Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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JNCL is a neurodegenerative disease of childhood caused by mutations in the CLN3 gene. A mouse model for JNCL was created by disrupting exons 1-6 of Cln3, resulting in a null allele. Cln3 null mice appear clinically normal at 5 months of age; however, like JNCL patients, they exhibit intracellular accumulation of autofluorescent material. A second approach will generate mice in which exons 7 and 8 of Cln3 are deleted, mimicking the common mutation in JNCL patients.
Mol Genet Metab 1999 Apr
PMID:A murine model for juvenile NCL: gene targeting of mouse Cln3. 1019 Nov 19

The CLN3 gene, which encodes the protein whose absence is responsible for Batten disease, the most common inherited neurovisceral storage disease of childhood, was identified in 1995. The function of the protein, Cln3p, still remains elusive. We previously cloned the Saccharomyces cerevisiae homolog to the human CLN3 gene, designated BTN1, whose product is 39% identical and 59% similar to Cln3p. We report that yeast strains lacking Btn1p, btn1-Delta deletion yeast strains, are more resistant to d-(-)-threo-2-amino-1-[p-nitrophenyl]-1,3-propanediol (ANP), in a pH-dependent manner. This phenotype is complemented in yeast by the human CLN3 gene. In addition, point mutations characterized in CLN3 from individuals with less severe forms of Batten disease, when introduced into BTN1, altered the degree of ANP resistance. Severity of Batten disease due to mutations in CLN3 and the degree of ANP resistance in yeast are related when the equivalent amino acid replacements in Cln3p and Btn1p are compared. These results indicate that yeast can be used as a model for the study of Batten disease.
Mol Genet Metab 1999 Apr
PMID:Investigation of Batten disease with the yeast Saccharomyces cerevisiae. 1019 Nov 20

Although the gene responsible for Batten disease, CLN3, was positionally cloned in 1995, the function of Cln3p and the molecular basis of the disease still remain elusive. We previously reported that the yeast Saccharomyces cerevisiae contains a homolog to Cln3p, designated Btn1p, and that the human Cln3p complemented the pH-dependent resistance to D-(-)-threo-2-amino-1-[p-nitrophenyl]-1, 3-propanediol in btn1-Delta yeast mutants. We have determined that yeast lacking Btn1p have an elevated ability to acidify media during growth that correlates with an elevated plasma membrane ATPase activity. Btn1p may be involved in maintaining pH homeostasis of yeast cells.
Mol Genet Metab 1999 Apr
PMID:Studies of pH regulation by Btn1p, the yeast homolog of human Cln3p. 1019 Nov 21

Neuronal ceroid lipofuscinosis (NCL) is one of the most common inherited neurological diseases in childhood. It occurs every 12,500 births in northern-European populations. Mental retardation, visual impairment, and seizures are common symptoms. The prevalence of NCL is variable depending upon the races or countries. Although a wealth information is available in Caucasian populations, there is little information about NCL in Asian people. Because a nationwide survey in Japanese patients with NCL has never been performed, we pursued an epidemiological survey. We identified 36 NCL patients in Japan. Patients with infantile, late infantile, juvenile, and adult type accounted for 2, 15, 15, and 4 cases, respectively. Seizures were a major initial symptom in the late infantile type. In the juvenile type, visual failure was present in 73% at onset. Recently, the juvenile NCL (Batten disease) gene has been isolated. Studies of the mutations in this gene demonstrated that a 1.02-kb deletion was the most prevalent mutation among Caucasian patients, accounting for 81% of total alleles. To determine the prevalence of this 1.02-kb deletion in Japanese patients, we performed a rapid allele-specific polymerase chain reaction test. No 1.02-kb major deletion was detected in 5 Japanese juvenile NCL cases. These data suggest that the distribution of NCL and clinical findings are similar to those of Caucasian subjects; however, prevalence of mutations in Japanese patients with NCL would be distinct from that observed in Caucasians.
Mol Genet Metab 1999 Apr
PMID:Clinical and molecular analysis of Japanese patients with neuronal ceroid lipofuscinosis. 1019 Nov 27

