INTRODUCTION: Mutations in the lysosomal @entity15675 ( @entity15675 ) gene increase the risk of @entity191 ( @entity191 ). We determined the frequency and relative risk of major @entity15675 mutations in a large series of Italian @entity1 with primary @entity304 . METHODS: We studied 2766 unrelated consecutive @entity1 with clinical diagnosis of @entity191 (including 2350 @entity191 ), and 1111 controls. The entire cohort was screened for mutations in @entity15675 exons 9 and 10, covering approximately 70% of mutations, including the two most frequent defects, @entity10727 and @entity10726 . RESULTS: Four known mutations were identified in heterozygous state: 3 missense mutations ( @entity10727 , @entity10726 , and @entity52890 ), and the splicing mutation @entity68135 , which results in the in-frame exon-10 skipping. Molecular characterization of 2 additional rare variants, potentially interfering with splicing, suggested a neutral effect. @entity15675 mutations were more frequent in @entity191 (4.5%, RR  =  7.2, CI  =  3.3-15.3) and in @entity1832 ( @entity1832 ) (13.8%, RR  =  21.9, CI  =  6.8-70.7) than in controls (0.63%). but not in the other forms of @entity304 such as @entity7463 ( @entity7463 , 2%), and Corticobasal Degeneration (CBD, 0%). Considering only the @entity191 group, @entity15675 -carriers were younger at onset (52      10 vs. 57      10 years, P  <  0.0001) and were more likely to have a positive family history of @entity191 (34% vs. 20%, P  <  0.001). CONCLUSION: @entity15675 dysfunction is relevant for synucleinopathies, such as @entity191 and @entity1832 , except for MSA, in which pathology involves oligodendrocytes, and the @entity7463 and CBD. The risk of developing @entity1832 is three-fold higher than @entity191 , suggesting a more @entity146 phenotype.

XXXX mutations in primary @entity304 .

@entity1 :: ('9606', 'Species') :: ['patients'] @entity304 :: ('MESH:D010302', 'Disease') :: ['parkinsonism'] @entity10727 :: ('p|SUB|N|370|S', 'ProteinMutation') :: ['p.N370S'] @entity146 :: ('MESH:D001523', 'Disease') :: ['aggressive'] @entity15675 :: ('2629', 'Gene') :: ['GBA', 'glucocerebrosidase'] @entity191 :: ('MESH:D010300', 'Disease') :: ['primary degenerative parkinsonism', "Parkinson's Disease", 'PD'] @entity1832 :: ('MESH:D020961', 'Disease') :: ['Dementia with Lewy Bodies', 'DLB'] @entity68135 :: ('c|SUB|G|IVS10+1|T', 'DNAMutation') :: ['IVS10+1G>T'] @entity10726 :: ('p|SUB|L|444|P', 'ProteinMutation') :: ['p.L444P'] @entity7463 :: ('MESH:D013494', 'Disease') :: ['PSP', 'Progressive Supranuclear Palsy', 'tauopathies PSP'] @entity52890 :: ('p|SUB|D|443|N', 'ProteinMutation') :: ['p.D443N']
@entity15675 :: (2629,Gene) :: ['Glucocerebrosidase']
