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Gaucher disease is classified into neuronopathic and non-neuronopathic forms with wide phenotypic variation among patients sharing the same genotype. While homozygosity for the common L444P allele usually correlates with the neuronopathic forms, how a defined genotype leads to a phenotype remains unknown.
The genetic and epigenetic factors causing...
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... had a recombinant or a fusion allele. Table 1 summarises the demographics and clinical course in this cohort. Among the 32 L444P homozygotes, there was a wide range of geographical and ethnic backgrounds, includ- ing three from the Norrbottnian region of Sweden, ten of Hispanic origin, two African-Americans, and one with Hispanic and Iranian heritage. ...
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Citations
... More than 400 GBA1 mutations have already been described, leading to an altered enzymatic activity and, in most cases, to systemic manifestations that involve the spleen, liver, bone marrow, lungs, and central nervous system [2][3][4] . GD is clinically classified into three major groups based on the absence (GD type 1) or presence and rate of progression of neurological manifestations (GD type 2 and 3) [5][6][7][8][9] . However, these categories are not strictly separated and, especially among the neuronopathic forms, there are many cases presenting an intermediate phenotype. ...
... Little is known about the molecular events leading to the different phenotypic manifestations and driving the wide clinical spectrum deriving from a common mutational event in the GBA1 gene. Also, the lack of correlation between the residual GCase activity and disease severity 6 supports the hypothesis that other modifier genes exist underlying the phenotypic variation. ...
Gaucher Disease (GD), the most common lysosomal disorder, arises from mutations in the GBA1 gene and is characterized by a wide spectrum of phenotypes, ranging from mild hematological and visceral involvement to severe neurological disease. Neuronopathic patients display dramatic neuronal loss and increased neuroinflammation, whose molecular basis are still unclear. Using a combination of Drosophila dGBA1b loss-of-function models and GD patient-derived iPSCs differentiated towards neuronal precursors and mature neurons we showed that different GD- tissues and neuronal cells display an impairment of growth mechanisms with an increased cell death and reduced proliferation. These phenotypes are coupled with the downregulation of several Hippo transcriptional targets, mainly involved in cells and tissue growth, and YAP exclusion from nuclei. Interestingly, Hippo knock-down in the GBA-KO flies rescues the proliferative defect, suggesting that targeting the Hippo pathway can be a promising therapeutic approach to neuronopathic GD.
... While it is accepted that patients with type 2 GD harbor more severe variants in GBA1 (Stone, Tayebi, Orvisky, et al., 2000), both the early clinical manifestations and the spectrum of variants associated can overlap with type 3 GD. Usually, genotype L444P/L444P (p.L483P/p.483P) is associated with GD3 (Goker- Alpan et al., 2005), while a null allele in combination with L444P or homozygosity for a null allele alone is associated with GD2 (Weiss et al., 2015). However, other genotypes such as R463C(p.R502C)/ null or D409H (p.D448H)/null, among others, are found both in patients with GD2 and GD3. ...
Gaucher disease (GD) is an autosomal recessive disorder resulting from glucocerebrosidase deficiency due to pathologic variants in GBA1. While clinically heterogeneous, GD encompasses three types, non-neuronopathic (GD1), acute neuronopathic (GD2), and chronic neuronopathic (GD3). Newborn screening (NBS), which has made remarkable inroads in detecting certain diseases before detrimental health consequences and fatality ensues, is now being piloted for GD in several states and countries. Early on, clinical features of GD2 can overlap with GD3; hence, predicting outcome is challenging. As NBS for GD becomes more available, the increased detection of GD in neonates is inevitable. As a result, health care providers and families will be faced with uncertainty with respect to clinical management. Since more severe GBA1 variants are generally associated with neuronopathic GD, there has been an increased dependence on genotypic information. We present an infant detected by NBS with genotype D409H(p.Asp448His)/RecNciI (p.Leu483Pro; p.Ala495Pro;p.Val499=). To assist in genetic counseling, we performed a retrospective review of other patients in our cohort carrying D409H and reviewed the literature. The study illustrates the challenges faced in counseling for infants with neuronopathic GD, even with known GBA1 variants, and the tough management decisions that can ensue from detection in newborns.
