The neurological mutant quaking(viable) is Parkin deficient.
The mouse mutant quaking(viable) ( qk(v)) has been studied for almost four decades as a model for dysmyelination of the central nervous system (CNS). The genetic lesion associated with the qk(v) phenotype is a large deletion of approximately 1 Megabase on mouse Chromosome (Chr) 17. This deficiency alters the expression of transcripts from the qkI locus in oligodendrocytes, resulting in improper myelination of the CNS in animals homozygous for the deletion. To determine whether other genes within the deletion contribute to the quaking(viable) phenotype, we physically mapped and sequenced the deleted interval. We determined that the mouse Parkin gene, as well as the Parkin co-regulated gene ( Pacrg), lies within the qk(v) deletion. We determined that qk(v) mutants completely lack the expression of the Parkin gene product. Loss-of-function mutations in the human PARKIN gene cause autosomal juvenile Parkinson's disease (AR-JP). Our studies show that the deletion of Parkin in qk(v) brains does not result in the loss of dopaminergic neurons typical of AR-JP patients. Also, alpha-synuclein, a target of Parkin-dependent ubiquitination, does not accumulate in qk(v) mutant brains. Despite the lack of AR-JP-like neuropathology in qk(v) mice, this mutant may constitute a readily available model for the study of the cellular function of Parkin. This is the first report of a gene distinct from qkI affected by the qk(v) deletion. The discovery of the multigenic nature of this classical mouse mutation calls for the re-evaluation of its phenotypic characterization.
Lorenzetti
Diego
D
Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Room S413, Houston, Texas 77030, USA.
Antalffy
Barbara
B
Vogel
Hannes
H
Noveroske
Janice
J
Armstrong
Dawna
D
Justice
Monica
M
D000818:Animals; D015139:Blotting, Southern; D015153:Blotting, Western; D002872:Chromosome Deletion; D002874:Chromosome Mapping; D022202:Chromosomes, Artificial, Bacterial; D016172:DNA Fingerprinting; D007150:Immunohistochemistry; D051379:Mice; D008821:Mice, Quaking / Q000235:genetics*; D008840:Microfilament Proteins; D018832:Molecular Chaperones; D009419:Nerve Tissue Proteins / Q000378:metabolism; D011233:Precipitin Tests; D011506:Proteins / Q000235:genetics*; D013378:Substantia Nigra / Q000378:metabolism; D051843:Synucleins; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism; D051844:alpha-Synuclein
D008840:Microfilament Proteins; D018832:Molecular Chaperones; D009419:Nerve Tissue Proteins; C471712:Pacrg protein, mouse; D011506:Proteins; C497605:Snca protein, mouse; D051843:Synucleins; D051844:alpha-Synuclein; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein