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Am J Hum Genet. 2014 Dec 4;95(6):729-35. doi: 10.1016/j.ajhg.2014.10.015. Epub 2014 Nov 26.

Mutations in RAB39B cause X-linked intellectual disability and early-onset Parkinson disease with α-synuclein pathology.

Author information

1
Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, Melbourne, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC 3052, Australia.
2
Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, Melbourne, VIC 3052, Australia.
3
Anatomical Pathology, The Alfred, Melbourne, VIC 3181, Australia; Australian Brain Bank Network, National Neuroscience Facility, Melbourne, VIC 3053, Australia.
4
Dulbecco Telethon Institute at Division of Neuroscience, San Raffaele Scientific Institute, Milan 20132, Italy; Pharmaceutical Research and Early Development, Neuroscience, Ophthalmology, and Rare Diseases, F. Hoffmann-La Roche, Grenzacherstrasse 124, Basel 4070, Switzerland.
5
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, VIC 3052, Australia.
6
Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, Ihnestrasse 73, Berlin 14195, Germany.
7
Department of Anesthesiology, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53792, USA.
8
Department of Biochemistry and Molecular Biology, Center for Genetics and Molecular Medicine, University of Louisville, Louisville, KY 40202, USA.
9
Bioinformatics Division, Walter and Eliza Hall Institute, Melbourne, VIC 3052, Australia.
10
Waisman Center, Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA.
11
Office of the State Forensic Pathologist, Royal Hobart Hospital, Hobart, TAS 7000, Australia.
12
Genetic Medicine Department, Royal Melbourne Hospital, Melbourne, VIC 3050, Australia.
13
Department of Neurology, Monash Children's Hospital, Melbourne, VIC 3168, Australia.
14
Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR 97239-3098, USA.
15
Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, Melbourne, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC 3052, Australia; Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne, VIC 3052, Australia; Department of Neurology, Royal Children's Hospital, Melbourne, VIC 3052, Australia.
16
Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, Melbourne, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC 3052, Australia; Clinical Genetics, Austin Health, Melbourne, VIC 3084, Australia.
17
Eskitis Institute for Drug Discovery, Griffith University, Nathan, QLD 4111, Australia.
18
Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, Ihnestrasse 73, Berlin 14195, Germany.
19
Dulbecco Telethon Institute at Division of Neuroscience, San Raffaele Scientific Institute, Milan 20132, Italy.
20
Bioinformatics Division, Walter and Eliza Hall Institute, Melbourne, VIC 3052, Australia; Department of Mathematics and Statistics, University of Melbourne, Melbourne, VIC 3010, Australia; Department of Medical Biology, University of Melbourne, Melbourne, VIC 3010, Australia.
21
Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, Melbourne, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC 3052, Australia. Electronic address: paul.lockhart@mcri.edu.au.

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 ∼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 α-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 α-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 α-synuclein homeostasis and a spectrum of neuropathological features that implicate RAB39B in the pathogenesis of Parkinson disease and potentially other neurodegenerative disorders.

Comment in

PMID:
25434005
PMCID:
PMC4259921
DOI:
10.1016/j.ajhg.2014.10.015
[Indexed for MEDLINE]
Free PMC Article

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