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PubMed1998

Isolation and characterization of new alleles of the cyclin-dependent kinase gene CDC28 with cyclin-specific functional and biochemical defects.

The G1 cyclin Cln2 negatively regulates the mating-factor pathway. In a genetic screen to identify factors required for this regulation, we identified an allele of CDC28 (cdc28-csr1) that blocked this function of Cln2. Cln2 immunoprecipitated from cdc28-csr1 cells was completely defective in histone H1 kinase activity, due to defects in Cdc28 binding and activation by Cln2. In contrast, Clb2-associated H1 kinase and Cdc28 binding was normal in immunoprecipitates from these cells. cdc28-csr1 was significantly deficient in other aspects of genetic interaction with Cln2. The cdc28-csr1 mutation was determined to be Q188P, in the T loop distal to most of the probable Cdk-cyclin interaction regions. We performed random mutagenesis of CDC28 to identify additional alleles incapable of causing CLN2-dependent mating-factor resistance but capable of complementing cdc28 temperature-sensitive and null alleles. Two such mutants had highly defective Cln2-associated kinase, but, surprisingly, two other mutants had levels of Cln2-associated kinase near to wild-type levels. We performed a complementary screen for CDC28 mutants that could cause efficient Cln2-dependent mating-factor resistance but not complement a cdc28 null allele. Most such mutants were found to alter residues essential for kinase activity; the proteins had little or no associated kinase activity in bulk or in association with Cln2. Several of these mutants also functioned in another assay for CLN2-dependent function not involving the mating-factor pathway, complementing the temperature sensitivity of a cln1 cln3 cdc28-csr1 strain. These results could indicate that Cln2-Cdc28 kinase activity is not directly relevant to some CLN2-mediated functions. Mutants of this sort should be useful in differentiating the function of Cdc28 complexed with different cyclin regulatory subunits.

Alleles↗
PubMed1998

Human cyclin K, a novel RNA polymerase II-associated cyclin possessing both carboxy-terminal domain kinase and Cdk-activating kinase activity.

The gene coding for human cyclin K was isolated as a CPR (cell-cycle progression restoration) gene by virtue of its ability to impart a Far- phenotype to the budding yeast Saccharomyces cerevisiae and to rescue the lethality of a deletion of the G1 cyclin genes CLN1, CLN2, and CLN3. The cyclin K gene encodes a 357-amino-acid protein most closely related to human cyclins C and H, which have been proposed to play a role in regulating basal transcription through their association with and activation of cyclin-dependent kinases (Cdks) that phosphorylate the carboxyl-terminal domain (CTD) of the large subunit of RNA polymerase II (RNAP II). Murine and Drosophila melanogaster homologs of cyclin K have also been identified. Cyclin K mRNA is ubiquitously expressed in adult mouse and human tissues, but is most abundant in the developing germ cells of the adult testis and ovaries. Cyclin K is associated with potent CTD kinase and Cdk kinase (CAK) activity in vitro and coimmunoprecipitates with the large subunit of RNAP II. Thus, cyclin K represents a new member of the "transcription" cyclin family which may play a dual role in regulating Cdk and RNAP II activity.

Amino Acid Sequence↗
PubMed1999

The yeast ser/thr phosphatases sit4 and ppz1 play opposite roles in regulation of the cell cycle.

