TY - JOUR
T1 - Mutations in RAB39B cause X-linked intellectual disability and early-onset parkinson disease with α-synuclein pathology
AU - Wilson, Gabrielle R.
AU - Sim, Joe C.H.
AU - McLean, Catriona
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.
N1 - Publisher Copyright:
© 2014 The American Society of Human Genetics.
PY - 2014/12/4
Y1 - 2014/12/4
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.
AB - 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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U2 - 10.1016/j.ajhg.2014.10.015
DO - 10.1016/j.ajhg.2014.10.015
M3 - Article
C2 - 25434005
AN - SCOPUS:84919650942
SN - 0002-9297
VL - 95
SP - 729
EP - 735
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 6
ER -