to other targeted genes could readily result in incorrect assignment of phenotype. This phenomenon could potentially account for some examples of markedly discordant results for experiments independently targeting the same gene.


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