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  Mutations in RAB39B Cause X-Linked Intellectual Disability and Early-Onset Parkinson Disease with alpha-Synuclein Pathology

Wilson, G. R., Sim, J. C., McLean, C., Giannandrea, M., Galea, C. A., Riseley, J. R., et al. (2014). Mutations in RAB39B Cause X-Linked Intellectual Disability and Early-Onset Parkinson Disease with alpha-Synuclein Pathology. The American Journal of Human Genetics, 95(6), 729-735. doi:10.1016/j.ajhg.2014.10.015.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0025-0C27-0 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0025-0C28-E
Genre: Journal Article

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© 2014 Elsevier B.V.
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 Creators:
Wilson, G. R., Author
Sim, J. C., Author
McLean, C., Author
Giannandrea, M., Author
Galea, C. A., Author
Riseley, J. R., Author
Stephenson, S. E., Author
Fitzpatrick, E., Author
Haas, S. A.1, Author              
Pope, K., Author
Hogan, K. J., Author
Gregg, R. G., Author
Bromhead, C. J., Author
Wargowski, D. S., Author
Lawrence, C. H., Author
James, P. A., Author
Churchyard, A., Author
Gao, Y., Author
Phelan, D. G., Author
Gillies, G., Author
Salce, N., AuthorStanford, L., AuthorMarsh, A. P., AuthorMignogna, M. L., AuthorHayflick, S. J., AuthorLeventer, R. J., AuthorDelatycki, M. B., AuthorMellick, G. D., AuthorKalscheuer, V. M.2, Author              D'Adamo, P., AuthorBahlo, M., AuthorAmor, D. J., AuthorLockhart, P. J., Author more..
Affiliations:
1Gene Structure and Array Design (Stefan Haas), Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479640              
2Chromosome Rearrangements and Disease (Vera Kalscheuer), Dept. of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479642              

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 Abstract: Advances in understanding the etiology of Parkinson disease have been driven by the identification of causative mutations in families. Genetic analysis of an Australian family with three males displaying clinical features of early-onset parkinsonism and intellectual disability identified a approximately 45 kb deletion resulting in the complete loss of RAB39B. We subsequently identified a missense mutation (c.503C>A [p.Thr168Lys]) in RAB39B in an unrelated Wisconsin kindred affected by a similar clinical phenotype. In silico and in vitro studies demonstrated that the mutation destabilized the protein, consistent with loss of function. In vitro small-hairpin-RNA-mediated knockdown of Rab39b resulted in a reduction in the density of alpha-synuclein immunoreactive puncta in dendritic processes of cultured neurons. In addition, in multiple cell models, we demonstrated that knockdown of Rab39b was associated with reduced steady-state levels of alpha-synuclein. Post mortem studies demonstrated that loss of RAB39B resulted in pathologically confirmed Parkinson disease. There was extensive dopaminergic neuron loss in the substantia nigra and widespread classic Lewy body pathology. Additional pathological features included cortical Lewy bodies, brain iron accumulation, tau immunoreactivity, and axonal spheroids. Overall, we have shown that loss-of-function mutations in RAB39B cause intellectual disability and pathologically confirmed early-onset Parkinson disease. The loss of RAB39B results in dysregulation of alpha-synuclein homeostasis and a spectrum of neuropathological features that implicate RAB39B in the pathogenesis of Parkinson disease and potentially other neurodegenerative disorders.

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Language(s): eng - English
 Dates: 2014-11-262014-12-04
 Publication Status: Published in print
 Pages: -
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 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1016/j.ajhg.2014.10.015
ISSN: 1537-6605 (Electronic)0002-9297 (Print)
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Title: The American Journal of Human Genetics
  Other : Am. J. Hum. Genet.
Source Genre: Journal
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Publ. Info: American Society of Human Genetics
Pages: - Volume / Issue: 95 (6) Sequence Number: - Start / End Page: 729 - 735 Identifier: ISSN: 0002-9297
CoNE: https://pure.mpg.de/cone/journals/resource/954925377893_1