Mammalian Genome

, Volume 10, Issue 9, pp 870-878

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

  • Mitchell  WalkowiczAffiliated withLife Sciences Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831-8077, USA
  • , Yonggang  JiAffiliated withDepartment of Genetics and Center for Human Genetics, Case Western Reserve University School of Medicine and University Hospitals of Cleveland, Cleveland OH 44106, USA
  • , Xiaojia  RenAffiliated withLife Sciences Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831-8077, USA
  • , Bernhard  HorsthemkeAffiliated withInstitute for Human Genetics, University Clinic Essen, D-4300 Essen 1, Germany
  • , Liane B.  RussellAffiliated withLife Sciences Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831-8077, USA
  • , Dabney  JohnsonAffiliated withLife Sciences Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831-8077, USA
  • , Eugene M.  RinchikAffiliated withLife Sciences Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831-8077, USA
  • , Robert D.  NichollsAffiliated withDepartment of Genetics and Center for Human Genetics, Case Western Reserve University School of Medicine and University Hospitals of Cleveland, Cleveland OH 44106, USA
  • , Lisa  StubbsAffiliated withLife Sciences Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831-8077, USA

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Abstract.

The juvenile development and fertility-2 (jdf2) locus, also called runty-jerky-sterile (rjs), was originally identified through complementation studies of radiation-induced p-locus mutations. Studies with a series of ethylnitrosourea (ENU)-induced jdf2 alleles later indicated that the pleiotropic effects of these mutations were probably caused by disruption of a single gene. Recent work has demonstrated that the jdf2 phenotype is associated with deletions and point mutations in Herc2, a gene encoding an exceptionally large guanine nucleotide exchange factor protein thought to play a role in vesicular trafficking. Here we describe the molecular characterization of a collection of radiation- and chemically induced jdf2/Herc2 alleles. Ten of the 13 radiation-induced jdf2 alleles we studied are deletions that remove specific 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 analyzed, 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 mutations.