Glucocerebrosidase N370S and L444P mutations as risk factors for Parkinson’s disease in Brazilian patients

Guimarães, Beatriz de Carvalho; Pereira, Ana Carolina Valente; Rodrigues, Fabíola da Costa; Santos, Adriana Vaz dos; Júnior, Mário Campos; Santos, J. M.; Santos, Flávia Lima dos; Rosso, Ana Lucia; Nicaretta, Denise Hack; Pereira, Joäo Santos; Silva, Delson José da; Coletta, Marcus Vinicius Della; Santos-Rebouças, Cíntia Barros; Pimentel, Márcia Mattos Gonçalves

doi:10.1016/j.parkreldis.2011.11.028

Cited by 21 publications

(11 citation statements)

References 4 publications

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“…The mean age of onset of the disease in PD patients was lower in patients with GBA mutations (49.6± 17.4 years) in comparison with those with no mutations (55.1±11.6 years) (Table 2). This finding is consistent with some 2,6,21,22 , but not all the other studies of GBA mutations in PD patients 7,9,26,30 . These differences may be accounted for by the fact that the modifier genes that contribute to development of the phenotype of the disease may also vary systematically in different populations.…”

Section: Discussionsupporting

confidence: 92%

“…Socal et al 24 also recorded mutations in only two (3.2%) of 62 PD patients from southern Brazil (one heterozygous for GBA c.1226A>G; p.N370S, the other for GBA c.1448T>C; p.L444P). Guimarães et al 26 used a larger sample of 347 PD patients; the frequencies were similar to Spitz et al 17 , with 13/347 mutations in PD patients (3.7%) and 0/341 mutations in controls (0%); with 1.4% being p.N370S carriers and 2.3% c.L444P carriers (Table 3).…”

Section: Discussionsupporting

confidence: 68%

“…We recorded higher frequencies of heterozygous patients (7.4%) GBA c.1226A>G; p.N370S and c.1448T>C; p.L444P alleles than those reported in three other studies of Brazilian PD populations 17,24,26 . Spitz et al 17 found only two (3.1%) of 65 PD patients from southeastern Brazil with mutations of the GBA gene (both heterozygous for GBA c.1448T>C; p.L444P), while no mutations were recorded in any of the 267 control participants (p = 0.0379).…”

Section: Discussioncontrasting

confidence: 54%

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GBA mutations p.N370S and p.L444P are associated with Parkinson's disease in patients from Northern Brazil

Amaral

Lopes

Ferreira

et al. 2019

Arq. Neuro-Psiquiatr.

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Mutations of the GBA gene have been reported in patients with Parkinson's disease (PD) from a number of different countries, including Brazil. In order to confirm this pattern in a sample of PD patients from northern Brazil, we conducted a case-control study of the occurrence of the two most common mutations of the GBA gene (c.1226A>G; p.N370S and c.1448T>C; p.L444P) in a group of 81 PD patients and 81 control individuals, using PCR-RFLP, confirmed by the direct sequencing of the PCR products. In the patient group, three patients (3.7%) were heterozygous for the GBA c.1226A>G; p.N370S mutation, and three (3.7%) for GBA c.1448T>C; p.L444P Neither mutation was detected in the control group (p =0.0284). Patients with the c.1448T>C; p.L444P mutation showed a tendency to have an earlier disease onset, but a larger sample number is required to confirm this observation. Our results suggest an association between the GBA c.1226A>G; p.N370S and c.1448T>C; p.L444P mutations and the development of PD in the population of patients from the Northern Brazil.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 68%

Section: Discussioncontrasting

confidence: 54%

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GBA mutations p.N370S and p.L444P are associated with Parkinson's disease in patients from Northern Brazil

Amaral

Lopes

Ferreira

et al. 2019

Arq. Neuro-Psiquiatr.

