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PubMed1995

Chromosome 16 microdeletion in a patient with juvenile neuronal ceroid lipofuscinosis (Batten disease).

The gene that is involved in juvenile neuronal ceroid lipofuscinosis (JNCL), or Batten disease--CLN3--has been localized to 16p12, and the mutation shows a strong association with alleles of microsatellite markers D16S298, D16S299, and D16S288. Recently, haplotype analysis of a Batten patient from a consanguineous relationship indicated homozygosity for a D16S298 null allele. PCR analysis with different primers on DNA from the patient and his family suggests the presence of a cytogenetically undetectable deletion, which was confirmed by Southern blot analysis. The microdeletion is embedded in a region containing chromosome 16-specific repeated sequences. However, putative candidates for CLN3, members of the highly homologous sulfotransferase gene family, which are also present in this region in several copies, were not deleted in the patient. If the microdeletion in this patient is responsible for Batten disease, then we conclude that the sulfotransferase genes are probably not involved in JNCL. By use of markers and probes flanking D16S298, the maximum size of the microdeletion was determined to be approximately 29 kb. The microdeletion may affect the CLN3 gene, which is expected to be in close proximity to D16S298.

Alleles↗
PubMed1993

Localization of juvenile, but not late-infantile, neuronal ceroid lipofuscinosis on chromosome 16.

The neuronal ceroid lipofuscinoses (NCL) are a group of progressive neurodegenerative disorders characterized by the deposition of autofluorescent proteinaceous fingerprint or curvilinear bodies. We have found that CLN3, the gene underlying the juvenile form of NCL, is very tightly linked to the dinucleotide repeat marker D16S285 on chromosome 16. Integration of D16S285 into the genetic map of chromosome 16 by using the Centre d'Etude du Polymorphisme Humain panel of reference pedigrees yielded a favored marker order in the CLN3 region of qtel-D16S150-.08-D16S285-.04-D16S148-.02-D16S 67-ptel. The most likely location of the disease gene, near D16S285 in the D16S150-D16S148 interval, was favored by odds of greater than 10(4):1 over the adjacent D16S148-D16S67 interval, which was recently reported as the minimum candidate region. Analysis of D16S285 in pedigrees with late-infantile NCL virtually excluded the CLN3 region, suggesting that these two forms of NCL are genetically distinct.

Adolescent↗
PubMed1992

Is START a switch?

The cell cycle in Saccharomyces cerevisiae is controlled by regulation of START in late G1. The CLN1, CLN2 and CLN3 family of cyclin homologues is required for cells to pass START. They probably act by activating the CDC28 protein kinase. Expression of CLN1 or CLN3 under the control of an inducible promoter shows that transcription of either gene is sufficient for cyclin-deficient strains arrested in G1 to traverse START. A model of START regulation involves activation of CDC28 kinase by any CLN protein, leading to activation of CLN1 and CLN2 transcription in a positive feedback loop and passage through START. The cell cycle-dependent transcriptional regulators SWI4 and SWI6 may be components of the feedback loop. Cell cycle commitment entails resistance to the inhibitory action of mating factor, which correlates with peak levels of CLN1 and CLN2 mRNAs. FAR1 encodes an alpha-factor-dependent inhibitor of CLN function whose expression is markedly reduced at the time of START. The interplay of all these factors may sharpen the START transition such that it is close to an all-or-nothing switch event. This may be important for several START-dependent events to be activated at the same time, leading to coordinated cell cycle progression.

Cell Cycle↗
PubMed1992

Mapping the gene for juvenile onset neuronal ceroid lipofuscinosis to chromosome 16 by linkage analysis.