... While our stability-based PRAMP classifier is attractive, other factors need to be considered when predicting disease severity, such as genetic background [44] and environmental factors [45]. For instance, patients homozygous for L444P present with a quite different clinical course depending on their genetic background [46], even though all have nGD. This suggests that the PRAMP score could be used to predict the type of GD, that is, type 1, 2, or 3, but may need to be combined with other factors in order to distinguish subtle differences in the clinical course of each type of disease in individual patients. ...
Acid‐β‐glucosidase (GCase, EC3.2.1.45), the lysosomal enzyme which hydrolyzes the simple glycosphingolipid, glucosylceramide (GlcCer), is encoded by the GBA1 gene. Biallelic mutations in GBA1 cause the human inherited metabolic disorder, Gaucher disease (GD), in which GlcCer accumulates, while heterozygous GBA1 mutations are the highest genetic risk factor for Parkinson's disease (PD). Recombinant GCase (e.g., Cerezyme®) is produced for use in enzyme replacement therapy for GD and is largely successful in relieving disease symptoms, except for the neurological symptoms observed in a subset of patients. As a first step toward developing an alternative to the recombinant human enzymes used to treat GD, we applied the PROSS stability‐design algorithm to generate GCase variants with enhanced stability. One of the designs, containing 55 mutations compared to wild‐type human GCase, exhibits improved secretion and thermal stability. Furthermore, the design has higher enzymatic activity than the clinically used human enzyme when incorporated into an AAV vector, resulting in a larger decrease in the accumulation of lipid substrates in cultured cells. Based on stability‐design calculations, we also developed a machine learning‐based approach to distinguish benign from deleterious (i.e., disease‐causing) GBA1 mutations. This approach gave remarkably accurate predictions of the enzymatic activity of single‐nucleotide polymorphisms in the GBA1 gene that are not currently associated with GD or PD. This latter approach could be applied to other diseases to determine risk factors in patients carrying rare mutations.
... Different theories have been formulated to explain how and to which extent GCase deficiency contributes to neurodegeneration [12]. It has been hypothesized that a central role could be played by the endolysosomal compartment where GlcCer accumulation could directly influence the abnormal lysosomal storage of alpha-synuclein oligomers, thus resulting in a further inhibition of GCase activity. ...
Beta-glucocerebrosidase is a lysosomal hydrolase involved in the catabolism of the sphin-golipid glucosylceramide. Biallelic loss of function mutations in this enzyme are responsible for the onset of Gaucher disease, while monoallelic β-glucocerebrosidase mutations represent the first genetic risk factor for Parkinson's disease. Despite this evidence, the molecular mechanism linking the impairment in β-glucocerebrosidase activity with the onset of neurodegeneration in still unknown. In this frame, we developed two in vitro neuronal models of β-glucocerebrosidase deficiency, represented by mouse cerebellar granule neurons and human-induced pluripotent stem cells-derived dopaminergic neurons treated with the specific β-glucocerebrosidase inhibitor conduritol B epox-ide. Neurons deficient for β-glucocerebrosidase activity showed a lysosomal accumulation of glu-cosylceramide and the onset of neuronal damage. Moreover, we found that neurons react to the lysosomal impairment by the induction of their biogenesis and exocytosis. This latter event was responsible for glucosylceramide accumulation also at the plasma membrane level, with an alteration in lipid and protein composition of specific signaling microdomains. Collectively, our data suggest that β-glucocerebrosidase loss of function impairs the lysosomal compartment, establishing a lysosome-plasma membrane axis responsible for modifications in the plasma membrane architecture and possible alterations of intracellular signaling pathways, leading to neuronal damage.
... The accumulation of these substrates is thought to drive development of the lysosomal storage disease known as Gaucher disease (GD) (2). Notably, GD patients show considerable phenotypic variability, particularly in the presence and severity of neuropathic symptoms, which are only weakly correlated to patient genotype (3)(4)(5). Underscoring the importance of GCase function within brain, its dysfunction has also emerged as the most prevalent genetic risk factor for Parkinson disease (PD), with 5-10% of PD patients carrying a mutation in GBA (6,7). A mechanistic role for loss of GCase activity contributing to PD pathogenesis is supported by observations that either chemical inhibition or loss of function mutations in GCase accelerates PD phenotypes (8,9). ...
