International Mammalian Genome Society

The 16th International Mouse Genome Conference (2002)

Oral Presentation

Monday 18 November

09:30 - 09:45 HRS


D Lorenzetti
Graduate Program in Molecular & Human Genetics, Baylor College of Medicine, Houston TX

Co-Authors: 2) Vogel H,† 3) Noveroske J, 1) Justice M
Institutions: 1)Molecular and Human Genetics, Baylor College of Medicine, 2)Lab. of Neuropahtology, Stanford University 3)Jacksonís Laboratory

Quakingviable (qkv) is a neurological mutant characterized by severe dysmyelination of the central nervous system. The qkV mutation is also associated with male infertility. The molecular defect in quakingviable consists of a deletion of approximately 1 Mb on mouse chromosome 17. This deficiency results in altered expression of transcripts from qkI, a gene mapping adjacent to the proximal deletion breakpoint. Given the large size of the qkv deficiency, we explored the possibility that other expressed sequences mapping to this interval may contribute to the quakingviable phenotype. To this end, a contig of BAC clones spanning the 1Mb deletion was assembled. Sequence derived from these BACs revealed that the mouse homologue of the human gene PARKIN maps to the qkv† deletion. The PARKIN locus is mutated in patients with autosomal recessive juvenile Parkinsonís disease (AR-JP) and encodes an E3 ubiquitin ligase.Parkin is completely absent from the brain of mice homozygous for the qkv deletion. Complementation analysis between the qkv deletion and qkI ENU-induced mutant alleles suggests that the loss of Parkin does not play a role in the CNS myelination defect observed in quaking. AR-JP brains display marked loss of dopaminergic neurons in the substantia nigra (SN). Immunohistochemical analysis on quakingviable mutant mice did not detect sign of neurodegeneration in the SN. We conclude that lack of Parkin does not effect the survival of nigral neurons in quakingviable mice. The finding that this classic mutant lacks Parkin may prompt further studies to investigate the molecular pathogenesis of AR-JP.

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