The enigma of the E326K mutation in acid β-glucocerebrosidase

Horowitz, Mia; Pasmanik‐Chor, Metsada; Ron, Idit; Kolodny, Edwin H.

doi:10.1016/j.ymgme.2011.07.002

Cited by 49 publications

(44 citation statements)

References 39 publications

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“…Our data are in line with previous in vitro studies, which described the N188S as a modifier variant 17 and the E326K as a very mild mutation. 18 However, while the N188S has been found as a single mutation in GD patients, the E326K has always appeared in association with another mutation on the same allele. As previously reported, mutants N370S and L444P retained a residual activity of 38 and 13% of WT, respectively.…”

Section: Resultsmentioning

confidence: 99%

Functional analysis of 11 novel GBA alleles

et al. 2013

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Gaucher disease is the most frequent lysosomal storage disorder due to the deficiency of the acid b-glucosidase, encoded by the GBA gene. In this study, we report the structural and functional characterization of 11 novel GBA alleles. Seven single missense alleles, P159S, N188I, E235K, P245T, W312S, S366R and W381C, and two alleles carrying in cis mutations, (N188S; G265R) and (E326K; D380N), were studied for enzyme activity in transiently transfected cells. All mutants were inactive except the P159S, which retained 15% of wild-type activity. To further characterize the alleles carrying two in cis mutations, we expressed constructs bearing singly each mutation. The presence of G265R or D380N mutations completely abolished enzyme activity, while N188S and E326K mutants retained 25 and 54% of wild-type activity, respectively. Two mutations, affecting the acceptor splice site of introns 5 (c.589-1G4A) and 9 (c.1389-1G4A), led to the synthesis of aberrant mRNA. Unpredictably, family studies showed that two alleles resulted from germline or 'de novo' mutations. These results strengthen the importance of performing a complete and accurate molecular analysis of the GBA gene in order to avoid misleading conclusions and provide a comprehensive functional analysis of new GBA mutations.

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Section: Resultsmentioning

confidence: 99%

Functional analysis of 11 novel GBA alleles

et al. 2013

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“…The fact that the magnitude of the effect of E326K on progression of motor symptoms (Table 4) and cognitive dysfunction (Table 5) is similar to or larger than that of GBA mutations is somewhat surprising because E326K does not cause Gaucher disease. 23,25–29 However, although E326K is a nonconserved residue and is not predicted to significantly alter glucocerebrosidase enzyme activity in silico , several studies expressing GBA constructs with E326K suggest that this polymorphism reduces enzyme activity. 27,30,31 …”

Section: Discussionmentioning

confidence: 99%

Association ofGBAMutations and the E326K Polymorphism With Motor and Cognitive Progression in Parkinson Disease

et al. 2016

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“…There is some evidence to suggest that E326K in a compound heterozygous state can act as a modifying factor, eventually inducing a pathogenic effect. Nevertheless, its own role in homozygous and single heterozygous states remains controversial [38]. A recent work developed by Alcalay et al shows a lower glucocerebrosidase enzymatic activity in those subjects carrying E326K than in the group of non-mutation carriers [39].…”

Section: Discussionmentioning

confidence: 99%

GBA Variants Influence Motor and Non-Motor Features of Parkinson’s Disease

et al. 2016

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The presence of mutations in glucocerebrosidase (GBA) gene is a known factor increasing the risk of developing Parkinson’s disease (PD). Mutations carriers have earlier disease onset and are more likely to develop neuropsychiatric symptoms than other sporadic PD cases. These symptoms have primarily been observed in Parkinson’s patients carrying the most common pathogenic mutations L444P and N370S. However, recent findings suggest that other variants across the gene may have a different impact on the phenotype as well as on the disease progression. We aimed to explore the influence of variants across GBA gene on the clinical features and treatment related complications in PD. In this study, we screened the GBA gene in a cohort of 532 well-characterised PD patients and 542 controls from southern Spain. The potential pathogeniticy of the identified variants was assessed using in-silico analysis and subsequently classified as benign or deleterious. As a result, we observed a higher frequency of GBA variants in PD patients (12.2% vs. 7.9% in controls, p = 0.021), earlier mean age at disease onset in GBA variant carriers (50.6 vs. 56.6 years; p = 0.013), as well as more prevalent motor and non-motor symptoms in patients carrying deleterious variants. In addition, we found that dopaminergic motor complications are influenced by both benign and deleterious variants. Our results highlight the fact that the impact on the phenotype highly depends on the potential pathogenicity of the carried variants. Therefore, the course of motor and non-motor symptoms as well as treatment-related motor complications could be influenced by GBA variants.

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The enigma of the E326K mutation in acid β-glucocerebrosidase

Cited by 49 publications

References 39 publications

Functional analysis of 11 novel GBA alleles

Functional analysis of 11 novel GBA alleles

Association ofGBAMutations and the E326K Polymorphism With Motor and Cognitive Progression in Parkinson Disease

GBA Variants Influence Motor and Non-Motor Features of Parkinson’s Disease

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