Loss of activity of the lysosomal glycosidase β-glucocerebrosidase (GCase) causes the lysosomal storage disease Gaucher disease (GD) and has emerged as the greatest genetic risk factor for the development of both Parkinson disease (PD) and dementia with Lewy bodies. There is significant interest into how GCase dysfunction contributes to these diseases, however, progress toward a full understanding is complicated by presence of endogenous cellular factors that influence lysosomal GCase activity. Indeed, such factors are thought to contribute to the high degree of variable penetrance of GBA mutations among patients. Robust methods to quantitatively measure GCase activity within lysosomes are therefore needed to advance research in this area, as well as to develop clinical assays to monitor disease progression and assess GCase-directed therapeutics. Here, we report a selective fluorescence-quenched substrate, LysoFQ-GBA, which enables measuring endogenous levels of lysosomal GCase activity within living cells. LysoFQ-GBA is a sensitive tool for studying chemical or genetic perturbations of GCase activity using either fluorescence microscopy or flow cytometry. We validate the quantitative nature of measurements made with LysoFQ-GBA using various cell types and demonstrate that it accurately reports on both target engagement by GCase inhibitors and the GBA allele status of cells. Furthermore, through comparisons of GD, PD, and control patient-derived tissues, we show there is a close correlation in the lysosomal GCase activity within monocytes, neuronal progenitor cells, and neurons. Accordingly, analysis of clinical blood samples using LysoFQ-GBA may provide a surrogate marker of lysosomal GCase activity in neuronal tissue.
... El-Morsy et al. (31) reported p.Leu483Pro homozygosity in 23.1% of patients with Gaucher disease type I but none in patients with neuronopathic types. The phenotypic variability of p.Leu483Pro mutant allele has been attributed to the effect of modifier genes (25,35) . Of note, we can't exclude the possibility that some patients with Gaucher disease diagnosed as type I in this study may develop later-onset neurological features and, accordingly, would be reclassified as neuronopathic type. ...
... GBA analysis revealed that she was homozygous for the p.L483P (c.1448 T > C) variant. p.L483P is the most common pathogenic variant in Japanese patients with GD [22] and is involved in the development of neurological symptoms [23,24]. ERT was started at the age of 84 days and improved her anemia, thrombocytopenia, and hepatosplenomegaly. ...
... This variant is the most frequent in patients with neuropathic GD [33] and Japanese patients with GD [22]. Although most patients with the homozygous p.L483P variant develop GD3 [24,30], they may have a variety of clinical courses [23]. There is an unclear relationship between the clinical course of GD and residual GCase activity [23]. ...
... Although most patients with the homozygous p.L483P variant develop GD3 [24,30], they may have a variety of clinical courses [23]. There is an unclear relationship between the clinical course of GD and residual GCase activity [23]. Patient 3 showed slow horizontal saccades since the age of 1 year, whereas patient 4 had no horizontal saccades. ...
Gaucher disease (GD) is an autosomal recessive inborn metabolic disorder caused by a glucocerebrosidase (GCase) defect. GD is classified into three main types depending on accompanying neurological symptoms. Enzyme replacement therapy and substrate reduction therapy are limited in the treatment of neurological symptoms, and using genotype and GCase activity to discriminate between non-neuronopathic and neuronopathic GD may be challenging as the two sometimes phenotypically overlap. The number of patients exhibiting neurological symptoms in Japan is significantly higher than that in Europe and the United States, and newborn screening (NBS) is still not actively performed in Japan. Definitive determination of the actual frequency and proportion of the type of GD from the results of NBS remains inconclusive. We performed NBS for Fabry disease, Pompe disease, and GD, mainly in the Kyushu area in Japan. Herein, we discuss the results of NBS for GD, as well as, the insights gained from following the clinical course of patients diagnosed through NBS. A total of 155,442 newborns were screened using an enzyme activity assay using dried blood spots. We found four newborns showing lower GCase activity and were definitively diagnosed with GD by GBA gene analysis. The frequency of GD diagnosis through NBS was 1 in 77,720 when limited to the probands. This frequency is higher than that previously estimated in Japan. In the future, NBS for GD is expected to be performed in many regions of Japan and contribute to detecting more patients with GD. Early screening and diagnosis may have a very significant impact on the quality of life and potentially longevity in infants with GD.
