CLN3, the protein associated with batten disease: Structure, function and localization

Phillips, Seasson N.; Benedict, Jared W.; Weimer, Jill M.; Pearce, David A.

doi:10.1002/jnr.20367

Cited by 102 publications

(83 citation statements)

References 38 publications

(92 reference statements)

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“…There are currently no effective therapies for this disorder and the mechanisms underlying neurodegeneration are unknown. In addition, the function of the CLN3 protein has not yet been determined (Phillips et al, 2005). To gain a better understanding the mechanisms underlying the disease pathology and to test potential approaches to therapy, it is important that a suitable animal model for JNCL be developed.…”

Section: Discussionmentioning

confidence: 99%

“…Children with this disorder typically begin to exhibit symptoms at 5 to 7 years of age and seldom live past their mid-twenties. Juvenile NCL results from mutations in the CLN3 gene which encodes a putative membrane protein of unknown function (Consortium, 1995;Kaczmarski et al, 1999;Mao et al, 2003;Mitchison et al, 1997;Phillips et al, 2005;Rakheja et al, 2004). Animal models could be of great value in developing a better understanding of the mechanisms underlying neuropathology in JNCL and in developing therapies for this disorder.…”

Section: Introductionmentioning

confidence: 99%

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Phenotypic characterization of a mouse model of juvenile neuronal ceroid lipofuscinosis

Katz

Johnson

Tullis

2008

Neurobiology of Disease

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Juvenile neuronal ceroid lipofuscinosis (JNCL) is an autosomal recessively inherited neurodegenerative disorder that results from mutations in the CLN3 gene. JNCL is characterized by accumulation of autofluorescent lysosomal storage bodies, vision loss, seizures, progressive cognitive and motor decline, and premature death. Studies were undertaken to characterize the neuronal ceroid lipofuscinosis phenotype in a Cln3 knockout mouse model. Progressive accumulation of autofluorescent storage material was observed in brain and retina of affected mice. The Cln3 -/-mice exhibited progressively impaired inner retinal function, altered pupillary light reflexes, losses of inner retinal neurons, and reduced brain mass. Behavioral changes included reduced spontaneous activity levels and impaired learning and memory. In addition, Cln3 -/-mice had significantly shortened life spans. These phenotypic features indicate that the mouse model will be useful for investigating the mechanisms underlying the disease pathology in JNCL and provide quantitative markers of disease pathology that can be used for evaluating the efficacies of therapeutic interventions.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Phenotypic characterization of a mouse model of juvenile neuronal ceroid lipofuscinosis

Katz

Johnson

Tullis

2008

Neurobiology of Disease

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“…1,2 JNCL is due to mutations of the CLN3 3 gene that encodes a ubiquitously expressed protein of unknown function localized to the lysosomal membrane 4,5 ; modeling studies suggest a role in substrate trafficking. 5,6 Most cases of JNCL are caused by an approximately 1-kb deletion in the CLN3 3,7 gene, encompassing exons 7 and 8. Approximately 74% of patients with JNCL are homozygous for this common deletion, and 22% are compound heterozygotes for this deletion and another CLN3 mutation.…”

mentioning

confidence: 99%

Quantifying physical decline in juvenile neuronal ceroid lipofuscinosis (Batten disease)