Yeast cells overexpressing the Ser/Thr protein phosphatase Ppz1 display a slow-growth phenotype. These cells recover slowly from alpha-factor or nutrient depletion-induced G1 arrest, showing a considerable delay in bud emergence as well as in the expression of the G1 cyclins Cln2 and Clb5. Therefore, an excess of the Ppz1 phosphatase interferes with the normal transition from G1 to S phase. The growth defect is rescued by overexpression of the HAL3/SIS2 gene, encoding a negative regulator of Ppz1. High-copy-number expression of HAL3/SIS2 has been reported to improve cell growth and to increase expression of G1 cyclins in sit4 phosphatase mutants. We show here that the described effects of HAL3/SIS2 on sit4 mutants are fully mediated by the Ppz1 phosphatase. The growth defect caused by overexpression of PPZ1 is intensified in strains with low G1 cyclin levels (such as bck2Delta or cln3Delta mutants), whereas mutation of PPZ1 rescues the synthetic lethal phenotype of sit4 cln3 mutants. These results reveal a role for Ppz1 as a regulatory component of the yeast cell cycle, reinforce the notion that Hal3/Sis2 serves as a negative modulator of the biological functions of Ppz1, and indicate that the Sit4 and Ppz1 Ser/Thr phosphatases play opposite roles in control of the G1/S transition.

Cell Cycle↗
PubMed2000

Cks1 is required for G(1) cyclin-cyclin-dependent kinase activity in budding yeast.

p13(suc1) (Cks) proteins have been implicated in the regulation of cyclin-dependent kinase (CDK) activity. However, the mechanism by which Cks influences the function of cyclin-CDK complexes has remained elusive. We show here that Cks1 is required for the protein kinase activity of budding yeast G(1) cyclin-CDK complexes. Cln2 and Cdc28 subunits coexpressed in baculovirus-infected insect cells fail to exhibit protein kinase activity towards multiple substrates in the absence of Cks1. Cks1 can both stabilize Cln2-Cdc28 complexes and activate intact complexes in vitro, suggesting that it plays multiple roles in the biogenesis of active G(1) cyclin-CDK complexes. In contrast, Cdc28 forms stable, active complexes with the B-type cyclins Clb4 and Clb5 regardless of whether Cks1 is present. The levels of Cln2-Cdc28 and Cln3-Cdc28 protein kinase activity are severely reduced in cks1-38 cell extracts. Moreover, phosphorylation of G(1) cyclins, which depends on Cdc28 activity, is reduced in cks1-38 cells. The role of Cks1 in promoting G(1) cyclin-CDK protein kinase activity both in vitro and in vivo provides a simple molecular rationale for the essential role of CKS1 in progression through G(1) phase in budding yeast.

Adaptor Proteins, Signal Transducing↗
PubMed2000

CLN1 and its repression by Xbp1 are important for efficient sporulation in budding yeast.

Xbp1, a transcriptional repressor of Saccharomyces cerevisiae with homology to Swi4 and Mbp1, is induced by stress and starvation during the mitotic cycle. It is also induced late in the meiotic cycle. Using RNA differential display, we find that genes encoding three cyclins (CLN1, CLN3, and CLB2), CYS3, and SMF2 are downregulated when Xbp1 is overexpressed and that Xbp1 can bind to sequences in their promoters. During meiosis, XBP1 is highly induced and its mRNA appears at the same time as DIT1 mRNA, but its expression remains high for up to 24 h. As such, it represents a new class of meiosis-specific genes. Xbp1-deficient cells are capable of forming viable gametes, although ascus formation is delayed by several hours. Furthermore, Xbp1 target genes are normally repressed late in meiosis, and loss of XBP1 results in their derepression. Interestingly, we find that a deletion of CLN1 also reduces the efficiency of sporulation and delays the meiotic program but that sporulation in a Deltacln1 Deltaxbp1 strain is not further delayed. Thus, CLN1 may be Xbp1's primary target in meiotic cells. We hypothesize that CLN1 plays a role early in the meiotic program but must be repressed, by Xbp1, at later stages to promote efficient sporulation.

Base Sequence↗
PubMed2005

The F-box protein Met30 is required for multiple steps in the budding yeast cell cycle.

