Lisa Stubbs, Cymbeline Culiat, Ethan Carver, Nestor Cacheiro, Gary Wright, and Walderico Generoso
Biology Division, Oak Ridge National Laboratory, P.O. Box 2009,Oak Ridge, TN, 37831-8077.
Balanced translocations have proved invaluable tools in the mapping and molecular cloning of a number of different acquired and inherited human diseases including Neurofibromatoma type I, Autosomal recessive polycystic kidney disease, and several different types of human cancers. Because the balanced translocations are cytologically visible, and generally produce profound disturbances in both gene expression and DNA structure, this type of mutation provides a valuable "tag" that greatly simplifies mapping, cloning, and assessment of candidate genes associated with a disease. Although balanced translocations are relatively rare in human populations, they are readily induced in the mouse. Using various mutagenesis protocols, we have generated numerous translocation-bearing mutant mouse strains that display an impressive variety of health-related anomalies, including limb and skeletal deformities, neural tube defects, ataxias, tremors, hereditary deafness and blindness, reproductive dysfunction, and complex behavioral defects. The ability to map the genes associated with translocation breakpoints cytogenetically, first crudely through straightforward banding techniques and then to a higher level of resolution using fluorescence in situ hybridization methods, allows us to avoid the costly and time-consuming crosses that are required for the mapping of most mutant genes. With this rapid, crude-level mapping information, we can readily assess possible relationships between newly arising mutant phenotypes and linked candidate genes, or related diseases that map to the homologous regions of specific human chromosomes. Using this approach, we have recently begun to define the map positions of several mutations, including one producing hydrocephalus, two associated with progressive ataxia, one causing a subtle and complex behavioral disorder, and two producing different types of congenital inner ear defects. Mapping results have clearly indicated that one of these mutations affects the murine homolog of the gene disrupted in Usher's syndrome type 1C, an uncloned human disorder associated with severe congenital deafness, balance defects, and early-onset blindness. We have recently identified a candidate gene corresponding to this mutation, and are poised to begin investigations of the gene's role in inner ear and eye development in mice and in affected human families.
To date, we have characterized and mapped only a fraction of the large and growing number of translocation-bearing strains that comprise this valuable mutant collection. The breakpoints that have been mapped so far, which represent primarily those associated with severe, early onset, and easily detectable phenotypes, are scattered widely throughout the mouse genome and map to a broad selection of human homology regions. Over the next few years, as new breakpoints are located and large numbers of newly-sequenced cDNA clones are assigned to the mouse and human maps, the potential for rapid association between cloned gene and mapped mutation will no doubt increase dramatically. This large collection of murine translocation mutants therefore represents a powerful resource for linking mapped cDNA clones to health-related phenotypes throughout the genome.
 University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd., Dallas, TX 75235
This work was supported by USDOE under contract DE-AC05840R21400 with Lockheed-Martin Energy Systems, Inc.
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