A mouse gene knockout model for juvenile ceroid‐lipofuscinosis (batten disease)

Katz, Martin L.; Shibuya, Hisashi; Liu, Po‐Ching; Kaur, Satbir; Gao, Chun-Lan; Johnson, Gary S.

doi:10.1002/(sici)1097-4547(19990815)57:4<551::aid-jnr15>3.3.co;2-i

Cited by 15 publications

(21 citation statements)

References 8 publications

(8 reference statements)

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“…This hypothesis is supported by the comparison of Cln3 Δex7/8 knock‐in mice with the Cln3 Δex7/8 described by Katz et al In these transgenic strains, exons 7 and 8 are deleted, albeit using differing strategies and targeted regions would result in a predicted truncated protein without exons 7 and 8. The Cln3 Δex7/8 (Katz) model exhibited a later onset of pathological changes (Katz et al 1999, 2008) in a time frame more consistent with the Cln3 Δex1‐6 and Cln3 LacZ mice. This illustrates the need to perform a comprehensive characterization of the available murine JNCL models on a standard genetic background to allow proper comparison.…”

Section: Discussionmentioning

confidence: 70%

Neurodevelopmental delay in the Cln3^Δex7/8 mouse model for Batten disease

Osório

Sampaio‐Marques

Chan

et al. 2009

Genes Brain and Behavior

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Juvenile neuronal ceroid lipofuscinosis (JNCL), also known as Batten disease, is a fatal inherited neurodegenerative disorder. The major clinical features of this disease are vision loss, seizures and progressive cognitive and motor decline starting in childhood. Mutations in CLN3 are known to cause the disease, allowing the generation of mouse models that are powerful tools for JNCL research. In this study, we applied behavioural phenotyping protocols to test for early behavioural alterations in Cln3Dex7/8 knock-in mice, a genetic model that harbours the most common disease-causing CLN3 mutation. We found delayed acquisition of developmental milestones, including negative geotaxis, grasping, wire suspension time and postural reflex in both homozygous and heterozygous Cln3Dex7/8 preweaning pups. To further investigate the consequences of this neurodevelopmental delay, we studied the behaviour of juvenile mice and found that homozygous and heterozygous Cln3Dex7/8 knock-in mice also exhibit deficits in exploratory activity. Moreover, when analysing motor behaviour, we observed severe motor deficits in Cln3Dex7/8 homozygous mice, but only a mild impairment in motor co-ordination and ambulatory gait in Cln3Dex7/8 heterozygous animals. This study reveals previously overlooked behaviour deficits in neonate and young adult Cln3Dex7/8 mice indicating neurodevelopmental delay as a putative novel component of JNCL.

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Section: Discussionmentioning

confidence: 70%

Neurodevelopmental delay in the Cln3^Δex7/8 mouse model for Batten disease

Osório

Sampaio‐Marques

Chan

et al. 2009

Genes Brain and Behavior

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“…A number of spontaneous animal forms of NCL have been described including sheep, dogs, and mice [42-44]. The mouse models of NCLs, Ppt1 −/− [45], Ppt1 Δex4 knockout [46], Tpp1 neo ins Arg446His knockout [47], Cln5 −/− knockout [48], Cln6 nclf spontaneous mutant [49], Cln8 mnd spontaneous mutant [50], Cln3 −/− knockout [51], Cln3 Δex7/8 knock-in [52], Cln3 knockout [53] demonstrate phenotypes that closely resemble the major features of human NCLs. They all show clinically relevant behavioral and pathological changes that exhibit a progressive neurodegenerative disorder.…”

Section: Discussionmentioning

confidence: 99%

Cln6 mutants associated with neuronal ceroid lipofuscinosis are degraded in a proteasome-dependent manner

2009

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Neuronal ceroid lipofuscinoses (NCL), a group of inherited neurodegenerative lysosomal storage diseases predominantly affecting children, are due to autosomal recessive mutations within one of the nine cln genes. The wild type cln gene products are comprised of membrane and soluble proteins that localize to the lysosome or endoplasmic reticulum. However, the destiny of the Cln variants has not been fully characterized. To explore a possible link between ER quality control and processing of Cln mutants, we investigated the fate of two NCL-related Cln6 mutants found in patient samples (Cln6 G123D and Cln6 M241T ) in neuronal-derived human cells. The point mutations are predicted to be in the putative transmembrane domains and most likely generate misfolded membrane proteins that are subjected to ER quality control. Consistent with this paradigm, both mutants underwent rapid proteasome-mediated degradation and complexed with components of the ER extraction apparatus, Derlin-1 and p97. In addition, knock down of SEL1L, a member of an E3 ubiquitin ligase complex involved in ER protein extraction rescued significant amounts of Cln6 G123D and Cln6 M241T polypeptides. The results implicate ER quality control in the instability of the Cln variants that likely contributes to the development of NCL.