The Saccharomyces cerevisiae ubiquitin ligase SCF(Met30) is essential for cell cycle progression. To identify and characterize SCF(Met30)-dependent cell cycle steps, we used temperature-sensitive met30 mutants in cell cycle synchrony experiments. These experiments revealed a requirement for Met30 during both G(1)/S transition and M phase, while progression through S phase was unaffected by loss of Met30 function. Expression of the G(1)-specific transcripts CLN1, CLN2, and CLB5 was very low in met30 mutants, whereas expression of CLN3 was unaffected. However, overexpression of Cln2 could not overcome the G(1) arrest. Interestingly, overexpression of Clb5 could induce DNA replication in met30 mutants, albeit very inefficiently. Increased levels of Clb5 could not, however, suppress the cell proliferation defect of met30 mutants. Consistent with the DNA replication defects, chromatin immunoprecipitation experiments revealed significantly lower levels of the replication factors Mcm4, Mcm7, and Cdc45 at replication origins in met30 mutants than in wild-type cells. These data suggest that Met30 regulates several aspects of the cell cycle, including G(1)-specific transcription, initiation of DNA replication, and progression through M phase.

Cell Cycle↗
PubMed2006

Batten disease: features to facilitate early diagnosis.

AIMS: To ascertain the clinical and electrophysiological features in patients with juvenile neuronal ceroid lipofuscinosis (jNCL/Batten disease) and to identify those features that facilitate early diagnosis. METHODS: Nine patients with jNCL were identified retrospectively and their case notes reviewed. All had undergone an extensive clinical examination, including electrophysiology. Blood and molecular genetic testing confirmed the diagnosis. RESULTS: Age at onset ranged from 4-8 years. At presentation, two of nine patients had normal fundi; only two of nine patients had a bull's eye maculopathy. The electroretinogram (ERG) findings in this series included undetectable rod specific ERGs, an electronegative maximal response, reduced and delayed cone flicker ERGs, reduction in the b:a ratio in the photopic single flash ERG, and an undetectable pattern ERG. Vacuolated lymphocytes on peripheral blood film testing were present in eight of nine patients. Five of eight patients were homozygous for the 1.02 kb deletion on the CLN3 gene on molecular genetic testing; two of eight patients were heterozygous for that deletion. CONCLUSION: jNCL should be considered in children of 10 years and under presenting with visual loss and fundal changes ranging from normal through to pigmentary/atrophic changes or a bull's eye maculopathy. Electrophysiology may suggest jNCL. Although currently untreatable, early diagnosis is important to institute appropriate counselling and support.

Child↗
PubMed1996

Rapid diagnostic test for the major mutation underlying Batten disease.

Batten disease is the most common progressive neurodegenerative disorder of childhood in western countries. A novel cDNA responsible for Batten disease has recently been identified. We have developed a rapid diagnostic solid phase minisequencing test to detect the major 1.02 kb deletion which is responsible for 81% of affected chromosomes in Batten disease worldwide. In Finland, 90% of Batten chromosomes carry the major deletion owing to the enrichment of the CLN3 gene in the isolated Finnish population.

DNA Mutational Analysis↗
PubMed1995

The neuronal ceroid-lipofuscinoses.

