The Association between E326K of <i>GBA</i> and the Risk of Parkinson’s Disease

Huang, Yongpan; Deng, Langmei; Zhong, Yanjun; Yi, Minhan

doi:10.1155/2018/1048084

Cited by 32 publications

(33 citation statements)

References 28 publications

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“…p.E365K is not itself associated with GD, and only results in a mild loss-of-function enzyme. A recent meta-analysis indicates that there is a correlation between this mutation and PD in total populations (OR = 1.99; 95% CI = 1.57-2.51) [25]. That study also found that p.E365K predicted a more rapid progression of cognitive decline and motor symptom dysfunction.…”

Section: Modest Risk Variants: Pn409s Pe365k and Pt408 Mmentioning

confidence: 76%

Nanopore sequencing of the glucocerebrosidase (GBA) gene in a New Zealand Parkinson's disease cohort

Graham

Pitcher

Liau

et al. 2020

Parkinsonism & Related Disorders

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Introduction: Bi-allelic mutations in the gene for glucocerebrosidase (GBA) cause Gaucher disease, an autosomal recessive lysosomal storage disorder. Gaucher disease causing GBA mutations in the heterozygous state are also high risk factors for Parkinson's disease (PD). GBA analysis is challenging due to a related pseudogene and structural variations (SVs) that can occur at this locus. We have applied and refined a recently developed nanopore DNA sequencing method to analyze GBA variants in a clinically assessed New Zealand longitudinal cohort of PD. Method: We examined amplicons encompassing the coding region of GBA (8.9 kb) from 229 PD cases and 50 healthy controls using the GridION nanopore sequencing platform, and Sanger validation. Results: We detected 23 variants in 21 PD cases (9.2% of patients). We detected modest PD risk variant p.N409S (rs76763715) in one case, p.E365K (rs2230288) in 12 cases, and p.T408 M (rs75548401) in seven cases, one of whom also had p.E365K. We additionally detected the possible risk variants p.R78C (rs146774384) in one case, p.D179H (rs147138516) in one case which occurred on the same haplotype as p.E365K, and one novel variant c.335C > T or p.(L335 =), that potentially impacts splicing of GBA transcripts. Additionally, we found a higher prevalence of dementia among patients with GBA variants. Conclusion: This work confirmed the utility of nanopore sequencing as a high-throughput method to identify known and novel GBA variants, and to assign precise haplotypes. Our observations may contribute to improved understanding of the effects of variants on disease pathogenesis, and to the development of more targeted treatments.

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Section: Modest Risk Variants: Pn409s Pe365k and Pt408 Mmentioning

confidence: 76%

Nanopore sequencing of the glucocerebrosidase (GBA) gene in a New Zealand Parkinson's disease cohort

Graham

Pitcher

Liau

et al. 2020

Parkinsonism & Related Disorders

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“…E365K is not itself associated with GD, and only results in a mild loss-of-function enzyme. A recent meta-analysis indicates that there is a correlation between this mutation and PD in total populations, Asians, and Caucasians, respectively (OR = 1.99; 95% CI) [27]. That study also found that E365K predicted a more rapid progression of cognitive decline and motor symptom dysfunction.…”

Section: Modest Risk Alleles: E365k and T408mmentioning

confidence: 78%

Nanopore sequencing of the glucocerebrosidase (GBA) gene in a New Zealand Parkinson’s disease cohort