The ceroid-lipofuscinoses are a group of inherited neurodegenerative disorders characterised by the accumulation of autofluorescent lipopigment in neurones and other cell types. The underlying biochemical defect is unknown. Juvenile onset neuronal ceroid lipofuscinosis (Batten disease; Spielmeyer-Vogt disease) is an autosomal recessive trait. Linkage studies were undertaken to determine the location of the Batten disease (CLN3) mutation. Studies were carried out on 205 members of 42 families in which there were 76 affected individuals. Families originated from 7 North European countries and Canada. Serum samples from 23 families, including a total of 48 affected children, were tested for a set of "classical markers." A positive lod score was found with the haptoglobin (Hp) system. The combined male and female maximum lod score was 3.00 at theta = 0.00 and theta = 0.26, respectively. This provided an indication of localisation to the long arm of chromosome 16. Linkage analysis was then carried out in 42 families using DNA markers for loci on human chromosome 16. The maximal lod score between Batten disease and the locus D16S148 calculated for combined sexes was 6.05. No recombinants were observed. Multilocus analysis using 5 loci indicated the most likely order to be HP-D16S151-D16S150-CLN3-D16S148-D16S147. Work is in progress to refine the genetic and physical localisation of the Batten disease gene using additional markers in this region and a panel of somatic cell hybrids. Methods are now available which should allow the gene to be isolated and characterised.

Child↗
PubMed1995

Late onset juvenile neuronal ceroid-lipofuscinosis with granular osmiophilic deposits (GROD).

The juvenile-onset subtype of the neuronal ceroid lipofuscinoses (JNCL) is well known [Hofman, ISBN90-71534-19-7 1990] and ultrastructurally characterized by fingerprints and/or curvilinear bodies in many cell types. Linkage studies indicated a most likely location for CLN3, the gene involved in JNCL, in the interval between loci D16S297 and D16S57, within close proximity of the loci D16S298 and D16S299 [Mitchison et al., Genomics 22:465-468, 1993]. We present two sibs with a late onset progressive disease of mental deterioration, progressive macular degeneration, motor disturbances, and epilepsy. Histological symptoms of neuronal ceroid lipofuscinosis and ultrastructural granular osmiophilic deposits (GROD) in lymphocytes and neurons are found. Individual haplotypes at polymorphic marker loci on chromosome 16 were constructed to determine whether JNCL with GROD is linked to the CLN3 locus.

Adolescent↗
PubMed1995

Carrier detection of Batten disease (juvenile neuronal ceroid-lipofuscinosis).

Batten disease, or the juvenile form of neuronal ceroid lipofuscinosis, is an autosomal recessive neurodegenerative disorder manifesting with progressive blindness, seizures, and dementia, leading to an early death. The CLN3 locus which is involved in Batten disease had been localized to chromosome 16p11.2. Linkage disequilibrium has been observed between CLN3 and polymorphic microsatellite markers D16S288, D16S299, and D16S298, making carrier detection and prenatal diagnosis by haplotype analysis possible. For the purpose of carrier detection, haplotypes from Dutch Batten patients and their families were constructed. Most patients share the same D16S298 allele, suggesting the presence of a founder effect in the Dutch population. In a large inbred Dutch family, in which Batten disease occurs with high frequency, haplotype analysis has been carried out with high accuracy for carrier detection.

Alleles↗
PubMed1993

Yeast G1 cyclins CLN1 and CLN2 and a GAP-like protein have a role in bud formation.

Cyclin-dependent protein kinases have a central role in cell cycle regulation. In Saccharomyces cerevisiae, Cdc28 kinase and the G1 cyclins Cln1, 2 and 3 are required for DNA replication, duplication of the spindle pole body and bud emergence. These three independent processes occur simultaneously in late G1 when the cells reach a critical size, an event known as Start. At least one of the three Clns is necessary for Start. Cln3 is believed to activate Cln1 and Cln2, which can then stimulate their own accumulation by means of a positive feedback loop. They (or Cln3) also activate another pair of cyclins, Clb5 and 6, involved in initiating S phase. Little is known about the role of Clns in spindle pole body duplication and budding. We report here the isolation of a gene (CLA2/BUD2/ERC25) that codes for a homologue of mammalian Ras-associated GTPase-activating proteins (GAPs) and is necessary for budding only in cln1 cln2 cells. This suggests that Cln1 and Cln2 may have a direct role in bud formation.