The neuronal ceroid-lipofuscinoses, a group of progressive neurodegenerative diseases in children and in adults, have now been recognized for some 90 years, and the childhood forms represent one of the largest groups of progressive neurodegenerative diseases in children. Apart from a core group of major clinical forms-the infantile, the late-infantile, the juvenile, and the adult forms--numerous atypical patients afflicted with neuronal ceroid-lipofuscinosis have now been identified, constituting 10% to 20% of all patients with neuronal ceroid-lipofuscinosis. These "atypical" patients have, over the past 10 years, prompted the suggestion of 15 atypical variants or minor syndromes, many of them displaying the lipopigments of classic curvilinear and fingerprint ultrastructure, but others displaying granular osmiophilic deposits. The former lipopigments contain the subunit C of the mitochondrial adenosine triphosphate synthase, but lipopigments of the granular osmiophilic deposits including the classic infantile type Santavuori-Haltia, apparently do not, the latter type exhibiting sphingolipid activator proteins. The nosologic significance of both the subunit C of the adenosine triphosphate synthase and the sphingolipid activator proteins, although they make up a considerable amount of the crude auto-fluorescent lipopigments in neuronal ceroid-lipofuscinosis, is still unclear. In spite of numerous pathogenetic principles invoked, such as a defect in lipid peroxidation, abnormalities of dolichols and dolichol phosphates, and defects in protease inhibitors, precise pathogenesis and etiology of the neuronal ceroid-lipofuscinoses remain elusive. Recent promising molecular genetic studies have, however, revealed the gene for infantile neuronal ceroid-lipofuscinosis, CLN1, on chromosome 1p32; the gene for juvenile neuronal ceroid-lipofuscinosis, CLN3, on chromosome 16p12.1-11.2; and the gene for a Finnish variant of late-infantile neuronal ceroid-lipofuscinosis, CLN5, on chromosome 13q31-32. The genes for classic late-infantile neuronal ceroid-lipofuscinosis, CLN2, and for adult neuronal ceroid-lipofuscinosis, CLN4, have not been located, the former having been excluded from chromosomes 1 and 16. However, the gene products of the normal allelic forms have not yet been identified. A considerable number of sporadic animal models is now available, largely equivalent to the juvenile and infantile forms of neuronal ceroid-lipofuscinosis, with those of the English setter and the South Hampshire sheep evaluated best. Recently, several mouse models have been added to this list of autosomal-recessive models, again the one most thoroughly studied being the motor-neuron disease mouse. Progress has also been made in the prenatal diagnosis of neuronal ceroid-lipofuscinosis: now the infantile, late-infantile, and juvenile forms can be recognized prenatally by a combined genetic and electron microscopic approach.

Animals↗
PubMed2004

Membrane trafficking and mitochondrial abnormalities precede subunit c deposition in a cerebellar cell model of juvenile neuronal ceroid lipofuscinosis.

BACKGROUND: JNCL is a recessively inherited, childhood-onset neurodegenerative disease most-commonly caused by a approximately 1 kb CLN3 mutation. The resulting loss of battenin activity leads to deposition of mitochondrial ATP synthase, subunit c and a specific loss of CNS neurons. We previously generated Cln3Deltaex7/8 knock-in mice, which replicate the common JNCL mutation, express mutant battenin and display JNCL-like pathology. RESULTS: To elucidate the consequences of the common JNCL mutation in neuronal cells, we used P4 knock-in mouse cerebella to establish conditionally immortalized CbCln3 wild-type, heterozygous, and homozygous neuronal precursor cell lines, which can be differentiated into MAP-2 and NeuN-positive, neuron-like cells. Homozygous CbCln3Deltaex7/8 precursor cells express low levels of mutant battenin and, when aged at confluency, accumulate ATPase subunit c. Recessive phenotypes are also observed at sub-confluent growth; cathepsin D transport and processing are altered, although enzyme activity is not significantly affected, lysosomal size and distribution are altered, and endocytosis is reduced. In addition, mitochondria are abnormally elongated, cellular ATP levels are decreased, and survival following oxidative stress is reduced. CONCLUSIONS: These findings reveal that battenin is required for intracellular membrane trafficking and mitochondrial function. Moreover, these deficiencies are likely to be early events in the JNCL disease process and may particularly impact neuronal survival.

Animals↗
PubMed2025

Genetic pleiotropy underlying obesity and autoimmune disorders: a large-scale cross-trait gwas analysis in European ancestry populations.

