Reference - Detail
|Author||Traka M, Millen KJ, Collins D, Elbaz B, Kidd GJ, Gomez CM, Popko B.|
|Title||WDR81 is necessary for purkinje and photoreceptor cell survival.|
The gene encoding the WD repeat-containing protein 81 (WDR81) has recently been described as the disease locus in a consanguineous family that suffers from cerebellar ataxia, mental retardation, and quadrupedal locomotion syndrome (CAMRQ2). Adult mice from the N-ethyl-N-nitrosourea-induced mutant mouse line nur5 display tremor and an abnormal gait, as well as Purkinje cell degeneration and photoreceptor cell loss. We have used polymorphic marker mapping to demonstrate that affected nur5 mice carry a missense mutation, L1349P, in the Wdr81 gene. Moreover, homozygous nur5 mice that carry a wild-type Wdr81 transgene are rescued from the abnormal phenotype, indicating that Wdr81 is the causative gene in nur5. WDR81 is expressed in Purkinje cells and photoreceptor cells, among other CNS neurons, and like the human mutation, the nur5 modification lies in the predicted major facilitator superfamily domain of the WDR81 protein. Electron microscopy analysis revealed that a subset of mitochondria in Purkinje cell dendrites of the mutant animals displayed an aberrant, large spheroid-like structure. Moreover, immunoelectron microscopy and analysis of mitochondrial-enriched cerebellum fractions indicate that WDR81 is localized in mitochondria of Purkinje cell neurons. Because the nur5 mouse mutant demonstrates phenotypic similarities to the human disease, it provides a valuable genetic model for elucidating the pathogenic mechanism of the WDR81 mutation in CAMRQ2.
|MeSH||Actins / metabolism Alkylating Agents / pharmacology Analysis of Variance Animals Animals, Newborn Calbindins Cell Line, Transformed Cell Survival / drug effects Cell Survival / genetics Cerebellum / pathology Chromosome Mapping Disease Models, Animal Ethylnitrosourea / pharmacology Functional Laterality Gait Apraxia / genetics* Gait Apraxia / pathology* Gene Expression Regulation / genetics Humans Mice Mice, Inbred C57BL Microscopy, Electron, Scanning Mitochondria / metabolism Mitochondria / pathology Mitochondria / ultrastructure Mutagenesis / drug effects Mutation, Missense / drug effects Mutation, Missense / genetics Nerve Tissue Proteins / metabolism Nuclear Proteins / genetics Nuclear Proteins / metabolism* Photoreceptor Cells / drug effects Photoreceptor Cells / metabolism* Photoreceptor Cells / ultrastructure Prostaglandin-Endoperoxide Synthases / metabolism Purkinje Cells / drug effects Purkinje Cells / metabolism* Purkinje Cells / ultrastructure RNA, Messenger / metabolism S100 Calcium Binding Protein G / metabolism Sequence Analysis, DNA Transfection|
|DNA material||MSM Mouse BAC (RDB04214) MSMg01-261K04.|