TY - JOUR
T1 - Glucocerebrosidase mutations in primary parkinsonism
AU - Asselta, Rosanna
AU - Rimoldi, Valeria
AU - Siri, Chiara
AU - Cilia, Roberto
AU - Guella, Ilaria
AU - Tesei, Silvana
AU - Soldà, Giulia
AU - Pezzoli, Gianni
AU - Duga, Stefano
AU - Goldwurm, Stefano
PY - 2014/11/1
Y1 - 2014/11/1
N2 - Introduction: Mutations in the lysosomal glucocerebrosidase (GBA) gene increase the risk of Parkinson's Disease (PD). We determined the frequency and relative risk of major GBA mutations in a large series of Italian patients with primary parkinsonism. Methods: We studied 2766 unrelated consecutive patients with clinical diagnosis of primary degenerative parkinsonism (including 2350 PD), and 1111 controls. The entire cohort was screened for mutations in GBA exons 9 and 10, covering approximately 70% of mutations, including the two most frequent defects, p.N370S and p.L444P. Results: Four known mutations were identified in heterozygous state: 3 missense mutations (p.N370S, p.L444P, and p.D443N), and the splicing mutation IVS10+1G>T, which results in the in-frame exon-10 skipping. Molecular characterization of 2 additional rare variants, potentially interfering with splicing, suggested a neutral effect. GBA mutations were more frequent in PD (4.5%, RR=7.2, CI=3.3-15.3) and in Dementia with Lewy Bodies (DLB) (13.8%, RR=21.9, CI=6.8-70.7) than in controls (0.63%). but not in the other forms of parkinsonism such as Progressive Supranuclear Palsy (PSP, 2%), and Corticobasal Degeneration (CBD, 0%). Considering only the PD group, GBA-carriers were younger at onset (52±10 vs. 57±10 years, P
AB - Introduction: Mutations in the lysosomal glucocerebrosidase (GBA) gene increase the risk of Parkinson's Disease (PD). We determined the frequency and relative risk of major GBA mutations in a large series of Italian patients with primary parkinsonism. Methods: We studied 2766 unrelated consecutive patients with clinical diagnosis of primary degenerative parkinsonism (including 2350 PD), and 1111 controls. The entire cohort was screened for mutations in GBA exons 9 and 10, covering approximately 70% of mutations, including the two most frequent defects, p.N370S and p.L444P. Results: Four known mutations were identified in heterozygous state: 3 missense mutations (p.N370S, p.L444P, and p.D443N), and the splicing mutation IVS10+1G>T, which results in the in-frame exon-10 skipping. Molecular characterization of 2 additional rare variants, potentially interfering with splicing, suggested a neutral effect. GBA mutations were more frequent in PD (4.5%, RR=7.2, CI=3.3-15.3) and in Dementia with Lewy Bodies (DLB) (13.8%, RR=21.9, CI=6.8-70.7) than in controls (0.63%). but not in the other forms of parkinsonism such as Progressive Supranuclear Palsy (PSP, 2%), and Corticobasal Degeneration (CBD, 0%). Considering only the PD group, GBA-carriers were younger at onset (52±10 vs. 57±10 years, P
KW - Association analysis
KW - Functional characterization
KW - GBA
KW - Parkinson's disease
KW - Parkinsonism
KW - Splicing mutation
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U2 - 10.1016/j.parkreldis.2014.09.003
DO - 10.1016/j.parkreldis.2014.09.003
M3 - Article
C2 - 25249066
AN - SCOPUS:84908568615
VL - 20
SP - 1215
EP - 1220
JO - Parkinsonism and Related Disorders
JF - Parkinsonism and Related Disorders
SN - 1353-8020
IS - 11
ER -