Mutations in the glucocerebrosidase gene confer a risk for Parkinson disease in North Africa

Lesage, Suzanne; Condroyer, Christel; Hecham, Nassima; Anheim, Mathieu; Belarbi, Soreya; Lohman, Ebba; Viallet, François; Pollak, Pierre; Abada, M.; Dürr, Alexandra; Tazir, M.; Brice, Alexis

doi:10.1212/wnl.0b013e318207b01e

Cited by 39 publications

(21 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…15e20 Although recessive mutations in the GBA gene cause GD, a large collaborative international multicenter study of more than 5000 patients affected by Parkinson disease (PD) and age-matched controls definitively showed the association between the presence of heterozygous GBA mutations and PD. 21 These data were supported further by studies performed in different clinical cohorts of PD patients from several regions, including Europe, 22e25 America, 26e28 Africa, 29 and Asia. 30,31 As expected, the highest frequency of GBA mutations in patients affected by PD has been found in Ashkenazi Jewish populations.…”

mentioning

confidence: 69%

GBA Analysis in Next-Generation Era

Zampieri

Cattarossi

Bembi

et al. 2017

The Journal of Molecular Diagnostics

View full text Add to dashboard Cite

Mutations in the gene encoding the lysosomal enzyme acid β-glucosidase (GBA) are responsible for Gaucher disease and represent the main genetic risk factor for developing Parkinson disease. In past years, next-generation sequencing (NGS) technology has been applied for the molecular analysis of the GBA gene, both as a single gene or as part of gene panels. However, the presence of complex gene-pseudogene rearrangements, resulting from the presence of a highly homologous pseudogene (GBAP1) located downstream of the GBA gene, makes NGS analysis of GBA challenging. Therefore, adequate strategies should be adopted to avoid misdetection of GBA recombinant mutations. Here, we validated a strategy for the identification of GBA mutations using parallel massive sequencing and provide an overview of the major drawbacks encountered during GBA analysis by NGS. We implemented a NGS workflow, using a set of 38 patients with Gaucher disease carrying different GBA alleles identified previously by Sanger sequencing. As expected, the presence of the pseudogene significantly affected data output. However, the combination of specific procedures for the library preparation and data analysis resulted in maximal repeatability and reproducibility, and a robust performance with 97% sensitivity and 100% specificity. In conclusion, the pipeline described here represents a useful approach to deal with GBA sequencing using NGS technology.

show abstract

mentioning

confidence: 69%

GBA Analysis in Next-Generation Era

Zampieri

Cattarossi

Bembi

et al. 2017

The Journal of Molecular Diagnostics

View full text Add to dashboard Cite

show abstract

“…Mutations in GBA (glucosidase, beta, acid), encoding the lysosomal enzyme glucocerebrosidase, are important risk factors for Parkinson disease (PD) worldwide. 1 Positive association between GBA mutations and PD was demonstrated in various populations, including Asians, [2][3][4][5][6] Europeans, [7][8][9][10][11][12] North Africans, 13 North Americans [14][15][16] and South Americans, [17][18][19][20] but most frequently among Jews of Ashkenazi origin. 21,22 When inherited from both parents, GBA mutations cause Gaucher disease (GD), a lysosomal storage disorder with 3 clinical types: nonneuropathic (type I), acute neuropathic (type II), and chronic neuropathic (type III).…”

mentioning

confidence: 99%

Differential effects of severe vs mild GBA mutations on Parkinson disease

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Founder mutations in GBA can be detected in 1 out of 16 Ashkenazi Jews, and were shown to be important risk factors for Parkinson disease (PD) in this population 2,3 and in many other populations worldwide. [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] Three other lysosomal storage diseases that are caused by founder mutations can be found in the AJ population: Tay-Sachs disease 19 (carrier frequency of 1:27 20 ), Niemann-Pick disease type A 21 (1:115 20 ), and mucolipidosis type IV 22 (1:89 20 ). These 3 autosomal recessive diseases are caused by mutations in genes encoding lysosomal enzymes, 23 and their deficiency results in cellular accumulation of the enzymes' substrates.…”

mentioning

confidence: 99%

The p.L302P mutation in the lysosomal enzyme gene SMPD1 is a risk factor for Parkinson disease

et al. 2013

View full text Add to dashboard Cite

Objective: To study the possible association of founder mutations in the lysosomal storage disorder genes HEXA, SMPD1, and MCOLN1 (causing Tay-Sachs, Niemann-Pick A, and mucolipidosis type IV diseases, respectively) with Parkinson disease (PD).Methods: Two PD patient cohorts of Ashkenazi Jewish (AJ) ancestry, that included a total of 938 patients, were studied: a cohort of 654 patients from Tel Aviv, and a replication cohort of 284 patients from New York. Eight AJ founder mutations in the HEXA, SMPD1, and MCOLN1 genes were analyzed. The frequencies of these mutations were compared to AJ control groups that included large published groups undergoing prenatal screening and 282 individuals matched for age and sex.Results: Mutation frequencies were similar in the 2 groups of patients with PD. The SMPD1 p.L302P was strongly associated with a highly increased risk for PD (odds ratio 9.4, 95% confidence interval 3.9-22.8, p , 0.0001), as 9/938 patients with PD were carriers of this mutation compared to only 11/10,709 controls. Conclusions:The SMPD1 p.L302P mutation is a novel risk factor for PD. Although it is rare on a population level, the identification of this mutation as a strong risk factor for PD may further elucidate PD pathogenesis and the role of lysosomal pathways in disease development.

show abstract

Mutations in the glucocerebrosidase gene confer a risk for Parkinson disease in North Africa

Cited by 39 publications

References 12 publications

GBA Analysis in Next-Generation Era

GBA Analysis in Next-Generation Era

Differential effects of severe vs mild GBA mutations on Parkinson disease

The p.L302P mutation in the lysosomal enzyme gene SMPD1 is a risk factor for Parkinson disease

Contact Info

Product

Resources

About