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CLN3 patients with differing progression of the disease

ABSTRACT: Mutations in the CLN3 gene lead to juvenile neuronal ceroid lipofuscinosis, a pediatric neurodegenerative disorder characterized by visual loss, epilepsy and psychomotor deterioration. Although most CLN3 patients carry the same 1 kb deletion in the CLN3 gene, their disease phenotype can be variable. The aims of this study were (1) to identify genes that are dysregulated in CLN3 disease regardless of the clinical course that could be useful as biomarkers, and (2) to find modifier genes that affect the progression rate of the disease. Genome-wide expression profiling was performed in 8 CLN3 patients, homozygous for the 1 kb deletion, with different disease progression and compared to seven age and gender matched controls.

ORGANISM(S): Homo sapiens

PROVIDER: GSE22225 | GEO | 2011/06/08

SECONDARY ACCESSION(S): PRJNA128865

REPOSITORIES: GEO

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CLN3 patients with differing progression of the disease

Project description:Mutations in the CLN3 gene lead to juvenile neuronal ceroid lipofuscinosis, a pediatric neurodegenerative disorder characterized by visual loss, epilepsy and psychomotor deterioration. Although most CLN3 patients carry the same 1 kb deletion in the CLN3 gene, their disease phenotype can be variable. The aims of this study were (1) to identify genes that are dysregulated in CLN3 disease regardless of the clinical course that could be useful as biomarkers, and (2) to find modifier genes that affect the progression rate of the disease. Genome-wide expression profiling was performed in 8 CLN3 patients, homozygous for the 1 kb deletion, with different disease progression and compared to seven age and gender matched controls. Lymphocytes from eight patients diagnosed with CLN3 disease,all homozygous for the 1 kb deletion in the CLN3 gene and classified as having rapid (n = 2), average (n=4), and slow disease progression (n = 2), were used. These eight patients did not receive anticonvulsive medication. In addition, lymphocytes of seven age and gender matched controls were included in the study. Lymphocytes were prepared from fresh patient blood samples by Ficoll-gradient centrifugation (BiocollM-BM-., Biochrom AG, Berlin, Germany) according to the manufacturerM-bM-^@M-^Ys protocol and used for RNA isolation (RNeasyM-BM-. Micro Kit, Qiagen, Hilden, Germany).

2011-06-08 | E-GEOD-22225 | biostudies-arrayexpress

Synapse alterations precede neuronal damage and storage pathology in a human cerebral organoid model of CLN3-Juvenile Neuronal Ceroid Lipofuscinosis

Project description:We developed an invitro model for Juvenile Neuronal Ceroid Lipofuscinosis (JNCL) using isogenic CLN3 mutated human iPS cell lines and performed transcriptomic profiling of brain organoids derived from these lines to identify transcriptomic changes in the early developing brain model.

2020-01-03 | GSE137420 | GEO

Lysosomal alterations and altered electrophysiological activity in atypical juvenile neuronal ceroid lipofuscinoses (CLN3 1 kb deletion, E295K) patient-derived cortical neurons

Project description:Juvenile neuronal ceroid lipofuscinoses (JNCL) is a lysosomal storage disorder associated with fatal neurodegeneration that is caused by mutations in CLN3. Most individuals with JNCL carry at least one allele with 1 kb deletion in CLN3 which results in the deletion of exons 7 and 8. There is a need for more physiologically relevant human cell-based JNCL models to better understand the cellular changes during the disease process. Using CRISPR/Cas9, we have corrected a 1 kb deletion mutation in human induced pluripotent stem cells (iPSC) of a compound heterozygous patient (CLN3 Δ1 kb and E295K), to generate an isogenic control to be used for disease modeling along with the unedited CLN3 patient iPSCs. iPSC-derived neurons carrying this particular CLN3 mutation, CLN3 neurons, had lower levels of spike, burst and network burst activity for most of the culture period. Proteomics analysis showed downregulation of proteins related to axon guidance and endocytosis on day in vitro (DIV) 14 and 42 in CLN3 neurons. This was accompanied by an increase in lysosomal-related proteins in CLN3 neurons. Western blot analysis of LAMP1 expression revealed a new finding where LAMP1 was hyperglycosylated in CLN3 neurons on DIV 14, 28 and 42, which was not apparent in control neurons. Ultrastructural analysis of CLN3 neurons showed numerous membrane-bound vacuoles containing diverse types of storage material, ranging from curvilinear deposits, multilamellar structures to osmiophilic deposits. Our findings suggest alterations in lysosomal function and neurodevelopment involving axon guidance and synaptic transmission in CLN3-deficient neuronal derivatives, which could be potential targets for therapy.

2022-12-07 | PXD032191 | Pride

Gene expression in leucocytes of patients with autosomal dominat neronal ceroid lipofuscinosis (Kufs disease)

Project description:Identification of differentially expressed genes in lecocytes of patients with autosomal dominat neronal ceroid lipofuscinosis (Kufs disease)

2011-10-01 | GSE30369 | GEO

Transcriptional control of lysosomal homeostasis by the disease-related CLN3 membrane protein

Project description:CLN3 is a type II transmembrane protein localized in the late endosomal/lysosomal compartment. A deficiency of CLN3 leads to the development of a certain type of Neuronal Ceroid Lipofuscinosis, a neurodegenerative disorder of childhood caused by aggregation of undegraded material in the lysosomal compartment. Cultured, immortalized wild type and Cln3(Δex7/8) cerebellar granule cells were used in this project to determine the influence of Cln3 deficiency on the proteome of the lysosomal compartment. For this purpose, cells were labelled by stable amino acid labelling in cell culture and lysosomes were isolated by magnetic beads.

