Large-scale screening of the Gaucher's disease-related glucocerebrosidase gene in Europeans with Parkinson's disease.
Pathogenic variants in the glucocerebrosidase gene (GBA) encoding the enzyme deficient in Gaucher's disease (GD) are associated with Parkinson's disease (PD). To investigate the sequence variants, their association with PD and the related phenotypes in a large cohort of European, mostly French, patients and controls, we sequenced all exons of GBA in 786 PD patients from 525 unrelated multiplex families, 605 patients with apparently sporadic PD and 391 ethnically matched controls. GBA mutations were significantly more frequent (odds ratio=6.98, 95% confidence interval 2.54-19.21; P=0.00002) in the PD patients (76/1130=6.7%) than in controls (4/391=1.0%) and in patients with family histories of PD (8.4%) than in isolated cases (5.3%). Twenty-eight different mutations were identified in patient and control groups, including seven novel variants. N370S and L444P accounted for 70% of all mutant alleles in the patient group. PD patients with GBA mutations more frequently had bradykinesia as the presenting symptom and levodopa-induced dyskinesias. The phenotype was similar in patients with one, two or complex GBA mutations, although the two patients with c.1263del+RecTL and N370S/RecΔ55 mutations had signs of GD. Segregation analyses in 21 multiplex families showed that 17% of the affected relatives did not carry GBA mutations found in the given family, indicating heterogeneity of the aetiology, but 46% of the unaffected relatives were GBA mutation carriers. These genotype and clinical analyses on the largest homogeneous sample of European patients studied to date confirmed that GBA mutations are the most common genetic risk factor for PD, particularly in familial forms.
Université Pierre et Marie Curie-Paris 6, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, UMR-S975, and Department of Genetics and Cytogenetics, Pitié-Salpêtrière Hospital, Paris, France.
Suzanne
S
Lesage
Mathieu
M
Anheim
Christel
C
Condroyer
Pierre
P
Pollak
Franck
F
Durif
Céline
C
Dupuits
François
F
Viallet
Ebba
E
Lohmann
Jean-Christophe
JC
Corvol
Aurélie
A
Honoré
Sophie
S
Rivaud
Marie
M
Vidailhet
Alexandra
A
Dürr
Alexis
A
Brice
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D005260:Female; D005776:Gaucher Disease / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D056914:Genomic Structural Variation / Q000235:genetics; D005962:Glucosylceramidase / Q000235:genetics*; D006801:Humans; D018476:Hypokinesia / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010300:Parkinson Disease / Q000235:genetics*; D012307:Risk Factors; D044465:White People / Q000235:genetics
D005962:Glucosylceramidase