Advances in understanding the etiology of @entity191 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 @entity304 and @entity717 identified a    45 kb deletion resulting in the complete loss of @entity54322 . We subsequently identified a missense mutation ( @entity68461 [ @entity68462 ]) in @entity68463 B 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 @entity54322 resulted in a reduction in the density of a-synuclein immunoreactive puncta in dendritic processes of cultured neurons. In addition, in multiple cell models, we demonstrated that knockdown of @entity54322 was associated with reduced steady-state levels of a-synuclein. Post mortem studies demonstrated that loss of @entity54322 resulted in pathologically confirmed @entity191 . 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 @entity68463 B cause @entity717 and pathologically confirmed early-onset @entity191 . The loss of @entity54322 results in dysregulation of a-synuclein homeostasis and a spectrum of neuropathological features that implicate @entity68463 B in the pathogenesis of @entity191 and potentially other @entity179 .

Mutations in XXXX B cause X-linked intellectual disability and early-onset @entity191 with a-synuclein pathology.

@entity304 :: ('MESH:D010302', 'Disease') :: ['parkinsonism'] @entity68462 :: ('p|SUB|T|168|K', 'ProteinMutation') :: ['p.Thr168Lys'] @entity68463 :: ('54734', 'Gene') :: ['RAB39'] @entity191 :: ('MESH:D010300', 'Disease') :: ['Parkinson disease'] @entity54322 :: ('116442', 'Gene') :: ['RAB39B', 'Rab39b'] @entity179 :: ('MESH:D019636', 'Disease') :: ['neurodegenerative disorders'] @entity717 :: ('MESH:D009069', 'Disease') :: ['intellectual disability'] @entity68461 :: ('c|SUB|C|503|A', 'DNAMutation') :: ['c.503C>A']
@entity68463 :: (54734,Gene) :: ['RAB39']