2019-05-13 | PXD004548 | Pride

Gene expression in leucocytes of patients with autosomal dominat neronal ceroid lipofuscinosis (Kufs disease)

Project description:Identification of differentially expressed genes in lecocytes of patients with autosomal dominat neronal ceroid lipofuscinosis (Kufs disease) Leucocyte RNA expression of consanguineous Kufs disease cases (n=4) and unrelated healthy controls (n=4)

2011-09-30 | E-GEOD-30369 | biostudies-arrayexpress

The Batten disease gene product CLN3 is required for the efflux of glycerophosphodiesters from lysosomes

Project description:The lysosome has many cellular roles, including degrading and recycling macromolecules and signaling to the mTORC1 growth regulator. Lysosomal dysfunction occurs in various human diseases, including common neurodegenerative diseases as well as monogenic lysosomal storage disorders (LSDs). For most LSDs the causal genes have been identified, but in many cases the function of the implicated gene is unknown. Here, we develop the LysoTag mouse line for the tissue-specific isolation of intact lysosomes that are compatible with the multimodal profiling of their contents. We apply it to the study of CLN3, a lysosomal transmembrane protein of unclear function whose loss causes juvenile neuronal ceroid lipofuscinosis (Batten disease), a lethal neurodegenerative LSD. Untargeted metabolite profiling of lysosomes from the brains of mice lacking CLN3 revealed a massive accumulation of glycerophosphodiesters (GPDs), the end products of glycerophospholipid catabolism. GPDs also accumulate in the lysosomes of CLN3-deficient cultured cells and stable isotope tracing experiments show that CLN3 is required for their lysosomal egress. Loss of CLN3 also alters upstream glycerophospholipid catabolism in the lysosome. Our results suggest that CLN3 is a lysosomal effluxer of GPDs and reveal Batten disease as the first, to our knowledge, neurodegenerative LSD with a primary defect in glycerophospholipid metabolism.

2022-07-11 | PXD018624 | Pride

Transcription profiling of palmitoyl protein thioesterase-1 knockout mice

Project description:Infantile neuronal ceroid lipofuscinosis (aka infantile Batten disease) is a severe neurodegenerative disorder of early childhood characterized by cortical atrophy, blindness and seizures, leading to premature death in the first decade. The disorder is caused by deficiency in a soluble lysosomal enzyme, palmitoyl protein thioesterase-1 (PPT1). PPT1 knockout mice faithfully reproduce the features of the human disease, with motor deterioration, blindness, seizures, and death before 10 months of age. The progression of events leading from enzyme deficiency to organ failure is poorly defined. The neuronal ceroid lipofuscinoses are of particular interest because of the similarities between the accumulated material and lipofuscin that is associated with normal aging. We will determine changes in gene expression that occur during the course of neurodegeneration in PPT1 knockout as compared to control mice. Gene expression profiling of brain tissue from PPT1 knockout mice as compared to normal controls will provide insights into the mechanism of neurodegeneration. Comparison of this profile with gene expression profiles associated with normal aging may provide insights into the contribution of lipofuscin to aging and neurodegeneration. PPT1 knockout mice on a C57BL/6 background will be sacrificed under CO2 and whole brains removed and frozen under liquid nitrogen. Three mice will be used for each time point. Data points will be collected at 3 months, 5 months and 8 months of age. Normal age- and sex-matched C57BL/6 mice will be used as controls.

2008-06-15 | E-GEOD-6678 | biostudies-arrayexpress

Distinct Early Molecular Responses to Mutations Causing vLINCL and JNCL Presage ATP Synthase Subunit c Accumulation in Cerebellar Cells

Project description:Variant late-infantile (vLINCL) and juvenile neuronal ceroid lipofuscinosis (JNCL) share clinical and pathological features, including lysosomal accumulation of mitochondrial ATP synthase subunit c, but the unrelated CLN6 and CLN3 genes may initiate disease via similar or distinct cellular processes. To gain insight into the NCL pathways, we established murine wild-type and vLINCL CbCln6nclf cerebellar cells and compared them to wild-type and JNCL CbCln3∆ex7/8 cerebellar cells. CbCln6nclf/nclf cells and CbCln3∆ex7/8/∆ex7/8 cells both displayed abnormally elongated mitochondria and reduced cellular ATP levels and, as cells aged to confluence, exhibited accumulation of subunit c protein in Lamp 1-positive organelles. However, at sub-confluence, endoplasmic reticulum PDI immunostain was decreased only in CbCln6nclf/nclf cells, while fluid-phase endocytosis and LysoTracker labeled vesicles were decreased in both CbCln6nclf/nclf and CbCln3∆ex7/8/∆ex7/8 cells, though only the latter cells exhibited abnormal vesicle subcellular distribution. Furthermore, unbiased gene expression analyses revealed only partial overlap in the cerebellar cell genes and pathways that were altered by the Cln3∆ex7/8 and Cln6nclf mutations. Thus, these data support the hypothesis that vLINCL and JNCL mutations trigger distinct processes that converge on a shared pathway, which is responsible for proper subunit c protein turnover and neuronal cell survival. Genotype comparison. 3 replicates each of CD1 wild-type cells, CD1 Cln3 mutant cells, C57BL6 wild-type cells, and C57BL6 Cln6 mutant cells.

2011-02-01 | E-GEOD-24368 | biostudies-arrayexpress

Distinct Early Molecular Responses to Mutations Causing vLINCL and JNCL Presage ATP Synthase Subunit c Accumulation in Cerebellar Cells

2011-02-01 | GSE24368 | GEO

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