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PubMed1995

CLN3, not positive feedback, determines the timing of CLN2 transcription in cycling cells.

Transcriptional activation of the budding yeast CLN1 and CLN2 genes during the late G1 phase of the cell cycle has been attributed to a positive feedback loop, wherein the transcription of both genes is stimulated by the accumulation of their protein products. We demonstrate that in cycling cells CLN2 does not play a role in determining the timing of its own transcriptional activation. First, we show that CLN3 alone is sufficient to maximally activate CLN2 transcription. Cells that lack functional CLN1 and CLN2 genes activate the CLN2 promoter with the same kinetics and at the same size as cells in which all three CLN genes are functional. In addition, CLN2 transcription is activated with similar kinetics in cells that have CLN2 as their only functional CLN gene and in CLN-deficient cells. Promoter analysis shows that CLN3-dependent activation of CLN2 transcription is directed primarily through the previously identified UAS1 region although another cis-acting region, UAS2, also can contribute to CLN2 activation under some conditions. The ability to activate transcription of CLN2 is not a unique property of CLN3 because ectopically expressed CLN2 can both activate the endogenous CLN2 promoter and induce Start. We propose that failure of the endogenous CLN2 gene to contribute significantly to activation of its own transcription results from its relative effectiveness at inducing Start, cell cycle progression and, subsequently, inactivation of CLN2 expression.

Base Sequence↗

PubMed2004

Profound infantile neuroretinal dysfunction in a heterozygote for the CLN3 genetic defect.

The neuronal ceroid-lipofuscinoses are a group of diseases that are characterized by progressive neuroretinal symptomatology, progressive accumulation of autofluorescing waxy lipopigments (ceroid-lipofuscin) within the brain and other tissues, and cerebral atrophy. Juvenile neuronal ceroid-lipofuscinosis, or Batten disease, is a form of neuronal ceroid-lipofuscinosis that is characterized by onset of neuroretinal symptoms between 4 and 10 years. Juvenile neuronal ceroid-lipofuscinosis is the most common type of neuronal ceroid-lipofuscinosis in the United States and Europe and is inherited as an autosomal recessive genetic disorder. Research in the last decade has led to the identification of the responsible gene for juvenile neuronal ceroid-lipofuscinosis, which is designated as CLN3. CLN3 is located on chromosome 16p11.2-12.1. The major mutation is a 1.02 kb deletion, which removes exons 7 and 8. Both homozygotic and heterozygotic deletions at the CLN3 gene site have been associated with the clinical syndromes of juvenile neuronal ceroid-lipofuscinosis. We report a possible atypical case of neuronal ceroid-lipofuscinosis, an infant, who presented at 5 months of age with a lack of developmental milestones, poor vision, severe retinopathy, intractable seizures, and progressive cerebral atrophy. Extensive laboratory investigations, including thorough metabolic evaluations, were unremarkable except for neuroimaging studies, electroencephalography, and electroretinography, all of which showed abnormalities confirming both cerebral and retinal degeneration. Although skin and conjunctival biopsies did not show classic fingerprint cytosomes by electron microscopic study, which characterize juvenile neuronal ceroid-lipofuscinosis, a diagnosis of an atypical form of juvenile neuronal ceroid-lipofuscinosis was suspected on the basis of the clinical picture. The retinal abnormalities, surprisingly, were those believed to be diagnostic of juvenile-onset neuronal ceroid-lipofuscinosis, or Batten disease. Subsequently, a heterozygous mutation for the common 1.02 kb deletion characteristic of juvenile neuronal ceroid-lipofuscinosis was established.

Alleles↗

PubMed2005

[From gene to disease; from CLN1, CLN2 and CLN3 to neuronal ceroid lipofuscinosis].

The neuronal ceroid lipofuscinoses (NCL) are worldwide the most common lysosomal storage disorders of childhood. Clinical features often include progressive visual impairment, seizures, psychomotor deterioration, dementia, and premature death. Most NCL cases are caused by mutations in the CLN1, CLN2 and CLN3 genes, which play an essential role in lysosomal protein degradation. Laboratory diagnostics for a patient suspected of NCL should start with enzyme analysis in the case of INCL and LINCL and investigation of lymphocyte vacuolisation for JNCL. Diagnosis at the protein level is not available for JNCL, but CLN3 mutation analysis is possible. The carrier status of healthy relatives in families with known mutations in either CLN1, CLN2, CLN3 or CLN6 can be determined with certainty by mutation analysis.

Aminopeptidases↗

PubMed1998

Molecular screening of Batten disease: identification of a missense mutation (E295K) in the CLN3 gene.

