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Our case study shows that (1) non-syndromic CLN3 disease leads to rod and delayed primary cone degeneration resulting in constricting peripheral field and enlarging central scotoma and, (2) the c.175G>A CLN3 mutation, altered splicing of the CLN3 gene.
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the results of this study indicate that Cln3 functions in both conventional and unconventional protein secretion and that loss of Cln3 results in deregulated secretion during early development. Importantly, this is the first evidence in any system linking CLN3 function to protein secretion.
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AAV2-CLN3 was efficacious in restoring full-length CLN3 transcript and protein in patient-specific fibroblasts and iPSC-derived retinal neurons. When injected into the subretinal space of wild-type mice, purified AAV2-CLN3 did not show any evidence of retinal toxicity
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The lysosomal enzyme cathepsin D (CTSD) mediates the proteolytic cleavage of PSAP precursor into saposins A-D. Myc-CLN3 colocalized with CTSD and activity of CTSD decreased as myc-CLN3 expression increased, and clearly decreased under hyperosmotic conditions
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This is the first detailed morphological evaluation of CLN3 patients in the first years after the subjective onset of ocular symptoms. CLN3 is characterized by an early degeneration predominant of the first and second neuron compared to other macular and generalized retinal dystrophies.
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The age at onset and natural progression of retinal disease differs greatly between syndromic and nonsyndromic CLN3 disease, which may be associated with genotypic differences.
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CLN3 knockdown inhibits cell proliferation and induces G0/G1 cell cycle arrest in the A2780 cell line and its drug-resistant sub-lines.
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The membrane topology of human CLN3 protein.
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The eyes and vision of heterozygous carriers of CLN3 disease showed normal features when compared to a control group, which controverts a previously suggested retinal dysfunction in these subjects.
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This new model system, which allows for the study of Cln3 function in both single cells and a multicellular organism, together with the observation that expression of human CLN3 restores abnormalities in Dictyostelium cln3- cells
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These results further support an important role for the CLN3 protein in intracellular Ca(2+) handling and in autophagic pathway flux and establish a powerful new platform for therapeutic screening.
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CLN3 mutation is associated with neuronal ceroid lipofuscinosis.
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Genetic testing for CLN3 should be considered in autophagic vacuolar myopathy (AVM), with autophagic vacuoles and sarcolemmal features.
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CLN3 was identified as a novel disease gene for non-syndromic retinal diseases as supported by five unrelated patient families in this study.
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CLN3 is involved in the response and adaptation to cellular stress.
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Protein interaction mapping analysis suggests CLN3 is involved in transmembrane transport, lipid homeostasis, neuronal excitability and link it to G-protein signaling and protein folding/sorting in the endoplasmic reticulum.
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The data presented in this study provide novel insights into the role of CLN3 in late endosomal/lysosomal membrane transport.
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Btn1 controls retrograde sorting by regulating SNARE phosphorylation and assembly, a process that may be adversely affected in Batten Disease patients.
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The predominant distribution of CLN3 reporter neurons in visual, limbic and subcortical motor structures of transgenic mice correlates well with the clinical symptoms of juvenile neuronal ceroid lipofuscinosis.
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CLN6 and CLN3 mutations trigger distinct processes that converge on a shared pathway, which is responsible for proper subunit c protein turnover and neuronal cell survival.
