ArticleAmerican journal of hematology2012
Genome-wide association study of N370S homozygous Gaucher disease reveals the candidacy of CLN8 gene as a genetic modifier contributing to extreme phenotypic variation.
Article in American journal of hematology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 59 citations in OpenAlex.
- A Multiomic Network Approach to Uncover Disease Modifying Mechanisms of Inborn Errors of Metabolism.Journal of inherited metabolic disease · 2025Article
- Precision genomic profiling in Gaucher disease: insights from atypical presentations.Frontiers in genetics · 2025Article
- Gaucher disease provides a unique window into Parkinson disease pathogenesis.Nature reviews. Neurology · 2024Review
- Adult type I Gaucher disease with splenectomy caused by a compound heterozygous GBA1 mutation in a Chinese patient: a case report.Annals of hematology · 2024Article
- Multi-Omics Data Analysis Identifies Prognostic Biomarkers across Cancers.Medical sciences (Basel, Switzerland) · 2023Article
- Neuronopathic Gaucher disease models reveal defects in cell growth promoted by Hippo pathway activation.Communications biology · 2023Article
- A rare homozygous p.Arg87Trp variant of theClinical case reports · 2022Article
- Pathological α-syn aggregation is mediated by glycosphingolipid chain length and the physiological state of α-syn in vivo.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- The rapidly evolving view of lysosomal storage diseases.EMBO molecular medicine · 2021Review
- Genome-wide survey of tandem repeats by nanopore sequencing shows that disease-associated repeats are more polymorphic in the general population.BMC medical genomics · 2021Article
- The Genetic Basis of Phenotypic Heterogeneity in the Neuronal Ceroid Lipofuscinoses.Frontiers in neurology · 2021Review
- Reconstruction of the Cytokine Signaling in Lysosomal Storage Diseases by Literature Mining and Network Analysis.Frontiers in cell and developmental biology · 2021Article
- Glucocerebrosidase: Functions in and Beyond the Lysosome.Journal of clinical medicine · 2020Review
- Gaucher disease: single gene molecular characterization of one-hundred Indian patients reveals novel variants and the most prevalent mutation.BMC medical genetics · 2019Article
- Emerging new roles of the lysosome and neuronal ceroid lipofuscinoses.Molecular neurodegeneration · 2019Review
- Exploring genetic modifiers of Gaucher disease: The next horizon.Human mutation · 2018Review
- Recent advances in the diagnosis and management of Gaucher disease.Expert review of endocrinology & metabolism · 2018Article
- A Novel Functional Missense Mutation p.T219A in Type 1 Gaucher's Disease.Chinese medical journal · 2016Article
- A Next Generation Multiscale View of Inborn Errors of Metabolism.Cell metabolism · 2016Review
- Genetics of the neuronal ceroid lipofuscinoses (Batten disease).Biochimica et biophysica acta · 2015Review
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Authors and funding
11 authors at 4 institutions in 2 countries.
Funding
Abstract
Mutations in GBA1 gene result in defective acid β-glucosidase and the complex phenotype of Gaucher disease (GD) related to the accumulation of glucosylceramide-laden macrophages. The phenotype is highly variable even among patients harboring identical GBA1 mutations. We hypothesize that modifier gene(s) underlie phenotypic diversity in GD and performed a GWAS study in Ashkenazi Jewish patients with type 1 GD (GD1), homozygous for N370S mutation. Patients were assigned to mild, moderate, or severe disease categories using composite disease severity scoring systems. Whole-genome genotyping for >500,000 SNPs was performed to search for association signals using OQLS algorithm in 139 eligible patients. Several SNPs in linkage disequilibrium within the CLN8 gene locus were associated with the GD1 severity: SNP rs11986414 was associated with GD1 severity at P value 1.26 × 10(-6) . Compared to mild disease, risk allele A at rs11986414 conferred an odds ratio of 3.72 for moderate/severe disease. Loss of function mutations in CLN8 causes neuronal ceroid-lipofuscinosis, but our results indicate that its increased expression may protect against severe GD1. In cultured skin fibroblasts, the relative expression of CLN8 was higher in mild GD compared to severely affected patients, in whom CLN8 risk alleles were overrepresented. In an in vitro cell model of GD, CLN8 expression was increased, which was further enhanced in the presence of bioactive substrate, glucosylsphingosine. Taken together, CLN8 is a candidate modifier gene for GD1 that may function as a protective sphingolipid sensor and/or in glycosphingolipid trafficking. Future studies should explore the role of CLN8 in pathophysiology of GD.
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