Large-scale screening of the Gaucher's disease-related glucocerebrosidase gene in Europeans with Parkinson's disease

Abstract

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.

Specifically neuropathic Gaucher's mutations accelerate cognitive decline in Parkinson's

“…For 409 samples in DIGPD, exons and flanking intronic regions of GBA were sequenced. To avoid amplifying and sequencing the neighboring pseudogene, GBA was amplified in three large fragments (a 2,972‐bp fragment encompassing exons 1–5; a 2,049‐bp fragment encompassing exons 5–7, and a 1,682‐bp fragment encompassing exons 8–11), using previously described primers and a unique 648C to 548C touch‐down PCR program 29. PCR products were sequenced with internal primers, adjacent to coding exons and exon‐intron boundaries, using the Big Dye Terminator Cycle Sequencing Ready Reaction kit (Applied Biosystems, Foster City, CA), as prescribed.…”

The role of α-synuclein in neurodegeneration — An update

“…There are also genetic and pathological links between PD and the lysosomal disorder Sanfilippo syndrome [503]. GBA mutations -more than 28 of which are presently recognized [504] -are the most frequent genetic risk factor for PD [505,506], particularly in fPD [507], and glucocerebrosidase is present in AS inclusions in LB disorders [494]. This inflammatory response may occur after neuronal death, but it is also possible that AS is released via exocytosis [534] or even that cleaved portions are presented via antigene presentation, which could lead to a vicious cycle of inflammatory response, release of (modified) AS, and further inflammation.…”

GBA deficiency promotes SNCA/α-synuclein accumulation through autophagic inhibition by inactivated PPP2A

“…3 In recent years, mutations in the gene encoding GBA (glucosidase, b, acid) have been identified as the most common known genetic risk factor for the development of PD. [4][5][6][7] Gaucher disease (GD) is a rare, autosomal recessive lysosomal storage disorder that results from loss-of-function mutations in GBA. GBA is a lysosomal enzyme responsible for the conversion of glucocerebroside to glucose and ceramide.…”