Disease relevance of CLN3

• JNCL is a neurodegenerative disease of childhood caused by mutations in the CLN3 gene [1].
• Neuronal ceroid lipofuscinosis (Batten disease) encompasses a group of 8 or more inherited lysosomal storage diseases, with an overall frequency of 1 in 12,500 births [2].
• She had classical disease progression, suggesting that this mutation in CLN3 mimics the more prevalent 1 kb deletion and that progression of JNCL is predominantly the result of loss of CLN3 function [3].
• CLN3 is also up-regulated in mouse melanoma and breast carcinoma cancer cell lines [4].
• Because defects in regulation of apoptosis are involved in the development of cancer, we evaluated the expression of CLN3 on both mRNA and protein levels in a variety of cancer cell lines and solid colon cancer tissue [4].

Psychiatry related information on CLN3

• This study describes the phenotype/genotype analysis of 159 probands with neuronal ceroid lipofuscinosis (37 CLN1, 72 classic CLN2, 10 variant LINCL, and 40 CLN3) collected at the New York State Institute for Basic Research in Developmental Disabilities (IBR) [5].
• Mutations in the CLN3 gene result in juvenile neuronal ceroid lipofuscinosis or Batten disease, which currently is the most common cause of childhood dementia [6].
• Furthermore, our study indicates that CLN3 protein affects metabolism of proteins essential for cell functions, such as amyloid-beta protein precursor, implicated in Alzheimer's disease pathogenesis [7].
• We conclude that cln3 is present during critical periods of neuronal cell differentiation and brain development [8].
• Neuronal ceroid lipofuscinosis (NCL, Batten disease) is an autosomal recessive disease characterized by progressive mental retardation, cortical atrophy, seizures, and retinal degeneration [9].

High impact information on CLN3

• This phenotype was complemented by expression of human CLN3, demonstrating that yeast Btn1p and human CLN3 share the same function [10].
• Immunoreactivity of ceroid lipofuscin storage pigment in Batten disease with monoclonal antibodies to the amyloid beta-protein [11].
• Cytosomes filled with intensely fluorescent material in the form of curvilinear bodies were isolated by density gradient centrifugation followed by pronase digestion from the cerebral cortex of a child who had died at age 7 from the late infantile form of Batten disease [12].
• FINDINGS: The sputum eosinophil count was 63% (95% CI 24-100) lower over 12 months in the sputum management group than in the BTS management group (p=0.002) [13].
• The search for the adult polycystic kidney disease gene has recently been narrowed to the analysis of candidate loci on chromosome 16, and localization of the gene determining juvenile Batten disease has been further refined by disequilibrium mapping [14].

Chemical compound and disease context of CLN3

• PPT1 deficiency in humans causes a neurodegenerative disorder, infantile neuronal ceroid lipofuscinosis (also known as infantile Batten disease) [15].
• Mutations in the CLN1 gene encoding palmitoyl-protein thioesterase (PPT) underlie the recessive neurodegenerative disorder, infantile Batten disease, or infantile neuronal ceroid lipofuscinosis (INCL) [16].
• The decreased activity of GAD65 and increased levels of glutamate may have a causative role in astrocytic hypertrophy evident in cln3-knockout mice, and in altered expression of genes involved in the synthesis and utilization of glutamate that underlie a shift from synthesis to utilization of glutamate [17].
• BTS 74 398 (2.5, 5.0, or 10.0 mg/kg p.o.) co-administered with a threshold dose of L-dopa (2.5 mg/kg p.o.) did not evoke a motor response or induce dyskinesia [18].
• To illustrate our methods, we applied them to two groups of data sets, one is cystic fibrosis data collected from several European populations, and the other is data on several genetic diseases (diastrophic dysplasia, progressive myoclonus epilepsy, congenital chloride diarrhea, and Batten disease) all collected from the Finnish population [19].

