P-38 A novel malformation syndrome with micrognathia and preaxial polydactyly in SD-derived rats caused by a recessive mutation on chromosome 19

摘要

Outbred animals are commonly used in reproduction and developmental toxicity studies, where crosses of externally normal parents sometimes result in occurrences of congenital anomalies in F1 and/or F2 offspring. Perhaps many of these anomalies are due to a variety of recessive mutations harbored in outbred colonies; however, it is quite difficult to confirm whether they are genetic in origin or caused by the treatment. This motivated us to develop precise and reliable diagnosing methods for heritable anomalies, especially fetal malformations, observed in individuals derived from outbred colonies of animals by examining their phenotypic and genetic characteristics. In this study, we genetically analyzed a novel malformation syndrome with micrognathia and preaxial polydactyly in descendants of SD rats purchased from Charles River, Inc. Mating tests with both sexes of F1 rats derived from the outcross of a male that sired malformed neonates and BN females revealed that 49 fetuses or neonates (22%) among a total of 222 F2 offspring had the same anomalies such as micrognathia and preaxial polydactyly, demonstrating an autosomal recessive mode of inheritance. The following linkage analysis showed that the causative gene mutation should exist within an approximately 5 Mb region on chromosome 19. A possible candidate gene with the mutation is Rpgrip1l since the knock-out of this gene is reported to cause micrognathia and preaxial polydactyly in mice. These results suggest that breeding colonies of SD rats may keep the gene mutation on chromosome 19 to cause the same malformation syndrome in reproduction and developmental toxicity studies with this stock.