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Annual Report of Research
January 2008 - March 2009

University of Minnesota Twin Cities
College of Biological Sciences and Medical School
Department of Genetics, Cell Biology, and Development

PI: Laura P. W. Ranum

Genetic Mapping of a Novel Familial ALS Gene; Reversible Multisystemic Mouse Models of Myotonic Dystrophy Type 1 and Type 2

These researchers used MSI resources for two projects during this period. In the first, dealt with a genome screening strategy. In a simple autosomal dominant family, the goal of lineage analysis and a genome screen is to identify regions of the genome that are shared among affected individuals in the family. To enhance the power of the amyotrophic lateral sclerosis (ALS)-A family for informative linkage analysis, these researchers generated a panel of haploid cell lines for all available affected family members and other key individuals in the pedigree. This genome-wide panel of haploid cell lines generated over the past two and one-half years allows the researchers to directly establish and compare haplotypes for entire chromosomes among affected individuals. The results of this method allowed the researchers to directly identify regions that are shared by all affected family members and are thus candidate regions for the ALS-A gene, as well as regions that are clearly excluded. In addition to understanding ALS, an equally important goal of this project was to develop and validate the proposed haplotype genome screening strategy as a novel method to enhance the power of genetic mapping studies for other diseases.

The second project, begun during this period, investigates myotonic dystrophy (DM), the most common form of muscular dystrophy in adults. Type 1 DM is caused by a CTG expansion in the 3’ untranslated region of the myotonic dystrophy protein kinase (DMPK) gene while type 2 DM is associated with a CCTG expansion in intron 1 of the zinc finger protein 9 (ZNF9) gene. The clinical and molecular parallels between DM1 and DM2 strongly suggest that CUG and CCUG expansion expressed at the RNA level are pathogenic and cause the multisystemic features common to both diseases. The purpose of this research is to develop reversible mouse models of DM to test the hypothesis that CUG and CCUG repeat toxicity is comparable at the cellular and organism levels, that alterations in temporal and spatial expression patterns are responsible for both the phenotypic similarities and differences between DM1 and DM2, and that many of the multisystemic features of the disease are reversible.

Group Members

Katherine Dick, Graduate Student
Celine Kang, Graduate Student