BACKGROUND: Obesity and autoimmune disorders represent a significant comorbidity burden, yet their shared genetic architecture is not fully understood. Elucidating the pleiotropic genetic basis underlying both conditions is crucial for unraveling the mechanisms driving their co-occurrence and advancing therapeutic strategies. METHODS: We conducted a large-scale cross-trait analysis integrating genome-wide association study (GWAS) summary data for obesity and 17 autoimmune diseases. Genetic correlations were assessed using LD score regression and high-definition likelihood. Cross-trait pleiotropic analysis was performed using Stratified Pleiotropic Locus Mapping (PLACO) to identify shared loci, followed by Bayesian colocalization to confirm shared causal variants. Gene-level and tissue-specific heritability analyses were conducted, and drug targets were prioritized via summary-based Mendelian randomization (SMR). Finally, immune co-localization and bidirectional Mendelian randomization were employed to elucidate immunological mechanisms and causal relationships. RESULTS: Our analysis identified eight autoimmune diseases with significant genetic correlations to obesity. We discovered 10,324 pleiotropic SNPs, which mapped to 52 independent risk loci, with nine loci confirmed as shared causal variants by colocalization. Gene-level analysis revealed 133 unique pleiotropic genes, including CLN3, SH2B1, and MMEL1, enriched in pathways of hematopoietic cell differentiation and immune homeostasis. Tissue-specific heritability was most prominent in the spleen, whole blood, and EBV-transformed lymphocytes. Immuno-co-localization implicated six IgD+ CD38- %B cell-related traits as key pathological conduits. Bidirectional Mendelian randomization established a causal role of obesity in hypothyroidism, psoriasis, and multiple sclerosis, while revealing an inverse causal association of type 1 diabetes with obesity risk. CONCLUSIONS: This study demonstrates a robust shared genetic foundation between obesity and multiple autoimmune diseases, pinpointing specific pleiotropic loci, genes, and immune cell subsets. Our findings provide a mechanistic framework for their comorbidity and highlight potential targets for therapeutic intervention.

Humans↗
PubMed1999

Delayed classic and protracted phenotypes of compound heterozygous juvenile neuronal ceroid lipofuscinosis.

OBJECTIVE: To correlate the phenotypes with the genotypes of 10 Finnish juvenile neuronal ceroid lipofuscinosis (JNCL; late-onset Batten disease) patients who all are compound heterozygotes for the major 1.02-kb deletion in the CLN3 gene. METHODS: The mutations on the non-1.02-kb deletion chromosomes were screened in 6 patients; in the other 4 patients the mutations were known (one affecting a splice site, two missense mutations, and one deletion of exons 10 through 13). Clinical features were examined, and MRI, MRS, somatosensory evoked magnetic field (SEF), and overnight polysomnography (PSG) studies were performed. RESULTS: A novel deletion of exons 10 through 13 was found in 6 patients belonging to three families. In the patients carrying the deletions of exons 10 through 13 the clinical course of the disease was fairly similar. Variation was greatest in the time course to blindness. In these patients the mental and motor decline was slower than in classic JNCL, but more severe than in the two patients with missense mutations in exons 11 and 13. MRI showed brain atrophy in 4 patients. One patient had hyperintense periventricular white matter, otherwise brain signal intensities were normal. SEFs were enhanced in patients older than 14 years, whereas in PSG all but the youngest 6-year-old patient showed epileptiform activity in slow-wave sleep. CONCLUSIONS: JNCL can manifest as at least three different phenotypes: classic, delayed classic, and protracted JNCL with predominantly ocular symptoms. Finnish compound heterozygotes have the delayed classic or the protracted form of JNCL.

Adolescent↗
PubMed2001

Pheno/genotypic correlations of neuronal ceroid lipofuscinoses.