Batten disease, the juvenile form of neuronal ceroid lipofuscinosis, is a prevalent neuron degenerative disorder of childhood. A 1.02-kb genomic deletion in the Batten disease gene CLN3 has been determined to be a common mutation. We developed a PCR method to screen for this deletion and tested 43 Batten disease probands. We found 36% (31/86) of Batten disease chromosomes did not carry the 1.02-kb deletion. Of the three heterozygotes for the 1.02-kb deletion, a novel G-to-A missense mutation at nucleotide 1020 of the CLN3 cDNA sequence was found on two of the non-1.02-kb deletion chromosomes. The missense mutation resulted in a substitution of glutamic acid (E) by lysine (K) at position 295 (E295 K). The E295 K mutation causes a change in predicted local protein conformation. This glutamic acid is a highly conserved acidic amino acid, being present in human, mouse, dog and yeast, which suggests it may play an important role in the function of the Batten disease protein.

Alternative Splicing↗

PubMed1995

Isolation of a novel gene underlying Batten disease, CLN3. The International Batten Disease Consortium.

Batten disease (also known as juvenile neuronal ceroid lipofuscinosis) is a recessively inherited neurodegenerative disorder of childhood characterized by progressive loss of vision, seizures, and psychomotor disturbances. The Batten disease gene, CLN3, maps to chromosome 16p12.1. The so-called 56 chromosome haplotype defined by alleles at the D16S299 and D16S298 loci is shared by 73% of Batten disease chromosomes. Exon amplification of a cosmid containing D16S298 has yielded a candidate gene that is disrupted by a 1 kb genomic deletion in all patients carrying the 56 chromosome. Two separate deletions and a point mutation altering a splice site in three unrelated families have confirmed the candidate as the CLN3 gene. The disease gene encodes a novel 438 amino acid protein of unknown function.

Amino Acid Sequence↗

PubMed2004

Cln3 activates G1-specific transcription via phosphorylation of the SBF bound repressor Whi5.

G1-specific transcriptional activation by Cln3/CDK initiates the budding yeast cell cycle. To identify targets of Cln3/CDK, we analyzed the SBF and MBF transcription factor complexes by multidimensional protein interaction technology (MudPIT). Whi5 was identified as a stably bound component of SBF but not MBF. Inactivation of Whi5 leads to premature expression of G1-specific genes and budding, whereas overexpression retards those processes. Whi5 inactivation bypasses the requirement for Cln3 both for transcriptional activation and cell cycle initiation. Whi5 associates with G1-specific promoters via SBF during early G1 phase, then dissociates coincident with transcriptional activation. Dissociation of Whi5 is promoted by Cln3 in vivo. Cln/CDK phosphorylation of Whi5 in vitro promotes its dissociation from SBF complexes. Mutation of putative CDK phosphorylation sites, at least five of which are phosphorylated in vivo, strongly reduces SBF-dependent transcription and delays cell cycle initiation. Like mammalian Rb, Whi5 is a G1-specific transcriptional repressor antagonized by CDK.

Amino Acid Sequence↗

PubMed1997

Farnesylation of Batten disease CLN3 protein.

The carboxyl terminal of the predicted amino acid sequence of the Batten disease CLN3 gene protein is CQLS. This motif is expected to be a site for farnesylation at the cysteine residue. In order to determine whether this is indeed farnesylated we have carried out the in-vitro prenylation of tetrapeptides CVLS, CAIL and CQLS using a farnesyl transferase preparation from bovine brain. The data shows that the CQLS is a good acceptor of a farnesyl group similar to CVLS while it is a poor acceptor of a geranylgeranyl group unlike CAIL, which is a good acceptor of a geranylgeranyl group. This suggests that the CLN3 gene product may be a farnesylated protein.

Adolescent↗

PubMed2005

Two photoionization thresholds of N3 produced by ClN3 photodissociation at 248 nm: further evidence for cyclic N3.

We present results of near-threshold photoionization of N3 photofragments produced by laser photodissociation of ClN3 at 248 nm. The time of flight of recoiling N3 is used to resolve two photochemical channels producing N3, which exhibit different translational energy release. The two forms of N3 resolved in this way exhibit different photoionization thresholds, consistent with their assignment to linear (X 2pi(g)) and cyclic N3. This result agrees with the existing theoretical calculations of excited and ionic states of N3 and strengthens previous experimental results which suggested that the ClN3 photolysis produces a cyclic form of N3.

Algorithms↗

PubMed2004

A cell sizer network involving Cln3 and Far1 controls entrance into S phase in the mitotic cycle of budding yeast.