Kwon¹,

Adams²,

Rothberg³

et al. 2011

Neurology

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Objective: To use the Unified Batten Disease Rating Scale (UBDRS) to measure the rate of decline in physical and functional capability domains in patients with juvenile neuronal ceroid lipofuscinosis (JNCL) or Batten disease, a neurodegenerative lysosomal storage disorder. We have evaluated the UBDRS in subjects with JNCL since 2002; during that time, the scale has been refined to improve reliability and validity. Now that therapies are being proposed to prevent, slow, or reverse the course of JNCL, the UBDRS will play an important role in quantitatively assessing clinical outcomes in research trials. Methods:We administered the UBDRS to 82 subjects with JNCL genetically confirmed by CLN3 mutational analysis. Forty-four subjects were seen for more than one annual visit. From these data, the rate of physical impairment over time was quantified using multivariate linear regression and repeated-measures analysis. Results:The UBDRS Physical Impairment subscale shows worsening over time that proceeds at a quantifiable linear rate in the years following initial onset of clinical symptoms. This deterioration correlates with functional capability and is not influenced by CLN3 genotype. Conclusion:The UBDRS is a reliable and valid instrument that measures clinical progression in JNCL. Our data support the use of the UBDRS to quantify the rate of progression of physical impairment in subjects with JNCL in clinical trials. Neurology The neuronal ceroid lipofuscinoses (NCLs) are degenerative, autosomal recessive storage diseases with common clinical and pathologic features, including blindness, seizures, dementia, motor decline, and lysosomal accumulation of autofluorescent material (ceroid and lipofuscin).1 The NCLs are categorized by genetic etiology. The juvenile form of neuronal ceroid lipofuscinosis (JNCL), also called Batten disease, is the most prevalent NCL. Clinically, JNCL begins with progressive visual loss between 4 and 8 years of age, followed by seizures, then loss of motor coordination and dementia between 10 and 12 years. Death occurs by the third or fourth decade. 1,2 JNCL is due to mutations of the CLN3 3 gene that encodes a ubiquitously expressed protein of unknown function localized to the lysosomal membrane 4,5 ; modeling studies suggest a role in substrate trafficking. 5,6 Most cases of JNCL are caused by an approximately 1-kb deletion in the CLN3 3,7 gene, encompassing exons 7 and 8. Approximately 74% of patients with JNCL are homozygous for this common deletion, and 22% are compound heterozygotes for this deletion and another CLN3 mutation.8 There are no mutations consistently associated with better prognosis. 8 -10 From the University of Rochester (J.M.K., H.A., P.G.R., E. With biological advances, there is hope for rational therapies to prevent, slow, or reverse the course of JNCL. We developed the Unified Batten Disease Rating Scale (UBDRS) to measure disease progression in JNCL.11 We used the UBDRS to evaluate and quantify disease burden in 82 subjects with JNCL from 2002 through 2010...

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“…12 The function of CLN3 remains unknown but proposed functions include lysosomal acidification, sequestration of lysosomal enzymes, degradation of proteins and small molecule transport, organelle fusion, and apoptosis. 13,14 Mutations in CLN3 cause JNCL, the most common of a group of inherited, autosomal recessive, progressive, and ultimately fatal neurodegenerative disorders that share the clinical features of progressive loss of vision, myoclonic seizures, loss of cognitive function, pyramidal and extrapyramidal motor dysfunctions, and the pathologic features of progressive neuronal loss, with an accumulation of lipofuscin-like autofluorescent storage material in the cytoplasm of neurons and other cells (Table 1). 15 The presence of fingerprint patterns in the lysosomes of different tissues and the finding of vacuolated lymphocytes are considered as pathognomonic for JNCL.…”

Section: Discussionmentioning

confidence: 99%

An unusual clinical severity of 16p11.2 deletion syndrome caused by unmasked recessive mutation of CLN3

et al. 2013

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With the introduction of array comparative genomic hybridization (aCGH) techniques in the diagnostic setting of patients with developmental delay and congenital malformations, many new microdeletion syndromes have been recognized. One of these recently recognized microdeletion syndromes is the 16p11.2 deletion syndrome, associated with variable clinical outcomes including developmental delay, autism spectrum disorder, epilepsy, and obesity, but also apparently normal phenotype. We report on a 16-year-old patient with developmental delay, exhibiting retinis pigmentosa with progressive visual failure from the age of 9 years, ataxia, and peripheral neuropathy. Chromosomal microarray analysis identified a 1.7-Mb 16p11.2 deletion encompassing the 593-kb common deletion (B29.5 to B30.1 Mb; Hg18) and the 220-kb distal deletion (B28.74 to B28.95 Mb; Hg18) that partially included the CLN3 gene. As the patient's clinical findings were different from usual 16p11.2 microdeletion phenotypes and showed some features reminiscent of juvenile neuronal ceroid-lipofuscinosis (JNCL, Batten disease, OMIM 204200), we suspected and confirmed a mutation of the remaining CLN3 allele. This case further illustrates that unmasking of hemizygous recessive mutations by chromosomal deletion represents one explanation for the phenotypic variability observed in chromosomal deletion disorders.

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CLN3, the protein associated with batten disease: Structure, function and localization

Cited by 102 publications

References 38 publications

Phenotypic characterization of a mouse model of juvenile neuronal ceroid lipofuscinosis

Phenotypic characterization of a mouse model of juvenile neuronal ceroid lipofuscinosis

Quantifying physical decline in juvenile neuronal ceroid lipofuscinosis (Batten disease)

An unusual clinical severity of 16p11.2 deletion syndrome caused by unmasked recessive mutation of CLN3

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