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“…The disease has also been called Batten‐Mayou disease, Batten‐Spielmeyer‐Vogt disease, CLN3‐related neuronal ceroid‐lipofuscinosis, juvenile Batten disease, Juvenile cerebroretinal degeneration, juvenile neuronal ceroid lipofuscinosis, Spielmeyer‐Vogt disease and the term adopted in 2012, CLN3 disease. Using the Basic Local Alignment Search (BLAST) tool to align regions of similarity between known biological sequences, investigators discovered that the CLN3 gene is highly conserved amongst Homo sapiens, Canis Lupus familiaris, Mus musculus, Danio rerio, Drosophila melanogaster, Caenorhabditis elegans, Schizosaccharomyces cerevisiae, and Schizosaccharomyces pombe (Altschul et al, ; Katz et al, ; Mitchell, Porter, Kuwabara, & Mole, ; Pearce & Sherman, ) . The National Center for Biotechnology Information (NCBI) Gene lists 179 orthologs discovered through comparison of known sequences.…”

Section: General Informationmentioning

confidence: 99%

The CLN3 gene and protein: What we know

Mirza¹,

Vainshtein

DiRonza

et al. 2019

Molec Gen & Gen Med

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Background One of the most important steps taken by Beyond Batten Disease Foundation in our quest to cure juvenile Batten (CLN3) disease is to understand the State of the Science. We believe that a strong understanding of where we are in our experimental understanding of the CLN3 gene, its regulation, gene product, protein structure, tissue distribution, biomarker use, and pathological responses to its deficiency, lays the groundwork for determining therapeutic action plans. Objectives To present an unbiased comprehensive reference tool of the experimental understanding of the CLN3 gene and gene product of the same name. Methods BBDF compiled all of the available CLN3 gene and protein data from biological databases, repositories of federally and privately funded projects, patent and trademark offices, science and technology journals, industrial drug and pipeline reports as well as clinical trial reports and with painstaking precision, validated the information together with experts in Batten disease, lysosomal storage disease, lysosome/endosome biology. Results The finished product is an indexed review of the CLN3 gene and protein which is not limited in page size or number of references, references all available primary experiments, and does not draw conclusions for the reader. Conclusions Revisiting the experimental history of a target gene and its product ensures that inaccuracies and contradictions come to light, long‐held beliefs and assumptions continue to be challenged, and information that was previously deemed inconsequential gets a second look. Compiling the information into one manuscript with all appropriate primary references provides quick clues to which studies have been completed under which conditions and what information has been reported. This compendium does not seek to replace original articles or subtopic reviews but provides an historical roadmap to completed works.

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A mouse gene knockout model for juvenile ceroid‐lipofuscinosis (batten disease)

Cited by 15 publications

References 8 publications

Neurodevelopmental delay in the Cln3^Δex7/8 mouse model for Batten disease

Neurodevelopmental delay in the Cln3^Δex7/8 mouse model for Batten disease

Cln6 mutants associated with neuronal ceroid lipofuscinosis are degraded in a proteasome-dependent manner

The CLN3 gene and protein: What we know

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A mouse gene knockout model for juvenile ceroid‐lipofuscinosis (batten disease)

Cited by 15 publications

References 8 publications

Neurodevelopmental delay in the Cln3Δex7/8 mouse model for Batten disease

Neurodevelopmental delay in the Cln3Δex7/8 mouse model for Batten disease

Cln6 mutants associated with neuronal ceroid lipofuscinosis are degraded in a proteasome-dependent manner

The CLN3 gene and protein: What we know

Contact Info

Product

Resources

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Neurodevelopmental delay in the Cln3^Δex7/8 mouse model for Batten disease

Neurodevelopmental delay in the Cln3^Δex7/8 mouse model for Batten disease