Graham

Pitcher

Liau

et al. 2019

Preprint

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Highlights:-Validated nanopore sequencing of the GBA gene for mutation detection.-9.2% of patients from a New Zealand Parkinson's disease cohort carry GBA mutations.-Significantly higher prevalence of dementia in patients carrying GBA mutations -Three novel mutations were detected including a putative splicing variant.-Single molecule reads of GBA amplicons revealed 74 different GBA haplotypes. Abstract Introduction:Mutations in the gene for glucocerebrosidase (GBA) cause Gaucher disease, an autosomal recessive lysosomal storage disorder. GBA mutation carriers have an elevated risk of Parkinson's disease (PD) compared with non-carriers and can experience a more aggressive disease. GBA analysis is technically challenging due to a related pseudogene and structural variations (SVs) that can occur at this locus. We have applied a recently developed nanopore sequencing method to analyze GBA variants in a clinically assessed New Zealand longitudinal cohort of PD. Method:We examined amplicons encompassing the coding region of GBA (8.9kb) from 229 PD cases using the GridION nanopore-sequencing platform. Mutations were Sanger validated. Results:We detected 23 mutations in 21 PD cases (9.2% of patients). We detected a strong PD risk allele p.N409S (rs76763715) in one case. Modest risk mutations included p.E365K (rs2230288) in 12 cases, and p.T408M (rs75548401) in seven cases, one of whom also had p.E365K. We additionally detected the possible risk alleles R78C (rs146774384) in one case, D179H (rs147138516) in one case which occurred on the same haplotype as an E365K allele, and one novel mutation p.L335=, that is predicted to impact splicing of GBA transcripts.Additionally, we found a higher prevalence of dementia among GBA mutation carriers. Conclusion:This work confirmed the utility of nanopore sequencing as a high-throughput method to identify known and novel GBA mutations, and to assign precise haplotypes. This work may contribute to understanding the effects of these mutations on disease pathogenesis, and to the development of more targeted treatments.

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“…Because the p.E326K and p.T369M variants do not cause Gaucher's disease, these have long been termed polymorphisms. However, it has been shown in metaanalyses that these variants do confer an increased risk of developing PD (OR, 1.99 for p.E326K and 1.74 for p.T369M) [31][32][33] and therefore, despite not causing GD, should not be considered neutral polymorphisms.…”

Section: Discussionmentioning

confidence: 99%

A Large‐Scale Full GBA1 Gene Screening in Parkinson's Disease in the Netherlands

et al. 2020

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Background The most common genetic risk factor for Parkinson's disease known is a damaging variant in the GBA1 gene. The entire GBA1 gene has rarely been studied in a large cohort from a single population. The objective of this study was to assess the entire GBA1 gene in Parkinson's disease from a single large population. Methods The GBA1 gene was assessed in 3402 Dutch Parkinson's disease patients using next‐generation sequencing. Frequencies were compared with Dutch controls (n = 655). Family history of Parkinson's disease was compared in carriers and noncarriers. Results Fifteen percent of patients had a GBA1 nonsynonymous variant (including missense, frameshift, and recombinant alleles), compared with 6.4% of controls (OR, 2.6; P < 0.001). Eighteen novel variants were detected. Variants previously associated with Gaucher's disease were identified in 5.0% of patients compared with 1.5% of controls (OR, 3.4; P < 0.001). The rarely reported complex allele p.D140H + p.E326K appears to likely be a Dutch founder variant, found in 2.4% of patients and 0.9% of controls (OR, 2.7; P = 0.012). The number of first‐degree relatives (excluding children) with Parkinson's disease was higher in p.D140H + p.E326K carriers (5.6%, 21 of 376) compared with p.E326K carriers (2.9%, 29 of 1014); OR, 2.0; P = 0.022, suggestive of a dose effect for different GBA1 variants. Conclusions Dutch Parkinson's disease patients display one of the largest frequencies of GBA1 variants reported so far, consisting in large part of the mild p.E326K variant and the more severe Dutch p.D140H + p.E326K founder allele. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC. on behalf of International Parkinson and Movement Disorder Society.

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The Association between E326K of GBA and the Risk of Parkinson’s Disease

Cited by 32 publications

References 28 publications

Nanopore sequencing of the glucocerebrosidase (GBA) gene in a New Zealand Parkinson's disease cohort

Nanopore sequencing of the glucocerebrosidase (GBA) gene in a New Zealand Parkinson's disease cohort

Nanopore sequencing of the glucocerebrosidase (GBA) gene in a New Zealand Parkinson’s disease cohort

A Large‐Scale Full GBA1 Gene Screening in Parkinson's Disease in the Netherlands

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