Molecular characterization of radiation- and chemically induced mutations associated with neuromuscular tremors, runting, juvenile lethality, and sperm defects in jdf2 mice

The juvenile development and fertility-2 (jdf2) locus, also called runty-je rky-sterile (rjs), was originally identified through complementation studie s of radiation-induced p-locus mutations. Studies with a series of ethylnit rosourea (ENU)-induced jdf2 alleles later indicated that the pleiotropic ef fects of these mutations were probably caused by disruption of a single gen e. Recent work has demonstrated that the jdf2 phenotype is associated with deletions and point mutations in Herc2, a gene encoding an exceptionally la rge guanine nucleotide exchange factor protein thought to play a role in ve sicular trafficking. Here we describe the molecular characterization of a c ollection of radiation- and chemically induced jdf2/Herc2 alleles. Ten of t he 13 radiation-induced jdf2 alleles we studied are deletions that remove s pecific portions of the Herc2 coding sequence; DNA rearrangements were also detected in two additional mutations. Our studies also revealed that Herc2 transcripts are rearranged, not expressed, or are present in significantly altered quantities in animals carrying most of the jdf2 mutations we analy zed, including six independent ENU-induced alleles. These data provide new molecular clues regarding the wide range of jdf2 and p phenotypes that are expressed by this collection of recently generated and classical p-region m utations.