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Title: Mutations in RAB39B cause X-linked intellectual disability and early-onset Parkinson disease with α-synuclein pathology.
Austin Authors: Wilson, Gabrielle R;Sim, Joe C H;McLean, Catriona A;Giannandrea, Maila;Galea, Charles A;Riseley, Jessica R;Stephenson, Sarah E M;Fitzpatrick, Elizabeth;Haas, Stefan A;Pope, Kate;Hogan, Kirk J;Gregg, Ronald G;Bromhead, Catherine J;Wargowski, David S;Lawrence, Christopher H;James, Paul A;Churchyard, Andrew;Gao, Yujing;Phelan, Dean G;Gillies, Greta;Salce, Nicholas;Stanford, Lynn;Marsh, Ashley P L;Mignogna, Maria L;Hayflick, Susan J;Leventer, Richard J;Delatycki, Martin B ;Mellick, George D;Kalscheuer, Vera M;D'Adamo, Patrizia;Bahlo, Melanie;Amor, David John;Lockhart, Paul J
Affiliation: Clinical Genetics, Austin Health, Heidelberg, Victoria, Australia 3084, Australia
Eskitis Institute for Drug Discovery, Griffith University, Nathan, QLD 4111, Australia
Department of Anesthesiology, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53792, USA
Genetic Medicine Department, Royal Melbourne Hospital, Melbourne, VIC 3050, Australia
Department of Neurology, Monash Children's Hospital, Melbourne, VIC 3168, Australia
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, VIC 3052, Australia
Office of the State Forensic Pathologist, Royal Hobart Hospital, Hobart, TAS 7000, Australia
Department of Medical Biology, University of Melbourne, Melbourne, VIC 3010, Australia
Department of Neurology, Royal Children's Hospital, Melbourne, VIC 3052, Australia
Australian Brain Bank Network, National Neuroscience Facility, Melbourne, VIC 3053, Australia
Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR 97239-3098, USA
Waisman Center, Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA
Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, Melbourne, VIC 3052, Australia
Department of Biochemistry and Molecular Biology, Center for Genetics and Molecular Medicine, University of Louisville, Louisville, KY 40202, USA
Department of Mathematics and Statistics, University of Melbourne, Melbourne, VIC 3010, Australia
Bioinformatics Division, Walter and Eliza Hall Institute, Melbourne, VIC 3052, Australia
Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne, VIC 3052, Australia
Anatomical Pathology, The Alfred, Melbourne, VIC 3181, Australia
Department of Paediatrics, University of Melbourne, Melbourne, VIC 3052, Australia
Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, Ihnestrasse 73, Berlin 14195, Germany.
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.
Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, Ihnestrasse 73, Berlin 14195, Germany.
Dulbecco Telethon Institute at Division of Neuroscience, San Raffaele Scientific Institute, Milan 20132, Italy.
Issue Date: 26-Nov-2014
Publication information: American Journal of Human Genetics 2014; 95(6): 729-35
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.
Gov't Doc #: 25434005
DOI: 10.1016/j.ajhg.2014.10.015
Journal: American journal of human genetics
Type: Journal Article
Subjects: Amino Acid Substitution
Base Sequence
Gene Expression Regulation
Genes, X-Linked
Intellectual Disability.genetics.physiopathology
Lewy Bodies.metabolism
Middle Aged
Models, Molecular
Molecular Sequence Data
Mutation, Missense
Nerve Degeneration.genetics.physiopathology
Parkinson Disease.genetics.physiopathology
Sequence Analysis, DNA
Sequence Deletion
Substantia Nigra.physiopathology
rab GTP-Binding Proteins.genetics.metabolism
Appears in Collections:Journal articles

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