Several neuronal ceroid lipofuscinoses (NCL) show storage of subunit c of mitochondrial ATP synthase. The neurodegenerative process, however, remains obscure. We previously reported a decreased basal ATP synthase activity in fibroblasts from late-infantile NCL (CLN2) and juvenile NCL (CLN3) patients. We have now extended the study of the ATP synthase system to an ovine NCL (a model for the late-infantile NCL variant, CLN6) and the infantile NCL (CLN1). In fibroblasts from healthy sheep, active regulation of ATP synthase in response to cellular energy demand was present similar to human cells: ATP synthase was down-regulated under conditions of anoxia or functional uncoupling and was up-regulated in response to calcium. In fibroblasts from NCL sheep, basal ATP synthase activity was slightly elevated and down-regulation in response to anoxia or uncoupling of mitochondria also occurred. Calcium produced an unexpected down-regulation to 55% of basal activity. Activities of respiratory chain enzymes did not differ between healthy and NCL sheep. In fibroblasts from CLN1 patients, basal ATP synthase activity was reduced and regulation of the enzyme was absent. Activities of respiratory chain complexes II and IV were reduced. The defect of ATP synthase regulation found in fibroblasts from NCL sheep and infantile NCL patients is different from the ATP synthase deficiencies demonstrated in late-infantile and juvenile NCL, but problems of mitochondrial energy production, if also expressed in brain, would be a common feature of several NCL forms. Deficient ATP supply could result in degeneration of neurons, especially in those with high energy requirements.
Mol Genet Metab 1999 Apr
PMID:Anomalies of mitochondrial ATP synthase regulation in four different types of neuronal ceroid lipofuscinosis. 1019 Nov 28

The neuronal ceroid lipofuscinoses (NCL, Batten disease) are a group of inherited neurodegenerative storage diseases in children. Mutations in different genes underlie different forms. Subunit c of mitochondrial ATP synthase is specifically stored in autofluorescent bodies in most of them, including a form in sheep. Mature bodies are lysosomal but the initial site of storage is not known, nor is it known how this leads to the characteristic neurodegeneration. Neurons were cultured in serum-free medium from control and affected sheep fetuses at 90 days gestation. They showed positive microtubule-associated protein staining, developed neurites, and had typical neuron morphology. Time-dependent accumulation of subunit c and of fluorescent storage bodies was observed in affected cells by immunocytochemistry and confocal microscopy. A small number of autofluorescent bodies were apparent after 4 days in culture. After 10 days these bodies were more numerous, more intensely autofluorescent, and often larger in size. By 14 and 21 days many neurons were packed with autofluorescent material. These bodies were not seen in control cultures. Immunocytochemistry revealed subunit c-positive storage material only in affected neurons and not in affected glial cells. Confocal microscope analysis, using organelle-specific dyes, demonstrated colocalization of autofluorescent bodies with lysosomes, not with mitochondria. Survival rates of the affected cells were unaffected by the storage body accumulation over a 3-month period. These cultures can now be used to study the mechanism of subunit c accumulation and of neurodegeneration and to test therapeutic possibilities.
Mol Genet Metab 1999 Apr
PMID:Disease-specific pathology in neurons cultured from sheep affected with ceroid lipofuscinosis. 1019 Nov 33

A hypothesis is outlined that the neurodegeneration of the Batten disease syndromes that involve an overaccumulation of subunit c is caused by a newly characterized function of the protein, its ability to assemble in the plasma membrane into ion pores (J. E. M. McGeoch and G. Guidotti, Brain Res 766: 188-194, 1997), rendering the cell liable to constant electrical excitability to a degree that causes cell death.
Mol Genet Metab 1999 Apr
PMID:Ion pores made of mitochondrial ATP synthase subunit c in the neuronal plasma membrane and Batten disease. 1019 Nov 34

