Mutations in RAB39B cause X-linked intellectual disability and early-onset Parkinson Disease with alpha-synuclein pathology
Details
Publication Year 2014-11-25,Volume 95,Issue #6,Page 729-35
Journal Title
Am J Hum Genet
Publication Type
Journal Article
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.
Publisher
Cell Press
Research Division(s)
Bioinformatics
NHMRC Grants
NHMRC/490037
Terms of Use/Rights Notice
Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.


Creation Date: 2014-12-03 09:29:16
Last Modified: 2014-12-10 03:38:43
An error has occurred. This application may no longer respond until reloaded. Reload 🗙