Evaluation of the detection of GBA missense mutations and other variants using the Oxford Nanopore MinION

ConclusionThe Oxford Nanopore MinION can detect missense mutations and an exonic deletion in this difficult gene, with the added advantages of phasing and intronic analysis. It can be used as an efficient research tool, but additional work is required to exclude all recombinants.
Source: Molecular Genetics & Genomic Medicine - Category: Genetics & Stem Cells Authors: Tags: METHOD Source Type: research

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Haploinsufficiency in the Gaucher disease GBA gene, which encodes the lysosomal glucocerebrosidase GBA, and ageing represent major risk factors for developing Parkinson ’s disease (PD). Recently, more than fifty o...
Source: Molecular Neurodegeneration - Category: Neurology Authors: Tags: Research article Source Type: research
Abstract While astrocytes, the most abundant cells found in the brain, have many diverse functions, their role in the lysosomal storage disorder Gaucher disease (GD) has not been explored. GD, resulting from the inherited deficiency of the enzyme glucocerebrosidase and subsequent accumulation of glucosylceramide and its acylated derivative glucosylsphingosine, has both non-neuronopathic (GD1) and neuronopathic forms (GD2 and 3). Furthermore, mutations in GBA1, the gene mutated in GD, are an important risk factor for Parkinson's disease (PD). To elucidate the role of astrocytes in the disease pathogenesis, we gener...
Source: Neurobiology of Disease - Category: Neurology Authors: Tags: Neurobiol Dis Source Type: research
Publication date: Available online 23 October 2019Source: Molecular Genetics and MetabolismAuthor(s): Parker Johnson, Neal J. Weinreb, James Cloyd, Paul J. Tuite, Reena V. KarthaAbstractThe discovery that patients with Gaucher Disease (GD), a rare lysosomal storage disorder, were developing symptoms similar to Parkinson's disease (PD) led to investigation of the relationship between the two seemingly unrelated pathologies. GD, an autosomal recessive disorder, is the result of a biallelic mutation in the gene GBA1, which encodes for the enzyme glucocerebrosidase (GCase). Since the observation of its relation to PD, GBA1 mut...
Source: Molecular Genetics and Metabolism - Category: Genetics & Stem Cells Source Type: research
Publication date: Available online 18 October 2019Source: Stem Cell ResearchAuthor(s): Ana Joana Duarte, Diogo Ribeiroa, Renato Santos, Luciana Moreira, José Bragança, Olga AmaralAbstractGaucher Disease (GD) type 3 is a neurological form of a multisystemic autosomal recessive disorder belonging to the group of lysosomal storage diseases. Mutations in glucocerebrosidase 1 (GBA1) commonly lead to abnormal protein and GD, heterozygosity is a genetic risk factor for Parkinson's disease. This work describes the use of a non-integrative approach using Sendai Virus delivery to establish iPSCs from fibroblasts from a...
Source: Stem Cell Research - Category: Stem Cells Source Type: research
ABSTRACT Bi-allelic GBA1 mutations cause Gaucher's disease (GD), the most common lysosomal storage disorder. Neuronopathic manifestations in GD include neurodegeneration, which can be severe and rapidly progressive. GBA1 mutations are also the most frequent genetic risk factors for Parkinson's disease. Dysfunction of the autophagy-lysosomal pathway represents a key pathogenic event in GBA1-associated neurodegeneration. Using an induced pluripotent stem cell (iPSC) model of GD, we previously demonstrated that lysosomal alterations in GD neurons are linked to dysfunction of the transcription factor EB (TFEB). TFEB controls t...
Source: DMM Disease Models and Mechanisms - Category: Biomedical Science Authors: Tags: Stem Cells, Rare diseases RESEARCH ARTICLE Source Type: research
ConclusionsCompared to previous studies, we demonstrate here a higher frequency of PD patients that carry two mutations. The GBA-E326K is more likely to affect PD risk when accompanied by another mutation, and an additive effect on risk and earlier AAO was proposed for carriers of LRRK2/mild-GBA double mutations. Altogether, these data support an oligogenic approach to PD genetics.
Source: Molecular Genetics and Metabolism - Category: Genetics & Stem Cells Source Type: research
We describe the generation and characterization of hiPSC lines of one type 1-Gaucher disease patient with Parkinson's disease and two unrelated Parkinson's disease patients heterozygous for GBA mutations. Human iPSCs were derived from lymphocytes reprogrammed with Sendai virus carrying the reprogramming factors OCT3/4, SOX2, KLF4 and MYC. The hiPSC lines were characterized according to established criteria, and retained the original GBA mutations found in the respective patients.
Source: Stem Cell Research - Category: Stem Cells Source Type: research
Abstract Homozygous and heterozygous mutations in GBA1, the gene implicated in Gaucher disease, increase the risk and severity of Parkinson disease (PD). We evaluated the design, phenotype, strengths, and limitations of current GBA1-associated PD mouse models. Although faithful modeling of a genetic risk factor poses many challenges, the different approaches taken were successful in revealing predisposing abnormalities in heterozygotes for GBA1 mutations and demonstrating the deleterious effects of GBA1 impairment on the PD course in PD models. GBA1-PD models differ in key parameters, with no single model recapitu...
Source: Trends in Neurosciences - Category: Neuroscience Authors: Tags: Trends Neurosci Source Type: research
Purpose of review GBA1 mutations, which result in the lysosomal disorder Gaucher disease, are the most common known genetic risk factor for Parkinson disease and Dementia with Lewy Bodies (DLB). The pathogenesis of this association is not fully understood, but further elucidation of this link could lead to new therapeutic options. Recent findings The characteristic clinical phenotype of GBA1-PD resembles sporadic Parkinson disease, but with an earlier onset and more severe course. Many different GBA1 mutations increase the risk of Parkinson disease, some primarily detected in specific populations. Glucocerebrosidase d...
Source: Current Opinion in Neurology - Category: Neurology Tags: MOVEMENT DISORDERS: Edited by Per Svenningsson and Steven J. Frucht Source Type: research
Gaucher disease (GD) is caused by deficiency of beta-glucocerebrosidase (GCase) due to biallelic variations in the GBA1 gene. Parkinson ’s disease (PD) is the second most common neurodegenerative condition. The cl...
Source: Orphanet Journal of Rare Diseases - Category: Internal Medicine Authors: Tags: Research Source Type: research
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