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

Gabrielle R. Wilson, Joe C H Sim, Catriona McLean, Maila Giannandrea, Charles A. Galea, Jessica R. Riseley, Sarah E M Stephenson, Elizabeth Fitzpatrick, Stefan A. Haas, Kate Pope, Kirk J. Hogan, Ronald G. Gregg, Catherine J. Bromhead, David S. Wargowski, Christopher H. Lawrence, Paul A. James, Andrew Churchyard, Yujing Gao, Dean G. Phelan, Greta GilliesNicholas Salce, Lynn Stanford, Ashley P L Marsh, Maria L. Mignogna, Susan J. Hayflick, Richard J. Leventer, Martin B. Delatycki, George D. Mellick, Vera M. Kalscheuer, Patrizia D'Adamo, Melanie Bahlo, David J. Amor, Paul J. Lockhart

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)729-735
Number of pages7
JournalAmerican Journal of Human Genetics
Volume95
Issue number6
DOIs
Publication statusPublished - Dec 4 2014

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Synucleins
Intellectual Disability
Parkinson Disease
Pathology
Lewy Bodies
Mutation
Dopaminergic Neurons
Parkinsonian Disorders
Substantia Nigra
Missense Mutation
Neurodegenerative Diseases
Computer Simulation
Small Interfering RNA
Homeostasis
Iron
Phenotype
Neurons
Brain
Proteins

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Wilson, G. R., Sim, J. C. H., McLean, C., Giannandrea, M., Galea, C. A., Riseley, J. R., ... Lockhart, P. J. (2014). Mutations in RAB39B cause X-linked intellectual disability and early-onset parkinson disease with α-synuclein pathology. American Journal of Human Genetics, 95(6), 729-735. https://doi.org/10.1016/j.ajhg.2014.10.015

Mutations in RAB39B cause X-linked intellectual disability and early-onset parkinson disease with α-synuclein pathology. / Wilson, Gabrielle R.; Sim, Joe C H; McLean, Catriona; 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 J.; Lockhart, Paul J.

In: American Journal of Human Genetics, Vol. 95, No. 6, 04.12.2014, p. 729-735.

Research output: Contribution to journalArticle

Wilson, GR, Sim, JCH, McLean, C, Giannandrea, M, Galea, CA, Riseley, JR, Stephenson, SEM, Fitzpatrick, E, Haas, SA, Pope, K, Hogan, KJ, Gregg, RG, Bromhead, CJ, Wargowski, DS, Lawrence, CH, James, PA, Churchyard, A, Gao, Y, Phelan, DG, Gillies, G, Salce, N, Stanford, L, Marsh, APL, Mignogna, ML, Hayflick, SJ, Leventer, RJ, Delatycki, MB, Mellick, GD, Kalscheuer, VM, D'Adamo, P, Bahlo, M, Amor, DJ & Lockhart, PJ 2014, 'Mutations in RAB39B cause X-linked intellectual disability and early-onset parkinson disease with α-synuclein pathology', American Journal of Human Genetics, vol. 95, no. 6, pp. 729-735. https://doi.org/10.1016/j.ajhg.2014.10.015
Wilson, Gabrielle R. ; Sim, Joe C H ; McLean, Catriona ; 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 J. ; Lockhart, Paul J. / Mutations in RAB39B cause X-linked intellectual disability and early-onset parkinson disease with α-synuclein pathology. In: American Journal of Human Genetics. 2014 ; Vol. 95, No. 6. pp. 729-735.
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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.",
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AU - Giannandrea, Maila

AU - Galea, Charles A.

AU - Riseley, Jessica R.

AU - Stephenson, Sarah E M

AU - Fitzpatrick, Elizabeth

AU - Haas, Stefan A.

AU - Pope, Kate

AU - Hogan, Kirk J.

AU - Gregg, Ronald G.

AU - Bromhead, Catherine J.

AU - Wargowski, David S.

AU - Lawrence, Christopher H.

AU - James, Paul A.

AU - Churchyard, Andrew

AU - Gao, Yujing

AU - Phelan, Dean G.

AU - Gillies, Greta

AU - Salce, Nicholas

AU - Stanford, Lynn

AU - Marsh, Ashley P L

AU - Mignogna, Maria L.

AU - Hayflick, Susan J.

AU - Leventer, Richard J.

AU - Delatycki, Martin B.

AU - Mellick, George D.

AU - Kalscheuer, Vera M.

AU - D'Adamo, Patrizia

AU - Bahlo, Melanie

AU - Amor, David J.

AU - Lockhart, Paul J.

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N2 - 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.

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