The neuronal ceroid lipofuscinoses (NCL) are a large group of autosomal recessive lysosomal storage disorders with both enzymatic deficiency and structural protein dysfunction. Previously, diagnosis of NCL was based on age at onset and clinicopathologic (C-P) findings, classified as 1) infantile (INCL), 2) late infantile (LINCL), 3) juvenile (JNCL), and 4) adult (ANCL). Most patients with NCL have progressive ocular and cerebral dysfunction, including cognitive/motor dysfunction and uncontrolled seizures. After reviewing 319 patients with NCL, the authors found that 64 (20%) did not fit into this classification of NCL. With research progress, four additional forms have been recognized: 5) Finnish, 6) Gypsy/Indian, and 7) Turkish variants of LINCL and 8) northern epilepsy, also known as progressive epilepsy with mental retardation. These eight NCL forms resulted from 100 different mutations on genes CLN1to CLN8 causing different phenotypes (http://www.ucl.ac.uk/ncl). The genes CLN1 and CLN2 encode lysosomal palmitoyl protein thioesterase and tripeptidyl peptidase 1. The function of CLN3, CLN5, and CLN8 gene-encoded products is unknown, although their predicted amino acid sequences suggest they have a transmembrane topology. The diagnosis of NCL is based on C-P findings, enzymatic assay, and molecular genetic testing. Before biochemical and genetic tests are conducted, ultrastructural studies (i.e., blood [buffy coat] or punch biopsies [skin, conjunctiva]) must be performed to confirm the presence and nature of lysosomal storage material (fingerprint or curvilinear profiles or granular osmiophilic deposits). The recognition of variable onset from infancy to middle age supersedes the traditional emphasis on age-related NCL forms.

Age of Onset↗
PubMed2005

Multiple pathways for suppression of mutants affecting G1-specific transcription in Saccharomyces cerevisiae.

In the budding yeast, Saccharomyces cerevisiae, control of cell proliferation is exerted primarily during G(1) phase. The G(1)-specific transcription of several hundred genes, many with roles in early cell cycle events, requires the transcription factors SBF and MBF, each composed of Swi6 and a DNA-binding protein, Swi4 or Mbp1, respectively. Binding of these factors to promoters is essential but insufficient for robust transcription. Timely transcriptional activation requires Cln3/CDK activity. To identify potential targets for Cln3/CDK, we identified multicopy suppressors of the temperature sensitivity of new conditional alleles of SWI6. A bck2Delta background was used to render SWI6 essential. Seven multicopy suppressors of bck2Delta swi6-ts mutants were identified. Three genes, SWI4, RME1, and CLN2, were identified previously in related screens and shown to activate G(1)-specific expression of genes independent of CLN3 and SWI6. The other four genes, FBA1, RPL40a/UBI1, GIN4, and PAB1, act via apparently unrelated pathways downstream of SBF and MBF. Each depends upon CLN2, but not CLN1, for its suppressing activity. Together with additional characterization these findings indicate that multiple independent pathways are sufficient for proliferation in the absence of G(1)-specific transcriptional activators.

Cell Cycle Proteins↗
PubMed1999

The molecular genetic bases of the progressive myoclonus epilepsies.

Among the epilepsies, the progressive myoclonus epilepsies (PMEs) form a heterogeneous group of rare diseases characterized by myoclonus, epilepsy, and progressive neurologic deterioration, particularly dementia and ataxia. The success of the Human Genome Project and the fact that most PMEs are inherited through a mendelian or mitochondrial mode have resulted in important advances in the definition of the molecular basis of PME. The gene defects for the most common forms of PME (Unverricht-Lundborg disease, the neuronal ceroid lipofuscinoses, Lafora disease, type I sialidosis, and myoclonus epilepsy with ragged-red fibers) have been either identified or mapped to specific chromosome sites. Unverricht-Lundborg disease has been shown to be caused by mutations in the gene that codes for cystatin B, an inhibitor of cysteine protease. The most common mutation in Unverricht-Lundborg disease is an expansion of a dodecamer repeat located in a noncoding region upstream of the transcription start site of the cystatin B gene, making it the first human disease associated with instability of a dodecamer repeat. Juvenile neuronal ceroid lipofuscinosis is caused by mutations in the CLN3 gene, a gene of unknown function that encodes a 438-amino-acid protein of possible mitochondrial location. Other forms of neuronal ceroid lipofuscinosis that occur as PME and Lafora disease have been mapped by means of linkage analysis, but the corresponding gene defects remain unknown. Sialidosis has been shown to be caused by mutations in the sialidase gene, and myoclonus epilepsy with ragged-red fibers is well known to be caused by mutations in the mitochondrial gene that codes for tRNA(Lys). How the different PME gene defects described produce the various PME phenotypes, including epileptic seizures, remains unknown. The development of animal models that bear these mutations is needed to increase our knowledge of the basic mechanisms involved in the PMEs. This knowledge should lead to the development of new and effective forms of therapy, which are especially lacking for the PMEs.