Biological context of CLN3

• 1. The D16S298/D16S299 haplotype "5/4" is highly overrepresented, accounting for 54% of CLN3 chromosomes as compared with 8% of control chromosomes (chi 2 = 117, df = 1, P < .001) [20].
• Examination of the haplotypes suggests that the CLN3 locus can be narrowed to the region immediately surrounding these markers in 16p12 [20].
• The gene loci for the juvenile (CLN3) and infantile (CLN1) types have been mapped to human chromosomes 16p and 1p, respectively, by linkage analysis [21].
• We find significant linkage disequilibrium between CLN3 and the dinucleotide repeat marker loci D16S288 (chi 2(7) = 46.5, P < .005), D16S298 (chi 2(6) = 36.6, P < .005), and D16S299 (chi 2(7) = 73.8, P < .005), and also a novel RFLP marker at the D16S272 locus (chi 2(1) = 5.7, P = .02) [20].
• Conversely, blocking CLN3 or CLN2 expression in hNT neurons with adenoviral antisense-CLN3 or antisense-CLN2-AAV2 constructs causes apoptosis [22].

Anatomical context of CLN3

• Subcellular localization identified the CLN3 protein within the nucleus and along cell membranes [23].
• The most abundant CLN3 protein expression was in the gray matter of the brain, where it was localized to astrocytes, capillary endothelium, and neurons [23].
• CLN3 was also evident in peripheral nerve, in pancreatic islet cells, and within the seminiferous tubules in the testis [23].
• The CLN3 protein is associated with lysosomal membranes and the intracellular location of the CLN5 protein is unknown [24].
• We now report a partial deficiency in three types of fatty acid oxidation in intact skin fibroblasts from CLN2 and CLN3 patients, but not CLN1 [25].

Associations of CLN3 with chemical compounds

• Flupirtine also prevents the death of CLN3- and CLN2-deficient postmitotic hNT neurons at the mitochondrial level [22].
• A role in vacuolar arginine transport for yeast Btn1p and for human CLN3, the protein defective in Batten disease [26].
• This point mutation resulted in a substitution of glutamic acid by lysine at position 295 of the CLN3 protein [27].
• A galactosylceramide binding domain is involved in trafficking of CLN3 from Golgi to rafts via recycling endosomes [28].
• Also, the intensity ratio of lipid methylene/methyl protons was decreased in spectra of CLN1 brain tissue compared with CLN3 and control brain tissue [29].

Regulatory relationships of CLN3

• Ex vivo spectra from CLN1 autopsy brain tissue (n = 9) significantly differed from those of the control (n = 9) and CLN3 (n = 5) groups, although no differences were found between the CLN3 and the control groups [29].
• CLN3 protein regulates lysosomal pH and alters intracellular processing of Alzheimer's amyloid-beta protein precursor and cathepsin D in human cells [7].
• CLN-3 protein is expressed in the pancreatic somatostatin-secreting delta cells [30].

Other interactions of CLN3

• The neuronal ceroid lipofuscinoses (NCL), also known as Batten disease, are a group of inherited severe neurodegenerative disorders primarily affecting children [31].
• The function of CLN3, CLN5, and CLN8 gene-encoded products is unknown, although their predicted amino acid sequences suggest they have a transmembrane topology [32].
• The gene locus causing the classical late infantile form (CLN2) has not yet been mapped but has been excluded from both CLN1 and CLN3 loci (8) [33].
• They result from mutations on genes CLN1, CLN2, and CLN3, respectively [34].
• Subunit c of mitochondrial ATP synthase specifically accumulates in most of them, including the juvenile CLN3 form and a sheep form orthologous to CLN6 [35].

Analytical, diagnostic and therapeutic context of CLN3

• Using oligonucleotide arrays we identified reproducible changes in gene expression in the brains of both 10-week-old Cln1- and Cln3-knockout mice as compared to wild-type controls, and confirmed changes in levels of several of the cognate proteins by immunoblotting [36].
• Pulse-chase labelling and immunoprecipitation of the two mutant proteins in COS-1-cells indicated that 461-677del is synthesized as an approximately 24 kDa truncated polypeptide, whereas the maturation of E295K [corrected] resembles that of the wild-type CLN3 polypeptide [37].
• In this study, we have confirmed the lysosomal localization of the CLN3 protein by immunoelectron microscopy by co-localizing it with soluble and membrane-associated lysosomal proteins [37].
• In the present study, we investigated the pathways and mechanisms of CLN3 sorting using biochemical binding assays and immunofluorescence methods [6].
• Different bands, some with different subcellular distributions, were detected by antisera against different regions of CLN3 on Western blots of sheep tissues [35].

References