Saccharomyces cerevisiae must reach a carbon source-modulated critical cell size, protein content per cell at the onset of DNA replication (Ps), in order to enter S phase. Cells grown in glucose are larger than cells grown in ethanol. Here, we show that an increased level of the cyclin-dependent inhibitor Far1 increases cell size, whereas far1 Delta cells start bud emergence and DNA replication at a smaller size than wild type. Cln3 Delta, far1 Delta, and strains overexpressing Far1 do not delay budding during an ethanol glucose shift-up as wild type does. Together, these findings indicate that Cln3 has to overcome Far1 to trigger Cln-Cdc28 activation, which then turns on SBF- and MBF-dependent transcription. We show that a second threshold is required together with the Cln3/Far1 threshold for carbon source modulation of Ps. A new molecular network accounting for the setting of Ps is proposed.

CDC28 Protein Kinase, S cerevisiae↗

PubMed2002

Neuronal ceroid lipofuscinoses are connected at molecular level: interaction of CLN5 protein with CLN2 and CLN3.

Neuronal ceroid lipofuscinoses (NCLs) are neurodegenerative storage diseases characterized by mental retardation, visual failure, and brain atrophy as well as accumulation of storage material in multiple cell types. The diseases are caused by mutations in the ubiquitously expressed genes, of which six are known. Herein, we report that three NCL disease forms with similar tissue pathology are connected at the molecular level: CLN5 polypeptides directly interact with the CLN2 and CLN3 proteins based on coimmunoprecipitation and in vitro binding assays. Furthermore, disease mutations in CLN5 abolished interaction with CLN2, while not affecting association with CLN3. The molecular characterization of CLN5 revealed that it was synthesized as four precursor forms, due to usage of alternative initiator methionines in translation. All forms were targeted to lysosomes and the longest form, translated from the first potential methionine, was associated with membranes. Interactions between CLN polypeptides were shown to occur with this longest, membrane-bound form of CLN5. Both intracellular targeting and posttranslational glycosylation of the polypeptides carrying human disease mutations were similar to wild-type CLN5.

Aminopeptidases↗

PubMed1997

A novel Mcm1-dependent element in the SWI4, CLN3, CDC6, and CDC47 promoters activates M/G1-specific transcription.

We have identified a novel promoter element that confers M/G1-specific transcription in Saccharomyces cerevisiae. This element, which we call an ECB (early cell cycle box), was first identified in the SWI4 promoter, but it is also present in the promoter of a G1 cyclin CLN3, as well as in the promoters of three DNA replication genes: CDC6, CDC47, and CDC46. Transcripts from all five of these genes oscillate during the cell cycle and peak at the M/G1 boundary, as do isolated ECB elements in reporter constructs. The ECB element contains an Mcm1 binding site to which Mcm1 binds in vitro, and an Mcm1-VP16 fusion, which places a constitutive activator on Mcm1-binding sites in vivo, can deregulate ECB-containing promoters. Mcm1 is a transcription factor that is also required for minichromosome maintenance. We provide evidence that the replication defect of mcm1 mutants can be suppressed by ectopic CDC6 transcription. Periodic expression of SWI4 and CLN3 may be important for cell cycle progression, as we find that these genes are both haploinsufficient and rate limiting for G1 progression. We suggest that ECB-regulated gene products play critical roles in promoting the initiation of S-phase, both by regulating CLN1 and CLN2 transcription and as components of the initiation complex on origins of replication.

Cell Cycle Proteins↗

PubMed2006

The F-box protein Grr1 regulates the stability of Ccn1, Cln3 and Hof1 and cell morphogenesis in Candida albicans.

Both G1 and mitotic cyclins have been implicated in regulating Candida albicans filamentous growth. We have investigated the functions of Grr1 whose orthologue in Saccharomyces cerevisiae is known to mediate ubiquitin-dependent degradation of the G1 cyclins Cln1 and Cln2. Here, we report that deleting C. albicans GRR1 causes significant stabilization of two G1 cyclins Ccn1 and Cln3 and pseudohyphal growth. grr1Delta cells are highly heterogeneous in length and many of them fail to separate after cytokinesis. Interestingly, some isolated rod-like G1 cells of similar sizes are present in the grr1Delta culture. Time-lapse microscopy revealed that the rod-shaped G1 cells first grew exclusively in width before budding and then the bud grew exclusively by apical extension until after cytokinesis, yielding rod-like daughter cells. Consistently, actin patches persistently localize to the bud tip until around the time of cytokinesis. Despite the pseudohyphal phenotype, grr1Delta cells respond normally to hyphal induction. Hyperphosphorylated Cln3 isoforms accumulate in grr1Delta cells, indicating that Grr1 selectively mediates their degradation in wild-type cells. grr1Delta pseudohyphal growth requires neither Hgc1 nor Swel, two important regulators of cell morphogenesis. Furthermore, the cellular level of Hof1, a protein having a role in cytokinesis, is also significantly increased in grr1Delta cells.