Amino Acid Sequence↗
PubMed2001

Saccharomyces cerevisiae YCRO17c/CWH43 encodes a putative sensor/transporter protein upstream of the BCK2 branch of the PKC1-dependent cell wall integrity pathway.

The Saccharomyces cerevisiae cwh43-2 mutant, originally isolated for its Calcofluor white hypersensitivity, displays several cell wall defects similar to mutants in the PKC1-MPK1 pathway, including a growth defect and increased release of beta-1,6-glucan and beta-glucosylated proteins into the growth medium at increased temperatures. The cloning of CWH43 showed that it corresponds to YCR017c and encodes a protein with 14-16 transmembrane segments containing several putative phosphorylation and glycosylation sites. The N-terminal part of the amino acid sequence of Cwh43p shows 40% similarity with the mammalian FRAG1, a membrane protein that activates the fibroblast growth factor receptor of rat osteosarcoma (FGFR2-ROS) and with protein sequences of four uncharacterized ORFs from Caenorhabditis elegans and one from Drosophila melanogaster. The C-terminus of Cwh43p shows low similarities with a xylose permease of Bacillus megaterium and with putative sugar transporter from D. melanogaster, and has 52% similarity with a protein sequence from a Schizosaccharomyces pombe cDNA. A Cwh43-GFP fusion protein suggested a plasma membrane localization, although localization to the internal structure of the cells could not be excluded, and it concentrates to the bud tip of small budded cells and to the neck of dividing cells. Deletion of CWH43 resulted in cell wall defects less pronounced than those of the cwh43-2 mutant. This allele-specific phenotype appears to be due to a G-R substitution at position 57 in a highly conserved region of the protein. Genetic analysis places CWH43 upstream of the BCK2 branch of the PKC1 signalling pathway, since cwh43 mutations were synthetic lethal with pkc1 deletion, whereas the cwh43 defects could be rescued by overexpression of BCK2 and not by high-copy-number expression of genes encoding downstream proteins of the PKC1 pathway However, unlike BCK2, whose disruption in a cln3 mutant resulted in growth arrest in G(1), no growth defect was observed in a double cwh43 cln3 mutants. Taken together, it is proposed that CWH43 encodes a protein with putative sensor and transporter domains acting in parallel to the main PKC1-dependent cell wall integrity pathway, and that this gene has evolved into two distinct genes in higher eukaryotes.

Amino Acid Sequence↗
PubMed2002

KNR4 is a member of the PKC1 signalling pathway and genetically interacts with BCK2, a gene involved in cell cycle progression in Saccharomyces cerevisiae.

In budding yeast, PKC1 plays an essential role in cell wall integrity and cell proliferation through a bifurcated PKC1/mitogen-activated protein (MAP) kinase pathway. The evidence that KNR4 is a member of the PKC1 pathway and genetically interacts with BCK2, a gene involved together with Cln3-Cdc28 in the G1 to S transition phase of the cell cycle, was as follows. Both KNR4 and BCK2 were isolated as a dosage suppressor of a calcofluor white hypersensitive ( cwh43) mutant. Overexpression of either of the two genes in a wild-type strain led to increased resistance to wall-affecting drugs, while this effect was not obtained in a bck2 Delta mutant that overexpressed KNR4. Deletion of KNR4 or BCK2 was synthetically lethal with components of the linear PKC1/MAP kinase pathway. Loss of Knr4 was lethal in combination with loss of Cln3, as was shown for Bck2. A protein interaction between Knr4 and Bck2 was measured using the two-hybrid system, although a direct physical interaction could not be detected by co-immunuprecipation methods. Finally, a genome-wide analysis of cells that overexpress BCK2 or KNR4 indicated that both genes also have effects independent of each other. In particular, the microarray data showed up-regulation of SWI4, which may account for the suppression of the cell lysis of a pkc1 null mutant, due to overexpression of BCK2.

Cyclin G↗
PubMed1991

The role of SWI4 and SWI6 in the activity of G1 cyclins in yeast.

