title: Mutations in RAB39B cause X-linked intellectual disability and early-onset Parkinson disease with α-synuclein pathology.
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.
authors.affiliation: 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.
authors.forename: Gabrielle R
authors.initials: GR
authors.lastname: Wilson
authors.affiliation: Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, Melbourne, VIC 3052, Australia.
authors.forename: Joe C H
authors.initials: JC
authors.lastname: Sim
authors.affiliation: Anatomical Pathology, The Alfred, Melbourne, VIC 3181, Australia; Australian Brain Bank Network, National Neuroscience Facility, Melbourne, VIC 3053, Australia.
authors.forename: Catriona
authors.initials: C
authors.lastname: McLean
authors.affiliation: 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.
authors.forename: Maila
authors.initials: M
authors.lastname: Giannandrea
authors.affiliation: Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, VIC 3052, Australia.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Galea
authors.affiliation: Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, Melbourne, VIC 3052, Australia.
authors.forename: Jessica R
authors.initials: JR
authors.lastname: Riseley
authors.affiliation: 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.
authors.forename: Sarah E M
authors.initials: SE
authors.lastname: Stephenson
authors.affiliation: Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, Melbourne, VIC 3052, Australia.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Fitzpatrick
authors.affiliation: Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, Ihnestrasse 73, Berlin 14195, Germany.
authors.forename: Stefan A
authors.initials: SA
authors.lastname: Haas
authors.affiliation: Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, Melbourne, VIC 3052, Australia.
authors.forename: Kate
authors.initials: K
authors.lastname: Pope
authors.affiliation: Department of Anesthesiology, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53792, USA.
authors.forename: Kirk J
authors.initials: KJ
authors.lastname: Hogan
authors.affiliation: Department of Biochemistry and Molecular Biology, Center for Genetics and Molecular Medicine, University of Louisville, Louisville, KY 40202, USA.
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Gregg
authors.affiliation: Bioinformatics Division, Walter and Eliza Hall Institute, Melbourne, VIC 3052, Australia.
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Bromhead
authors.affiliation: Waisman Center, Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Wargowski
authors.affiliation: Office of the State Forensic Pathologist, Royal Hobart Hospital, Hobart, TAS 7000, Australia.
authors.forename: Christopher H
authors.initials: CH
authors.lastname: Lawrence
authors.affiliation: Genetic Medicine Department, Royal Melbourne Hospital, Melbourne, VIC 3050, Australia.
authors.forename: Paul A
authors.initials: PA
authors.lastname: James
authors.affiliation: Department of Neurology, Monash Children's Hospital, Melbourne, VIC 3168, Australia.
authors.forename: Andrew
authors.initials: A
authors.lastname: Churchyard
authors.affiliation: Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, Melbourne, VIC 3052, Australia.
authors.forename: Yujing
authors.initials: Y
authors.lastname: Gao
authors.affiliation: 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.
authors.forename: Dean G
authors.initials: DG
authors.lastname: Phelan
authors.affiliation: Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, Melbourne, VIC 3052, Australia.
authors.forename: Greta
authors.initials: G
authors.lastname: Gillies
authors.affiliation: Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, Melbourne, VIC 3052, Australia.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Salce
authors.affiliation: Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR 97239-3098, USA.
authors.forename: Lynn
authors.initials: L
authors.lastname: Stanford
authors.affiliation: 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.
authors.forename: Ashley P L
authors.initials: AP
authors.lastname: Marsh
authors.affiliation: 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.
authors.forename: Maria L
authors.initials: ML
authors.lastname: Mignogna
authors.affiliation: Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR 97239-3098, USA.
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Hayflick
authors.affiliation: 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.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Leventer
authors.affiliation: 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.
authors.forename: Martin B
authors.initials: MB
authors.lastname: Delatycki
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University, Nathan, QLD 4111, Australia.
authors.forename: George D
authors.initials: GD
authors.lastname: Mellick
authors.affiliation: Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, Ihnestrasse 73, Berlin 14195, Germany.
authors.forename: Vera M
authors.initials: VM
authors.lastname: Kalscheuer
authors.affiliation: Dulbecco Telethon Institute at Division of Neuroscience, San Raffaele Scientific Institute, Milan 20132, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: D'Adamo
authors.affiliation: 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.
authors.forename: Melanie
authors.initials: M
authors.lastname: Bahlo
authors.affiliation: 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.
authors.forename: David J
authors.initials: DJ
authors.lastname: Amor
authors.affiliation: 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.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Lockhart
mesh_terms: D019943:Amino Acid Substitution; D001315:Australia; D001483:Base Sequence; D004298:Dopamine / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D050172:Genes, X-Linked; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000503:physiopathology; D016631:Lewy Bodies / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009410:Nerve Degeneration / Q000235:genetics* / Q000503:physiopathology; D010300:Parkinson Disease / Q000235:genetics* / Q000503:physiopathology; D010375:Pedigree; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion; D013378:Substantia Nigra / Q000503:physiopathology; D051844:alpha-Synuclein / Q000378:metabolism*; D020691:rab GTP-Binding Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D051844:alpha-Synuclein; C547812:Rab39B protein, human; D020691:rab GTP-Binding Proteins; D004298:Dopamine