Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CLN6, the gene for a variant late infantile neuronal ceroid lipofuscinosis, has been mapped to chromosome 15q21-23 by homozygosity mapping. At present the family resource consists of 31 families. By the analysis of additional polymorphic markers in this resource the critical region has been narrowed down from 12 cM to less than 4 cM. A physical map is being constructed using YAC and PAC clones as a prerequisite to transcript mapping.
Mol Genet Metab 1999 Apr
PMID:Genetic and physical mapping of the CLN6 gene on chromosome 15q21-23. 1019 Nov 23

Marked clinical heterogeneity is seen in the late-infantile subtype of NCL (LINCL), complicating genetic analysis. In addition to the classical subtype, encoded by CLN2 on chromosome 11p15.5, several variant subtypes have also been described. In this paper, we report our progress in cloning a variant LINCL gene mapped in a small group of Costa Rican families. Clinically, these patients appear similar to classical LINCL patients, except onset of the disease is delayed and the course is milder. Extended haplotype analysis confirms the localization of this gene to chromosome 15q21-22, where CLN6 has also been mapped. Using now-standard positional cloning techniques, we have developed a physical map of our candidate region. These clones have been used to order genetic markers, STSs, and ESTs in this region and will be used for the identification of the disease gene transcript.
Mol Genet Metab 1999 Apr
PMID:Progress toward the cloning of CLN6, the gene underlying a variant LINCL. 1019 Nov 24

To date two genes are known to be involved in variant LINCL, CLN5 and CLN6, which map to chromosomes 13q21 and 15q21-23. A subset of Turkish families with a variant phenotype has been identified. Affected individuals have curvilinear bodies and fingerprint profiles on EM but are recombinant at CLN5 and CLN6. These families appear to represent a new locus. Homozygosity mapping is being used to map this locus, which has been designated CLN7.
Mol Genet Metab 1999 Apr
PMID:A new locus for variant late infantile neuronal ceroid lipofuscinosis-CLN7. 1019 Nov 25

An overview of patients in the Netherlands who are known to us with neuronal ceroid lipofuscinosis (NCL) is presented. Several CLN genes involved in NCL have been isolated or mapped. We have analyzed families with different types of NCL with polymorphic markers linked to CLN loci to investigate the genetic heterogeneity of NCL in the Netherlands. Haplotype analysis suggests that in addition to the CLN2 and CLN6 genes another gene is involved in at least one family with late infantile NCL in the Netherlands. The CLN2 and CLN6 loci have also been excluded in a family with protracted juvenile NCL.
Mol Genet Metab 1999 Apr
PMID:Genetic heterogeneity of neuronal ceroid lipofuscinosis in The Netherlands. 1019 Nov 26

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 (NCLs) are lysosomal storage diseases with severe neurodegenerative pathology. An ovine model (OCL) has well-defined parallels with the human disease at the biochemical and pathological levels. The gene for OCL is located in the chromosomal region OAR7q13-15. This region is syntenic with HAS15q21-23, suggesting that OCL and CLN6 represent mutations in orthologous genes. New microsatellite markers have been developed enabling further refinement of the OCL critical region.
Mol Genet Metab 1999 Apr
PMID:Progress toward positional cloning of ovine neuronal ceroid lipofuscinosis, a model of the human late-infantile variant CLN6. 1019 Nov 31

It is proposed that ceroid lipofuscinosis in Southhampshire sheep (OCLSouthhampshire) be also known as OCL6 as it is syntenic with CLN6 of humans. Histopathological studies show a severe and progressive neurodegeneration of the cerebral cortex which sometimes appears to have a laminar pattern and which is accompanied by a severe midcortical astrocytosis. Other studies have shown that fibroblasts maintained in tissue culture have abnormal regulation of ATP synthase. If this was reflected in neurons, then selective neuron death is likely to be the result of energy-linked excitotoxicity of neurons receiving abundant glutamate input. Increased sensitivity of the NMDA receptor due to inefficient repolarization of the neuron membrane would allow increased cellular uptake of calcium, increased formation of free radicals, and neuron death. The general hypothesis, as developed for other chronic neurodegenerative diseases, is partly based on application of various drugs that block or mediate parts of the pathway involved. The same approach could be used to help test the hypothesis in OCL6 lambs and if successful some of the drugs might have therapeutic potential. As patterns of neurodegeneration are similar in various other forms of ceroid lipofuscinosis accumulating subunit c of mitochondrial ATP synthase, the model may have more general application than merely to CLN6.
Mol Genet Metab 1999 Apr
PMID:Ovine ceroid lipofuscinosis (OCL6): postulated mechanism of neurodegeneration. 1019 Nov 32

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

CLN6 is a polytopic membrane protein of unknown function resident in the endoplasmic reticulum (ER). Mutant CLN6 causes the lysosomal storage disorder neuronal ceroid lipofuscinosis. Defining the topology of CLN6, and the structural domains and motifs required for interaction with cytosolic and luminal proteins may allow insights into its function. In this study we analysed the topology, ER retention and oligomerization of CLN6. We demonstrated, by differential membrane permeabilization of transfected BHK cells using specific detergents and two distinct antibodies, that CLN6 contains an N-terminal cytoplasmic domain, seven transmembrane domains, and a luminal C terminus. Mutational analyses and confocal immunofluorescence microscopy showed that changes of potential ER localization signals in the N- or C-terminal domain (a triple arginine cluster, and a dileucine motif) did not alter the subcellular localization of CLN6. The deletion of a dilysine motif impaired partially the ER localization of CLN6. Furthermore, expression analyses of fusion and deletion constructs in non-neuronal and neuronal cells suggested that two portions of CLN6 contributed to its retention within the ER. We showed that the N-terminal domain was necessary but not sufficient for ER retention of CLN6 and that deletion of transmembrane domains 6 and 7 was accompanied with the loss of ER localization and, in some instances, trafficking to the cisGolgi. From these data we concluded that CLN6 maintains its ER localization by expressing retention signals present in both the N-terminal cytosolic domain and in the carboxy-proximal transmembrane domains 6 and 7. Additionally, the ability of CLN6 to homodimerize may also prevent exit from the ER via an interaction with membrane-associated factors.
Mol Membr Biol
PMID:Topology and endoplasmic reticulum retention signals of the lysosomal storage disease-related membrane protein CLN6. 1745 15

Neuronal ceroid lipofuscinoses (NCL) are caused by mutations in eight different genes, are characterized by lysosomal accumulation of autofluorescent storage material, and result in a disease that causes degeneration of the central nervous system (CNS). Although functions are defined for some of the soluble proteins that are defective in NCL (cathepsin D, PPT1, and TPP1), the primary function of the other proteins defective in NCLs (CLN3, CLN5, CLN6, CLN7, and CLN8) remain poorly defined. Understanding the localization and network of interactions for these proteins can offer clues as to the function of the NCL proteins and also the pathways that will be disrupted in their absence. Here, we present a review of the current understanding of the localization, interactions, and function of the proteins associated with NCL.
Cell Mol Life Sci 2011 Feb
PMID:Interactions of the proteins of neuronal ceroid lipofuscinosis: clues to function. 2068 Mar 90


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