Entry into the mitotic cycle (START) requires a protein kinase encoded by the CDC28 gene and one of three redundant G1-specific cyclins encoded by CLN1, -2, and -3. SWI4 and SWI6 are transcription factors required for the START-dependent activation of the HO endonuclease gene. They also fulfill an overlapping but essential role for cell division since cells deleted for both genes are inviable. We show that the essential role of SWI4 and SWI6 is to ensure the activity of G1-specific cyclin genes. SWI4 and SWI6 appear necessary for the transcription of CLN1 and CLN2, but not for that of CLN3. CLN3 function is, however, also dependent on SWI4 and SWI6.

Blotting, Northern↗
PubMed1990

Infantile neuronal ceroid-lipofuscinosis is not an allelic form of Batten disease: exclusion of chromosome 16 region with linkage analyses.

Infantile neuronal ceroid-lipofuscinosis (CLN1) is the form of neuronal ceroid-lipofuscinoses (NCL) with the earliest onset of symptoms. The locus of the most common form of these disorders, juvenile NCL (CLN3), has been mapped to chromosome 16. We report here linkage data of the same region in Finnish CLN1 families. Our results indicate that CLN1 is not allelic with CLN3 but represents a different locus, which is not located within about 70 cM in chromosome 16.

Alleles↗
PubMed2005

Behavioral assessment in mouse models of neuronal ceroid lipofuscinosis using a light-cued T-maze.

Learning impairment is a common feature of the neuronal ceroid lipofuscinoses (NCL), a family of lysosomal storage disorders associated with progressive neurodegeneration. Murine models for the neuronal ceroid lipofuscinoses include the well-characterized motor neuron degeneration (mnd/mnd) model for one variant of late infantile NCL (CLN8), and the more recently generated models for the infantile (CLN1) and juvenile (CLN3) forms of NCL. To determine whether these mouse models exhibit behavioral deficits analogous to the learning impairment characteristic of the human disorders, the performance of these animals on an associative learning task was assessed. The abilities of affected and normal control mice to associate a light stimulus with a food reward were evaluated in 14-16-week-old animals using a T-maze. Normal mice were able to reach a criterion for having learned to make the association within a mean of 9.4 trials. The CLN8 and CLN3 mice, on the other hand, required means of 26.2 and 27.5 trials, respectively, to reach the same performance criterion (p<0.05), whereas none of the CLN1 mice were able to reach the criterion within a limit of 30 trials. The poor performance of the mutant mice did not appear to result from impaired retinal function; mice of all three strains exhibited retinal electrophysiological responses to dim light flashes and displayed robust pupillary light reflexes. Associative learning deficits appear to be an early disease phenotype in the NCL mouse models that will be useful for assessing the efficacy of therapeutic interventions such as gene or stem cell therapies.

Analysis of Variance↗
PubMed2006

Coherence and timing of cell cycle start examined at single-cell resolution.

Cell cycle "Start" in budding yeast involves induction of a large battery of G1/S-regulated genes, coordinated with bud morphogenesis. It is unknown how intra-Start coherence of these events and inter-Start timing regularity are achieved. We developed quantitative time-lapse fluorescence microscopy on a multicell-cycle timescale, for following expression of unstable GFP under control of the G1 cyclin CLN2 promoter. Swi4, a major activator of the G1/S regulon, was required for a robustly coherent Start, as swi4 cells exhibited highly variable loss of cooccurrence of regular levels of CLN2pr-GFP expression with budding. In contrast, other known Start regulators Mbp1 and Cln3 are not needed for coherence but ensure regular timing of Start onset. The interval of nuclear retention of Whi5, a Swi4 repressor, largely accounts for wild-type mother-daughter asymmetry and for variable Start timing in cln3 mbp1 cells. Thus, multiple pathways may independently suppress qualitatively different kinds of noise at Start.

Cell Cycle↗
PubMed2006

Two novel CLN5 mutations in a Portuguese patient with vLINCL: insights into molecular mechanisms of CLN5 deficiency.

