Mutations of glucocerebrosidase gene and susceptibility to Parkinson’s disease: An updated meta-analysis in a European population

Zhao, Feng; Bi, Liu; Wang, W.; Wu, Xiaoxiao; Li, Y.; Gong, Feng-Feng; Lu, Shanshan; Feng, Fan; Qian, Zhiguo; Hu, Chao; Wu, Yun; Sun, Yehuan

doi:10.1016/j.neuroscience.2016.02.007

Cited by 27 publications

(30 citation statements)

References 38 publications

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“…For none of the patients in our study, a Jewish background was reported. Our observations are in line with previous studies, which scanned the entire gene and showed population‐specific frequencies between 4.2% and 9.8% for GBA carriers in PD cases of non‐Ashkenazi Jewish ancestry . The targeted next‐generation sequencing study from Spain had detected GBA variants in 17.8% of their EOPD cases and other studies focused on EOPD showed frequencies of 11.4% in a Greek sample and 25% in a sample from the United Kingdom .…”

Section: Discussionsupporting

confidence: 91%

“…Currently, the classification of low penetrance variants, which may reach higher frequencies than our frequency cutoff, is challenging, because in-silico prediction tools are still prone to mis- which scanned the entire gene and showed population-specific frequencies between 4.2% and 9.8% for GBA carriers in PD cases of non-Ashkenazi Jewish ancestry. 5,46 The targeted next-generation sequencing study from Spain had detected GBA variants in 17.8% of their EOPD cases and other studies focused on EOPD showed frequencies of 11.4% in a Greek sample and 25% in a sample from the United Kingdom. 47,48 To our knowledge, we are the first study to report a high frequency of GBA variants in Czech EOPD patients.…”

Section: Discussionmentioning

confidence: 99%

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Diagnostic exome sequencing in early‐onset Parkinson's disease confirms VPS13C as a rare cause of autosomal‐recessive Parkinson's disease

et al. 2018

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Parkinson's disease (PD) is a genetically heterogeneous disorder and new putative disease genes are discovered constantly. Therefore, whole-exome sequencing could be an efficient approach to genetic testing in PD. To evaluate its performance in early-onset sporadic PD, we performed diagnostic exome sequencing in 80 individuals with manifestation of PD symptoms at age 40 or earlier and a negative family history of PD. Variants in validated and candidate disease genes and risk factors for PD and atypical Parkinson syndromes were annotated, followed by further analysis for selected variants. We detected pathogenic variants in Mendelian genes in 6.25% of cases and high-impact risk factor variants in GBA in 5% of cases, resulting in overall maximum diagnostic yield of 11.25%. One individual was compound heterozygous for variants affecting canonical splice sites in VPS13C, confirming the causal role of protein-truncating variants in this gene linked to autosomal-recessive early-onset PD. Despite the low diagnostic yield of exome sequencing in sporadic early-onset PD, the confirmation of the recently discovered VPS13C gene highlights its advantage over using predefined gene panels.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Diagnostic exome sequencing in early‐onset Parkinson's disease confirms VPS13C as a rare cause of autosomal‐recessive Parkinson's disease

et al. 2018

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“…Though GD is present across all ethnicities, it is much more frequent in the Ashkenazi Jewish population 6 . People diagnosed with the α-synucleinopathies Parkinson disease (PD) and dementia with Lewy bodies (DLB) are 5–10 fold 7 and 8 fold 8 (respectively) more likely to carry GBA variants than healthy controls. The prevalence of GBA variants in Alzheimer’s disease (AD) has been found to be similar to the prevalence in controls 9 .…”

Section: Introductionmentioning

confidence: 99%

Frequency of GBA Variants in Autopsy‐proven Multiple System Atrophy

Sklerov

Kang

Liong

et al. 2017

Movement Disord Clin Pract

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Background Multiple system atrophy (MSA) is marked by abnormal inclusions of alpha-synuclein in oligodendrogliocytes. Etiology remains unknown. Variants in the glucocerebrosidase gene have been associated with other synucleinopathies, dementia with Lewy bodies and Parkinson disease. It is unclear whether glucocerebrosidase variants are associated with MSA. Objectives To analyze the frequency of glucocerebrosidase gene variants among autopsy-proven cases of MSA at a brain bank in New York City. Methods The glucocerebrosidase gene was fully sequenced in the 17 autopsy-proven MSA cases with extractable DNA at the Columbia University New York Brain Bank from 2002 to 2016. To test if the MSA cases in the brain bank are enriched for GBA variants, we compared the GBA variant frequency in MSA to all brain bank cases with pure Alzheimer’s disease (AD) at Columbia University for whom GBA genotype was available (n=82). Results 4/17 (23.5%) MSA cases carried glucocerebrosidase gene variants, including an individual homozygous for N370S, and one each who were heterozygous carriers of N370S, T369M and R496H. Among the comparator cases with pure AD, 3 of the 82 autopsies (3.7%) carried GBA variants (P = 0.0127, Fisher exact test), including one case each of N370S homozygote, and R496H and T369M heterozygous variant. Conclusion We found a higher frequency of glucocerebrosidase variants among pathologically diagnosed MSA cases in our brain bank compared to AD autopsies. This study demonstrates the need for further investigation into the role of glucocerebrosidase and lysosomal dysfunction in the etiology of MSA.

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“…For instance, one study showed that GCase activity from peripheral blood spots categorized by mutation did not correlate with the severity of those individual mutations in terms of PD. L444P PD cases for instance appear to have higher GCase activity than those with N370S, even though L444P mutations convey between two and three times the risk of PD compared to N370S [11,26,27]. Equally, heterozygous carriers of the 84GG mutation, which is a frameshift mutation and would be expected to be null in terms of GCase activity, had comparable enzyme activity with other missense GBA mutations [28,29].…”

Section: Mechanistic Explanations For Ngd and Gba Pdmentioning

confidence: 94%

Neurological effects of glucocerebrosidase gene mutations

Mullin

Hughes²,

Mehta³

et al. 2018

Euro J of Neurology

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The association between Gaucher disease ( GD ) and Parkinson disease ( PD ) has been described for almost two decades. In the biallelic state (homozygous or compound heterozygous) mutations in the glucocerebrosidase gene ( GBA ) may cause GD , in which glucosylceramide, the sphingolipid substrate of the glucocerebrosidase enzyme ( GC ase), accumulates in visceral organs leading to a number of clinical phenotypes. In the biallelic or heterozygous state, GBA mutations increase the risk for PD . Mutations of the GBA allele are the most significant genetic risk factor for idiopathic PD , found in 5%–20% of idiopathic PD cases depending on ethnicity. The neurological consequences of GBA mutations are reviewed and the proposition that GBA mutations result in a disparate but connected range of clinically and pathologically related neurological features is discussed. The literature relating to the clinical, biochemical and genetic basis of GBA PD , type 1 GD and neuronopathic GD is considered highlighting commonalities and distinctions between them. The evidence for a unifying disease mechanism is considered.

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Mutations of glucocerebrosidase gene and susceptibility to Parkinson’s disease: An updated meta-analysis in a European population

Cited by 27 publications

References 38 publications

Diagnostic exome sequencing in early‐onset Parkinson's disease confirms VPS13C as a rare cause of autosomal‐recessive Parkinson's disease

Diagnostic exome sequencing in early‐onset Parkinson's disease confirms VPS13C as a rare cause of autosomal‐recessive Parkinson's disease

Frequency of GBA Variants in Autopsy‐proven Multiple System Atrophy

Neurological effects of glucocerebrosidase gene mutations

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