Actins↗

PubMed1999

Molecular basis of the neuronal ceroid lipofuscinoses: mutations in CLN1, CLN2, CLN3, and CLN5.

The neuronal ceroid lipofuscinoses (NCLs), also referred to as Batten disease, are a group of neurodegenerative disorders characterised by the accumulation of an autofluorescent lipopigment in many cell types. Different NCL types are distinguished according to age of onset, clinical phenotype, ultrastructural characterisation of the storage material, and chromosomal location of the disease gene. At least eight genes underlie the NCLs, of which four have been isolated and mutations characterised: CLN1, CLN2, CLN3, CLN5. Two of these genes encode lysosomal enzymes, and two encode transmembrane proteins, at least one of which is likely to be in the lysosomal membrane. The basic defect in the NCLs appears to be associated with lysosomal function.

Aminopeptidases↗

PubMed1996

A model for Batten disease protein CLN3: functional implications from homology and mutations.

In an attempt to understand the molecular nature of Batten disease, we have examined the amino acid sequence of the affected CLN3 gene product (The International Batten Disease Consortium (1995) Cell 82, 949-957) and the site-specific mutations which give rise to the biological defect. Homology searches and molecular modeling have led to the development of a model for the folding and disposition of the protein, possibly within a mitochondrial membrane. High homology with a yeast protein of unknown function suggests a strong evolutionary conservation of function. We speculate that a possible role for the protein may be in chaperoning the folding/unfolding or assembly/ disassembly of other proteins, specifically subunit c of the mitochondrial ATP synthase complex.

Amino Acid Sequence↗

PubMed2004

Homogeneous polymerase chain reaction nucleobase quenching assay to detect the 1-kbp deletion in CLN3 that causes Batten disease.

Batten disease is an autosomal recessive disorder also known as juvenile neuronal ceroid lipofuscinosis. The most common mutation for this disease is an approximately 1-kbp deletion in the CLN3 gene, which accounts for about 80 to 85% of the mutation load. We developed a rapid assay for this mutation using the PCR to produce amplicons that are detected by nucleobase quenching of the fluorescent signal from a probe labeled with a fluorescent dye. The probe overlaps the deletion breakpoint and is completely base paired to the mutant amplicon. However, three bases at the 5' end of the probe do not base pair with the wild-type amplicon. The alleles are distinguished by the different melting temperatures of the probe amplicon hybrids. Comparison of this new method with an allele-specific PCR and gel electrophoresis-based method showed 100% concordance in determination of the genotype for 30 specimens (11 homozygous mutant, 8 heterozygotes, and 11 homozygous normal). PCR followed by allele-specific melting curve analysis using nucleobase quenching has utility as a rapid method for detection of the most common mutation that causes Batten disease.

Female↗

PubMed2000

Chromosomal assignment of canine TSC2, PKD1 and CLN3 genes by radiation hybrid- and linkage analyses.

The canine tuberous sclerosis 2 (TSC2) gene has been mapped to canine chromosome 6 using a canine whole genome radiation hybrid panel. There is close linkage between canine TSC2 and the polycystic kidney disease 1 gene (PKD1), as has been observed in humans and other mammalian species. The gene responsible for the human juvenile form of neuronal ceroid lipofuscinosis (CLN3), maps close to TSC2 and PKD1 in humans, and is also syntenic in the dog. We further demonstrate linkage to a group of polymorphic markers assigned to canine chromosome 6 (CFA6).

Animals↗

PubMed2001

A yeast model for classical juvenile Batten disease (CLN3).

The gene involved in the classical juvenile form of Batten disease, CLN3 has been identified as being highly homologous to the Saccharomyces cerevisiae YHC3 gene. To provide a simple model for the biochemical events underlying this disease, several disruptions have been made in YHC3 in three different S. cerevisiae strains. No obvious growth differences were observed, and neither was the previously reported phenotypic difference between wild-type and yeast disrupted in YHC3.

Cyclins↗

PubMed2001

Genomic structure of three CLN3-like genes in Caenorhabditis elegans.

The genome of Caenorhabditis elegans is predicted to carry three genes similar to CLN3, the gene underlying juvenile neuronal ceroid lipofuscinosis. All three genes are transcribed and the genomic structure has been determined. The number and position of exons for two of the genes differ from that predicted from the genomic sequence, but no discrepancies with the genomic nucleotide sequence were found. Gene F07B10.1 (cln-3.1) is predicted to have 7 exons and to encode a protein of 424 amino acids. Gene C01G8.2 (cln-3.2) has 9 exons and encodes a protein of 435 amino acids. Gene ZC190.1 (cln-3.3) is predicted to have 9 exons and to encode a protein of 416 amino acids.

Animals↗