The neuronal ceroid-lipofuscinoses are the most common neurodegenerative disorders in childhood characterized by progressive blindness, epilepsy, brain atrophy, and premature death. Based on the age at onset, disease progression and ultrastructural features three classical (infantile, late-infantile, and juvenile) and three variant late-infantile forms are generally distinguished (Finnish variant, Costa Rican variant, and epilepsy with progressive motor retardation). The Finnish variant late-infantile form has been associated with CLN5 gene defects, with only five mutations described to date. We report a patient with vLINCL/CLN5 who represents the first evidence of the disease in the Portuguese population. Mutational screening revealed the previously described missense mutation c.835G>A (D279N) inherited from the mother, and two novel mutations, c.565C>T (Q189X) and c.335G>C (R112P) from paternal and maternal inheritance, respectively. Based on data here reported: (i) the number of possible mutations in CLN5 gene is now 7; (ii) the CLN5 Portuguese case represents the third description of the disease outside northern Europe; (iii) the CLN5/mRNA expression level reduced to 45% supports the existence of one mRNA non-producing allele, further noticeable at the protein level; (iv) Western blotting data using a specific antibody to human CLN5p provided evidence for the presence of four integral membrane isoforms in human fibroblasts; (v) data from differential expression of CLN2, CLN3, and CLN5 suggest down-regulation of CLN3 gene expression in CLN2 and CLN5-deficient human patients and this observation strengths the hypothesis of functional redundancy of the CLN system.

Adolescent↗
PubMed2000

Histopathologic and immunocytochemical analysis of the retina and ocular tissues in Batten disease.

PURPOSE: To describe the pathophysiologic features of retinal degeneration in Batten disease (juvenile neuronal ceroid lipofuscinosis [JNCL]) caused by mutations in the CLN3 gene. STUDY DESIGN: Comparative human tissue study. MATERIALS: The retina and other ocular tissues of a 22-year-old man with JNCL were compared with the same tissues of a healthy 30-year-old man. DNA from whole blood and RNA from retina were used for genotype analysis. METHODS: The retinas, corneas, conjunctiva, and ciliary body were processed for histopathologic and immunofluorescence analysis. Genomic DNA was subjected to polymerase chain reaction (PCR) and nucleotide sequence analyses. Reverse transcriptase/PCR and sequence analysis were performed on retinal RNA. RESULTS: The JNCL donor was heterozygous for a approximately 1 kb deletion in CLN3, as found in most JNCL patients. The other allele had a single base pair deletion in exon 6 that resulted in a frame shift. Gross pathology of the JNCL retina resembled that in retinitis pigmentosa, including deposits of bone spicule pigment. Histopathologic studies revealed loss of neurons from all retinal layers. Immunofluorescence labeling with antibodies to rhodopsin, recoverin, and cone opsin demonstrated degenerate rods and cones with short outer segments in the far periphery. Autofluorescent lipopigment granules were prominent in ganglion cells and some cells of the inner nuclear layer, but not in the photoreceptors. The retinal pigment epithelium (RPE) had fewer lipofuscin granules than the control specimen. Increased numbers of lipofuscin granules were found in the epithelia of the ciliary body and conjunctiva, but not in the cornea of the JNCL eye. CONCLUSIONS: Immunofluorescence studies revealed degenerate rods and cones in the far periphery. Lipofuscin granules were decreased in the RPE, consistent with loss of photoreceptor outer segments. The novel finding that degenerate photoreceptors did not contain autofluorescent inclusions suggests that granule accumulation may not precede photoreceptor degeneration in JNCL. The presence of normal photoreceptor proteins in the degenerate rods and cones suggests that these cells may be capable of functional regeneration if a therapy for Batten disease is developed.

Adult↗
PubMed1998

Studies of atypical JNCL suggest overlapping with other NCL forms.