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“…The percentage of GBA mutation carriers has been slightly lower in other AJ PD cohorts, but the association between GBA and IPD in Ashkenazim remains robust 10, 22 . While it was initially unclear whether GBA mutations conferred an epidemiologically significant risk for IPD in other ethnic populations, the association between GBA mutations and IPD has been confirmed worldwide 23, 24 , although the predominant mutations and the magnitude of epidemiological risk varies from population to population 5-7, 25-39 .…”

Section: The Evidence Linking Gba and Parkinsonismmentioning

confidence: 99%

The Association Between ß-Glucocerebrosidase Mutations and Parkinsonism

Swan

Saunders‐Pullman

2013

Curr Neurol Neurosci Rep

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Mutations in the ß-glucocerebrosidase gene (GBA), which encodes the lysosomal enzyme ß-glucocerebrosidase, have traditionally been implicated in Gaucher disease, an autosomal-recessive lyososomal storage disorder. Yet the past two decades have yielded an explosion of epidemiological and basic-science evidence linking mutations in GBA with the development of Parkinson disease as well. Although the specific contribution of mutant GBA to the pathogenesis of parkinsonism remains unknown, evidence suggests both loss of function and toxic gain-of-function by abnormal ß-glucocerebrosidase may be important, and a close relationship between ß-glucocerebrosidase and α-synuclein. Furthermore, multiple lines of evidence suggest that while GBA-associated PD closely mimics idiopathic PD (IPD), it may present at a younger age, and is more frequently complicated by cognitive dysfunction. Understanding the clinical association between GBA and PD, and the relationship between ß-glucocerebrosidase and α-synuclein, may enhance understanding of the pathogenesis of IPD, improve prognostication and treatment of GBA carriers with parkinsonism, and may furthermore inform therapies for IPD not due to GBA mutations.

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“…early reports of Parkinsonism in GD patients and their heterozygote carrier family members unaffected by GD [3], it was found that heterozygote mutations confer a significant risk for developing PPD [4][5][6]. Heterozygotes have a 10-30% chance of developing PD by age 80, which constitutes a 20-fold increase compared to non-carriers [7][8][9][10], and approximately 5-25% of "idiopathic" PD patients carry GBA mutations, making GBA mutations the greatest risk factor for PD discovered to date [11,12].…”

Section: G O'regan Et Al / Gba In Parkinson Diseasementioning

confidence: 99%

Glucocerebrosidase Mutations in Parkinson Disease

O’Regan

deSouza

Balestrino

et al. 2017

JPD

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Abstract.Following the discovery of a higher than expected incidence of Parkinson Disease (PD) in Gaucher disease, a lysosomal storage disorder, mutations in the glucocerebrocidase (GBA) gene, which encodes a lysosomal enzyme involved in sphingolipid degradation were explored in the context of idiopathic PD. GBA mutations are now known to be the single largest risk factor for development of idiopathic PD. Clinically, on imaging and pharmacologically, GBA PD is almost identical to idiopathic PD, other than certain features that can be identified in the specialist research setting but not in routine clinical practice. In patients with a known GBA mutation, it is possible to monitor for prodromal signs of PD. The clinical similarity with idiopathic PD and the chance to identify PD at a pre-clinical stage provides a unique opportunity to research therapeutic options for early PD, before major irreversible neurodegeneration occurs. However, to date, the molecular mechanisms which lead to this increased PD risk in GBA mutation carriers are not fully elucidated. Experimental models to define the molecular mechanisms and test therapeutic options include cell culture, transgenic mice and other in vivo models amenable to genetic manipulation, such as drosophilia. Some key pathological pathways of interest in the context of GBA mutations include alpha synuclein aggregation, lysosomal-autophagy axis changes and endoplasmic reticulum stress. Therapeutic agents that exploit these pathways are being developed and include the small molecule chaperone Ambroxol. This review aims to summarise the main features of GBA-PD and provide insights into the pathological relevance of GBA mutations on molecular pathways and the therapeutic implications for PD resulting from investigation of the role of GBA in PD.

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Glucocerebrosidase N370S and L444P mutations as risk factors for Parkinson’s disease in Brazilian patients

Cited by 21 publications

References 4 publications

GBA mutations p.N370S and p.L444P are associated with Parkinson's disease in patients from Northern Brazil

GBA mutations p.N370S and p.L444P are associated with Parkinson's disease in patients from Northern Brazil

The Association Between ß-Glucocerebrosidase Mutations and Parkinsonism

Glucocerebrosidase Mutations in Parkinson Disease

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