? This project seeks to continue studies that were originally funded as part of an Interactive Research Project Grant (IRPG). The goal of the project was to perform functional analyses of an approximately 30 cM region of mouse Chromosome 5 using region-specific saturation mutagenesis with the point mutagen, ethylnitrosourea (ENU). Mice were screened for mutations causing embryonic lethality, infertility, behavioral defects, deafness, genome instability and eye defects. A set of chromosomal deletion complexes was created that spanned much of the target region, allowing a simple and rapid way to genetically map the identified mutations in complementation tests. The major aim of this work will be to characterize, genetically and phenotypically, the collection of mutations (projected to be 40-50) in greater detail. Most of the mutations we identified were embryonic lethal on Chr 5, detected on the basis of a """"""""loss-of-genotypic class"""""""" in the mating scheme. The timing and nature of developmental defects leading to the lethalities will be evaluated. The collection of deletions will be used to map the ENU induced mutations to small intervals and assemble them into complementation groups. One semilethal mutation causing skeletal patterning defects will be positionally cloned, as will a male sterility mutation resulting in severe sperm motility defects.
The second aim i s to explore the genetic basis for a haploinsufficiency phenotype, revealed by certain deletions, that model the Wolf-Hirschhorn contiguous gene syndrome. This disease causes mental retardation, skeletal dysmorphology, midline defects, and seizures. A combination of deletion mapping and BAC transgene complementation will be used to identify those regions responsible for components of the phenotype in mice. ? ?
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