... Therefore, no specific phenotype-genotype relationship has been defined thus far. [20] Giraldo et al. (2000) showed the high prevalence of the p.L483P in Spanish patients which suggested Hispanic ancestry among patients with this mutation. [21] According to studies conducted by Wilches et al. (2006), this is the most frequent mutation, among other GBA mutations, in the Colombian population, more specifically in the Cundinamarca and Boyacá regions. ...
Abstract Introduction Gaucher's disease (GD) is an autosomal-recessive lysosomal storage disorder that results from hereditary deficiency of the acid glucocerebrosidase enzyme, encoded by the GBA gene necessary for the degradation of glucosylceramide. Objective molecularly characterize the variants found in the GBA gene present in patients from the Southwest of Colombia with GD. Material and methods 19 patients were included in the study, clinically and enzymatically diagnosed with GD. A molecular analysis of the GBA gene was performed and the variants were subsequently searched in different population and clinical databases. A bioinformatic analysis was performed. Results The variants in the GBA gene reported were classified into: 14/19 homozygous patients, 4/19 compound heterozygote and 1/19 heterozygous. The presence of 7 variants coding for 8 different genotypes was reported. Also the known mutations like Asn409Ser, p.Leu483Pro, p.Lys237Glu, p.Glu427Lys, and p.Arg535His were identified in these patients. The most frequent genotype was p. Asn409Ser / Asn409Ser (36%). All the variants presented a pathogenic clinical significance. Conclusion The given study will make it possible to understand the susceptibility to GD in the population. This can help maintain the health quotient of the population through premarital counseling and therefore minimize the burden of disease among the population.
... As an inherited autosomal recessive mutation, both parents must be carriers for the child to be affected and even then, the possibility of having a GD affected child per single pregnancy is 25%. Though each of the three types of GD have the same type of inheritance, development of each type is based on a particular mutation presence in a homozygous or compound heterozygous genotype [17,18] . About 80 mutations in the GBA gene have been recognized and assigned to one of the three types of GD based on their associated signs, symptoms, and disease severity [14][15][16] . ...
... About 80 mutations in the GBA gene have been recognized and assigned to one of the three types of GD based on their associated signs, symptoms, and disease severity [14][15][16] . The (N370S) homozygote is associated with GD type I whereas the presence of one or two alleles (L444P) mutation is correlated with GD type II or III [17,18] . G B A n o r m a l l y e n c o d e s l y s o s o m a l glucocerebrosidase or β-glucosidase (Protein Data Bank: 1OGS). ...
... It is estimated that around 1 per 57,000 newborns is affected worldwide [1]. The disease's phenotype is associated with a mutation in the lysosomal glucosylceramidase (GBA) gene; however, it differs remarkably even in patients with the same type of mutation [2][3][4]. Three types of GD are recognized upon central nervous system (CNS) involvement: nonneuronopathic (GD type 1: OMIM #230800), acute neuronopathic (GD type 2: OMIM #230900) and chronic neuronopathic (GD type 3: OMIM #231000). The most common form of GD, covering approximately 94% of cases, is type 1, which can manifest itself at any age [5]. ...
Aims:
The aim of the work was to establish potential biomarkers or drug targets by analysing changes in miRNA concentration among patients with Gaucher disease (GD) compared to in healthy subjects.
Methods:
This study was an observational, cross-sectional analysis of 30 adult participants: 10 controls and 20 adults with GD type 1. Patients with GD type 1 were treated with enzyme replacement therapy (ERT) for at least two years. The control group was composed of healthy volunteers, unrelated to the patients, adjusted with age, sex and body mass index (BMI). The miRNA alteration between these groups was examined. After obtaining preliminary results on a group of six GD patients by the high-output method (TaqMan low-density array (TLDA)), potential miRNAs were selected for confirming the results by using the qRT-PCR method. With Diane Tools, we analysed miRNAs of which differential expression is most significant and their potential role in GD pathophysiology. We also determined the essential pathways these miRNAs are involved in.
Results:
266 dysregulated miRNAs were found among 753 tested. Seventy-eight miRNAs were downregulated, and 188 were upregulated. Thirty miRNAs were significantly altered; all of them were upregulated. The analysis of pathways regulated by the selected miRNAs showed an effect on bone development, inflammation or regulation of axonal transmission in association with Parkinson's disease.
Conclusions:
We revealed few miRNAs, like miR-26-5p, which are highly altered and fit the GD pathophysiological model, might be considered as novel biomarkers of disease progression but need further evaluation.