Chromosome Mapping↗
PubMed1994

A V lambda x-bearing monoclonal antibody with similar specificity and sequence to encephalitogenic T cell receptors.

The fine specificity of mAb F28C4 to myelin basic protein (MBP), acetyl residues 1-9, has been compared with the previously described specificity of an encephalitogenic T cell clone, PJR-25. F28C4 has been found to express a cross-reactive idiotope (CRI) that is shared with MBP acetyl peptide 1-9-specific TCR. The CRI seems to be located at or near the Ag-combining site of F28C4 and the TCR and, thus, might possibly result from overlapping epitope specificity. We tested the fine epitope specificity of F28C4 by using alanine-substituted peptide analogues and found that residues critical for TCR recognition, Cln3 and Pro6, are also necessary for F28C4 recognition. By using nuclear magnetic resonance, we found that the MBP acetyl peptide 1-9 binds F28C4 in an extended conformation and that the central residues are more tightly bound than the terminal residues, much like the MBP-TCR interaction. Furthermore, sequence homology (75% overall) was found between the regions that contained CDR3 of F28C4 VL and VH and the VDJ junction of the TCR V beta. This homology is not shared by other Ig CDR3 regions and arises, in part, because F28C4 uses an unusual V lambda light chain, V lambda x. Thus, F28C4 shares a CRI with the TCRs, possibly as a result of having similar fine epitope specificity and sequence homology. The anti-CRI mAb can down-modulate experimental allergic encephalomyelitis; thus, it is possible that Abs that are similar to F28C4 may play an important immunoregulatory role in experimental allergic encephalomyelitis in vivo.

Amino Acid Sequence↗
PubMed1993

Genetic heterogeneity in neuronal ceroid lipofuscinosis (NCL): evidence that the late-infantile subtype (Jansky-Bielschowsky disease; CLN2) is not an allelic form of the juvenile or infantile subtypes.

The neuronal ceroid lipofuscinoses (NCLs) are a group of inherited neurodegenerative disorders characterized by the accumulation of autofluorescent lipopigment in neurons and other cell types. Inheritance is autosomal recessive. Three main childhood subtypes are recognized: infantile (Haltia-Santavuori disease; MIM 256743), late infantile (Jansky-Bielschowsky disease; MIM 204500), and juvenile (Spielmeyer-Sjögren-Vogt, or Batten, disease; MIM 204200). The gene loci for the juvenile (CLN3) and infantile (CLN1) types have been mapped to human chromosomes 16p and 1p, respectively, by linkage analysis. Linkage analysis of 25 families segregating for late-infantile NCL has excluded these regions as the site of this disease locus (CLN2). The three childhood subtypes of NCL therefore arise from mutations at distinct loci.

Alleles↗
PubMed1996

[Neuronal ceroid lipofuscinosis. An unknown overload disease].

Neuronal ceroid lipofuscinosis comprises a group of lysosomal diseases transmitted by autosomal recessive inheritance. Often unrecognized, this disease should be evoked in children or adolescents with blindness due to retinal pigmentation, dementia and myoclonal seizures. Retinal pigmentation is lacking in adults. The characteristic feature is an accumulation of fluorescent lipopigments deposited within cells, especially neurons. Histology examination gives the diagnosis based on the ultrastructure of skin biopsies and identification of the disease-specific lysosomal inclusions. The disease can also be identified in children by identification of mutations on genes CLN1, CLN3 and CLN5. The pathophysiology of these diseases remains unknown and treatment is limited to symptomatic care.

Adult↗