Analysis of rare variants in lysosomal pathway genes in patients with Gaucher disease with and without Parkinson disease

Publication date: February 2020Source: Molecular Genetics and Metabolism, Volume 129, Issue 2Author(s): Pankaj Sharma, Shruthi Santhanakrishnan, Alta Steward, Barbara Stubblefield, Grisel Lopez, Nahid Tayebi, Ellen Sidransky
Source: Molecular Genetics and Metabolism - Category: Genetics & Stem Cells Source Type: research

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AbstractEvidence about the link between glucocerebrosidase (GCase) and parkinsonism is growing. Parkinsonism was described in adult type 1 Gaucher disease (GD); few case reports described it in type 3GD. To assess the presence of parkinsonian features in a cohort of Egyptian GD patients and correlate these findings to their genotype, phenotype, severity scoring index (SSI), cognitive function, and the presence of depressive symptoms. Twenty-four GD patients from the Pediatric Hematology Clinic, Ain Shams University, were assessed for medication history, neurological symptoms, depressive symptoms, and family history of park...
Source: Neurogenetics - Category: Genetics & Stem Cells Source Type: research
Publication date: February 2020Source: Molecular Genetics and Metabolism, Volume 129, Issue 2Author(s): Ari Zimran, Majdolen Istaiti, Michal Becker-Cohen, Walla Al-Hertani, Beom Hee Lee, Harri Niinikoski, Chia-Feng Yang, Beata Kiec-Wilk, Shoshana Revel-Vilk
Source: Molecular Genetics and Metabolism - Category: Genetics & Stem Cells Source Type: research
Bi-allelic mutations in the gene for glucocerebrosidase (GBA) cause Gaucher disease, an autosomal recessive lysosomal storage disorder. Gaucher disease causing GBA mutations in the heterozygous state are also high risk factors for Parkinson's disease (PD). GBA analysis is challenging due to a related pseudogene and structural variations (SVs) that can occur at this locus. We have applied and refined a recently developed nanopore DNA sequencing method to analyze GBA variants in a clinically assessed New Zealand longitudinal cohort of PD.
Source: Parkinsonism and Related Disorders - Category: Neurology Authors: Source Type: research
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
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