International Mammalian Genome Society

The 13th International Mouse Genome Conference
October 31-November 3, 1999

Table of Contents * Structure * Bioinformatics * Sequence * Mapping * New Tools * Gene Discovery * Developmental * Mutagenesis * Functional Genomics

H1 Application of Chemical Mutagenesis to Dissecting Neurodegenerative Disease Pathways

George A. Carlson, Sherry K. Turner, Dionne Peterson, and Julie Gilchrist. McLaughlin Research Institute, 1520 23rd Street South, Great Falls, Montana 59405

The goal of our mutagenesis program is to identify genes and pathways with relevance to two neurodegenerative diseases, prion disorders and Alzheimer's disease (AD). Our first approach is to identify mutations in genes that are relevant to the functions of amyloid precursor protein (APP) or prion protein (PrP). The working hypothesis is that App or Prnp null-mutant mice will show phenotypes different from those seen in mice expressing these proteins when mutations occur in genes relevant to their as-yet-unknown functions. N-ethyl-N-nitrosourea (ENU) is the mutagen of choice for our program because it primarily induces point mutations that can produce either gain of function or loss of function. Both a first generation dominant screen and a three generation recessive screen are underway. The screen, which takes approximately 5 minutes per mouse, targets behavioral or neurological abnormalities. Most of the mutations identified in the screen will not be in pathways relevant to App or Prnp function and many will be of little interest to scientists at McLaughlin Research Institute. Therefore, a list of phenodeviants and mutants is posted on the Internet and these mice will be available to the research community.

These studies will determine the feasibility of modifier screens in mice and compare alternative strategies for screening and mapping. Two distinct inbred strains carrying the each null allele will allow us to determine whether recovery of modifier mutations is more efficient when screening is done on an inbred background (with the risk of losing the phenotype when outcrossing for mapping) compared to screening and outcrossing simultaneously. To date (July 1, 1999) we have screened more than 1200 F1 mice and recovered 15 mutations, with more phenodeviants being progeny tested. In these initial studies, more than 30% of tested phenodeviants have been mutants.

This work is supported by an Alzheimer's Disease Research Grant from the American Health Assistance Foundation.


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