Gaucher disease: mutation and polymorphism spectrum in the glucocerebrosidase gene (GBA)

Hruska, Kathleen S.; LaMarca, Mary E.; Scott, C. Ronald; Sidransky, Ellen

doi:10.1002/humu.20676

Cited by 587 publications

(578 citation statements)

References 171 publications

(136 reference statements)

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“…The HRs for global cognitive impairment in mutation carriers versus noncarriers from the Mantel‐Haenszel procedure were examined for each of the seven independent cohorts. Proportional HRs across studies were homogeneous with I2 = 40.5%, p = 0.21 by Cochran's Q‐test for heterogeneity, suggesting it was not imperative, though permissible, to analyze “studies” as a random term in order to allow a more‐universal inference.…”

Section: Resultsmentioning

confidence: 99%

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

Liu

Boot

Locascio

et al. 2016

Annals of Neurology

236

240

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ObjectiveWe hypothesized that specific mutations in the β‐glucocerebrosidase gene (GBA) causing neuropathic Gaucher's disease (GD) in homozygotes lead to aggressive cognitive decline in heterozygous Parkinson's disease (PD) patients, whereas non‐neuropathic GD mutations confer intermediate progression rates.MethodsA total of 2,304 patients with PD and 20,868 longitudinal visits for up to 12.8 years (median, 4.1) from seven cohorts were analyzed. Differential effects of four types of genetic variation in GBA on longitudinal cognitive decline were evaluated using mixed random and fixed effects and Cox proportional hazards models.ResultsOverall, 10.3% of patients with PD and GBA sequencing carried a mutation. Carriers of neuropathic GD mutations (1.4% of patients) had hazard ratios (HRs) for global cognitive impairment of 3.17 (95% confidence interval [CI], 1.60–6.25) and a hastened decline in Mini–Mental State Exam scores compared to noncarriers (p = 0.0009). Carriers of complex GBA alleles (0.7%) had an HR of 3.22 (95% CI, 1.18–8.73; p = 0.022). By contrast, the common, non‐neuropathic N370S mutation (1.5% of patients; HR, 1.96; 95% CI, 0.92–4.18) or nonpathogenic risk variants (6.6% of patients; HR, 1.36; 95% CI, 0.89–2.05) did not reach significance.InterpretationMutations in the GBA gene pathogenic for neuropathic GD and complex alleles shift longitudinal cognitive decline in PD into “high gear.” These findings suggest a relationship between specific types of GBA mutations and aggressive cognitive decline and have direct implications for improving the design of clinical trials. Ann Neurol 2016;80:674–685

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Section: Resultsmentioning

confidence: 99%

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

Liu

Boot

Locascio

et al. 2016

Annals of Neurology

236

240

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“…Since many recombinant mutations caused by unequal recombination between functional GBA and pseudo-GBA have been recently found [6,8], it is very likely that the rate of genotyping will be increased by recombinant mutation studies. In this study, we identified 4 recombinant alleles in 4 patients ( Table 1).…”

Section: Resultsmentioning

confidence: 99%

“…Allelic heterogeneity in GD has been well described [7,8]. To date, more than 270 different GBA mutations have been reported in the Human Gene Mutation Database at the Institute of Medical Genetics in Cardiff (www.hgmd.cf.ac.uk).…”

Section: Introductionmentioning

confidence: 99%

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Clinical and genetic characteristics of Korean patients with Gaucher disease

Jeong

Park²,

Kim

2011

Blood Cells, Molecules, and Diseases

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“…4 To date, several GBA recombinant mutations, including gene conversion alleles and, less frequently, reciprocal crossing over alleles, have been identified and referred to by various aliases. 5 In this study, we report four GBA recombinant mutations including one novel allele identified in Korean GD patients using a long-range PCR approach.…”

Section: Introductionmentioning

confidence: 94%

Identification of a novel recombinant mutation in Korean patients with Gaucher disease using a long-range PCR approach

et al. 2011

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Gaucher disease (GD) is an autosomal recessive, lysosomal disorder caused by mutations in the gene for the b-glucocerebrosidase (GBA) enzyme. Presence of the non-functional GBAP pseudogene, which shares high sequence similarity with the functional GBA gene, has made it difficult to carry out molecular analyses of GD, especially recombinant mutations. Using a long-range PCR approach that has been skillfully devised for the easy detection of GBA recombinant mutations, we identified four recombinant mutations including two gene conversion alleles, Rec 1a and Rec 8a, one reciprocal gene fusion allele, Rec 1b, and one reciprocal gene duplication allele, Rec 7b, in Korean patients with GD. Rec 8a, in which the GBAP pseudogene sequence from intron 5 to exon 11 is substituted for the GBA gene is a novel recombinant mutation. All mutations were confirmed by full sequencing of PCR amplicons and/or Southern blot analysis. These results indicate that the usage of long-range PCR may allow the rapid and accurate detection of GBA recombinant mutations and contribute to the improvement of genotyping efficiency in GD patients.

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Gaucher disease: mutation and polymorphism spectrum in the glucocerebrosidase gene (GBA)

Cited by 587 publications

References 171 publications

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

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

Clinical and genetic characteristics of Korean patients with Gaucher disease

Identification of a novel recombinant mutation in Korean patients with Gaucher disease using a long-range PCR approach

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