title: WDR81 is necessary for purkinje and photoreceptor cell survival.
abstract: 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.
authors.affiliation: Department of Neurology, University of Chicago Center for Peripheral Neuropathy, University of Chicago, Chicago, Illinois 60637, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Traka
authors.forename: Kathleen J
authors.initials: KJ
authors.lastname: Millen
authors.forename: Devon
authors.initials: D
authors.lastname: Collins
authors.forename: Benayahu
authors.initials: B
authors.lastname: Elbaz
authors.forename: Grahame J
authors.initials: GJ
authors.lastname: Kidd
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Gomez
authors.forename: Brian
authors.initials: B
authors.lastname: Popko
mesh_terms: D000199:Actins / Q000378:metabolism; D000477:Alkylating Agents / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D064026:Calbindins; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002531:Cerebellum / Q000473:pathology; D002874:Chromosome Mapping; D004195:Disease Models, Animal; D005038:Ethylnitrosourea / Q000494:pharmacology; D007839:Functional Laterality; D020235:Gait Apraxia / Q000235:genetics* / Q000473:pathology*; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008855:Microscopy, Electron, Scanning; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D016296:Mutagenesis / Q000187:drug effects; D020125:Mutation, Missense / Q000187:drug effects / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010786:Photoreceptor Cells / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011689:Purkinje Cells / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D012333:RNA, Messenger / Q000378:metabolism; D064030:S100 Calcium Binding Protein G / Q000378:metabolism; D017422:Sequence Analysis, DNA; D014162:Transfection
chemical_list: D000199:Actins; D000477:Alkylating Agents; D064026:Calbindins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; D064030:S100 Calcium Binding Protein G; C558249:WDR18 protein, human; C000609634:WDR81 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D005038:Ethylnitrosourea