Specific storage of mitochondrial ATP synthase subunit c occurs in most forms of Batten disease, including the ovine form, but its relationship to the characteristic neurodegeneration is not clear. Storage occurs in most cell types but only neurons are functionally affected. Neurons were cultured from control and affected sheep. Ewes were superovulated and inseminated, and embryos were collected, frozen, stored, and later transplanted into surrogate dams for gestation at times to suit experimental demands. The optimal fetal age for cultures was investigated, from 50 to 125 days. There were no differences between control and affected embryos in this period of rapid growth. At 50 days brains consist of smooth-surfaced hemispheres and cerebellum with no obvious demarcation between gray and white matter. At 90 days they are like miniature adult brains. From 200 to 600 million viable cells were recovered from each fetus, regardless of age. DMEM/F12 with B27 was the most practical medium tested. Cell viability was not as good in medium containing serum. Treatment of surfaces with polylysine aided neuron adhesion. No developmental or viability differences were observed between normal and affected neuron cultures. At plating out cells were rounded. A day later single process outgrowths began. After 4 days these were over 200 microm and by Day 6 had created a network. Most neurons were bipolar. Neurons from 50 to 90-day old fetuses persisted in culture for over 100 days.
Mol Genet Metab 1999 May
PMID:In vitro culture of neurons from sheep with Batten disease. 1032 28

Batten disease [juvenile-onset neuronal ceroid lipofuscinosis (JNCL)], the most common progressive encephalopathy of childhood, is caused by mutations in a novel lysosomal membrane protein (CLN3) with unknown function. 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. We have analysed the intracellular processing and localization of two mutants, 461-677del, which is present in 85% of CLN3 alleles and causes the classical JNCL, and E295K [corrected], which is a rare missense mutation associated with an atypical form of JNCL. 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. Transient expression of the two mutants in BHK cells showed that 461-677del is retained in the endoplasmic reticulum, whereas E295K [corrected] was capable of reaching the lysosomal compartment. The CLN3 polypeptides were expressed further in mouse primary neurons where the wild-type CLN3 protein was localized both in the cell soma and in neuronal extensions, whereas the 461-677del mutant was arrested in the cell soma. Interestingly, co-localization of the wild-type CLN3 and E295K [corrected] proteins with a synaptic vesicle marker indicates that the CLN3 protein might participate in synaptic vesicle transport/transmission. The data presented here provide clear evidence for a cellular distinction between classical and atypical forms of Batten disease both in neural and non-neural cells.
Hum Mol Genet 1999 Jun
PMID:Defective intracellular transport of CLN3 is the molecular basis of Batten disease (JNCL) 1033 42

Mutations in different genes underlie different forms of the neuronal ceroid lipofuscinoses (NCLs, Batten disease). Subunit c of mitochondrial ATP synthase specifically accumulates in most of them, including the juvenile CLN3 form and a sheep form orthologous to CLN6. Products of these genes are likely to be components of a complex or pathway for subunit c turnover, and their expression may be cross-regulated. Different bands, some with different subcellular distributions, were detected by antisera against different regions of CLN3 on Western blots of sheep tissues. Affected liver blots were the same as controls but a specific 50-kDa band was at higher concentration in affected brain homogenates than in controls. Others have also reported bands reacting differently to different CLN3 antibodies. When the 3' end of sheep CLN3 cDNA was amplified by RT-PCR, four mRNA splicing variants were found. Different CLN3 splicing variants at the 5' end of the human cDNA have been reported. These mRNA splicing variants may account the variation of epitope distribution and the different subcellular locations of the CLN3 gene product(s). The predicted size of the unmodified CLN3 protein is 48 kDa. Significantly higher molecular weight bands may correspond to oligomers of a CLN3 isoform or to a CLN3 isoform tightly bound to another protein.
Mol Genet Metab 1999 Jun
PMID:Splicing variants in sheep CLN3, the gene underlying juvenile neuronal ceroid lipofuscinosis. 1035 17


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