In the United States, juvenile neuronal ceroid-lipofuscinosis (JNCL) is the most common form of NCL. This study analyzed 191 cases, diagnosed on the basis of age-at-onset, clinical symptomatology, and pathologic findings. Twenty percent (40/191) of these cases from 24/120 families manifested atypical clinical symptomatology and/or pathologic findings (typical revealed fingerprints and atypical revealed mixed inclusions, or only curvilinear or granular profiles) and, therefore, represent variant forms of JNCL. Those patients in the study with typical JNCL were a uniform group of cases, whereas the atypical were heterogenous and were divided into 8 subgroups based on the clinicopathologic findings. Forty-three families were analyzed (27 typical, 16 atypical) for the common 1.02 kb deletion and several pedigrees for novel mutations. In typical JNCL the common 1.02 kb deletion in both alleles (homozygous) were observed in 23/27, and only 1 allele (heterozygous) was exhibited in 4/27 families. In atypical JNCL families, 5/16 were heterozygous for the common 1.02 kb deletion. None of the remaining 11/16 families had the common 1.02 kb deletion in either allele, but in 9/11 cases the palmitoyl-protein thioesterase (PPT) levels were deficient. In cases where the mutation in CLN3 gene has not been identified, several possibilities may exist. The phenotype may be caused by a yet undefined mutation in CLN3 or may be due to overlapping with other forms of NCL.

Adolescent↗
PubMed1998

Genetic markers linked to neuronal ceroid lipofuscinosis in English setter dogs.

The neuronal ceroid lipofuscinoses (NCL) are a group of fatal autosomal recessive neurodegenerative diseases occurring in human and some domesticated animal species. A canine form of the disease (CNCL) has been extensively studied in a Norwegian colony of inbred English setters since 1960. A resource family developed for genetic mapping and comprising 170 individuals was typed for 103 genetic markers. Linkage analysis showed three genetic markers to be linked to the disease locus with the closest marker at a distance of about 3 CM. Two other loci were linked with these markers making a linkage group of five genetic markers. The linkage group spanned a distance of 54 CM. Two genes for human forms of the disease, CLN2 and CLN3, have been identified and mapped to human chromosome 11p15 and 16p12, respectively. The present study did not indicate any linkage between CNCL and the canine CLN3 homologue or to homologues of markers for genes that map close to human CLN2.

Aminopeptidases↗
PubMed1999

Novel sensing mechanisms and targets for the cAMP-protein kinase A pathway in the yeast Saccharomyces cerevisiae.

The cAMP-protein kinase A (PKA) pathway in the yeast Saccharomyces cerevisiae plays a major role in the control of metabolism, stress resistance and proliferation, in particular in connection with the available nutrient conditions. Extensive information has been obtained on the core section of the pathway, i.e. Cdc25, Ras, adenylate cyclase, PKA, and on components interacting directly with this core section, such as the Ira proteins, Cap/Srv2 and the two cAMP phosphodiesterases. Recent work has now started to reveal upstream regulatory components and downstream targets of the pathway. A G-protein-coupled receptor system (Gpr1-Gpa2) acts upstream of adenylate cyclase and is required for glucose activation of cAMP synthesis in concert with a glucose phosphorylation-dependent mechanism. Although a genuine signalling role for the Ras proteins remains unclear, they appear to mediate at least part of the potent stimulation of cAMP synthesis by intracellular acidification. Recently, several new targets of the PKA pathway have been discovered. These include the Msn2 and Msn4 transcription factors mediating part of the induction of STRE-controlled genes by a variety of stress conditions, the Rim15 protein kinase involved in stationary phase induction of a similar set of genes and the Pde1 low-affinity cAMP phosphodiesterase, which specifically controls agonist-induced cAMP signalling. A major issue that remains to be resolved is the precise connection between the cAMP-PKA pathway and other nutrient-regulated components involved in the control of growth and of phenotypic characteristics correlated with growth, such as the Sch9 and Yak1 protein kinases. Cln3 appears to play a crucial role in the connection between the availability of certain nutrients and Cdc28 kinase activity, but it remains to be clarified which nutrient-controlled pathways control Cln3 levels.

3',5'-Cyclic-AMP Phosphodiesterases↗