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

GR Wilson; JCH Sim; C McLean; M Giannandrea; CA Galea; JR Riseley; SEM Stephenson; E Fitzpatrick; SA Haas; K Pope; KJ Hogan; RG Gregg; CJ Bromhead; DS Wargowski; CH Lawrence; PA James; A Churchyard; Y Gao; DG Phelan; G Gillies; N Salce; L Stanford; APL Marsh; ML Mignogna; SJ Hayflick; RJ Leventer; MB Delatycki; GD Mellick; VM Kalscheuer; P D'Adamo; M Bahlo; DJ Amor; PJ Lockhart

Journal article

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

GR Wilson, JCH Sim, C McLean, M Giannandrea, CA Galea, JR Riseley, SEM Stephenson, E Fitzpatrick, SA Haas, K Pope, KJ Hogan, RG Gregg, CJ Bromhead, DS Wargowski, CH Lawrence, PA James, A Churchyard, Y Gao, DG Phelan, G Gillies Show all

American Journal of Human Genetics | Published : 2014

DOI: 10.1016/j.ajhg.2014.10.015

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 r..

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University of Melbourne Researchers

Catriona McLean Author

Paul James Author

Rick Leventer Author

Martin Delatycki Author

Grants

Awarded by Australian Research Council

Funding Acknowledgements

We thank the families for their participation in this study and the generous support of the Lefroy and Handbury families. This work was funded in part by Australian National Health and Medical Research Council (NHMRC) program grant 490037 to D.J.A. and M.B., NHMRC project grant APP1041860 to P.J.L., Parkinson's Disease Foundation grant PDF-IRG-1220 to P.J.L. and G.R.W., and the project GENCODYS (grant 241995 to V.M.K.), which was funded by the European Union Framework Programme 7. P.J.L. was supported by an NHMRC Career Development Fellowship (APP1032364), and M.B. was supported by an Australian Research Council Future Fellowship (FT100100764). This work was made possible through Victorian State Government Operational Infrastructure Support and the NHMRC Independent Medical Research Institutes Infrastructure Support Scheme.