The late-infantile-onset forms of neuronal ceroid lipofuscinosis (LINCL) are the most genetically heterogeneous group among the autosomal recessive neuronal ceroid lipofuscinoses (NCLs), with causative mutations found in CLN1, CLN2, CLN5, CLN6, CLN7 (MFSD8), and CLN8 genes. Homozygous mutations in CLN8 are associated with two distinct phenotypes: progressive epilepsy and mental retardation (EPMR), first identified in Finland; and a variant of late-infantile NCL (v-LINCL) described in a subset of Turkish and Italian patients. The function of the protein encoded by CLN8 is currently unknown. Here we report the identification of an Italian v-LINCL patient with a complete isodisomy of chromosome 8, leading to homozygosity of a maternally-inherited 3-bp deletion in CLN8 gene (c.180_182delGAA, p.Lys61del). Notably, uniparental disomy (UPD) has never been described associated with the NCLs. In addition, we provide evidence of the biological role of CLN8 characterized by expressing in different neuronal cell models the native protein, the protein carrying the mutation identified here, or three additional missense mutations previously described. Our results, validated through a gene silencing approach, indicate that CLN8 plays a role in cell proliferation during neuronal differentiation and in protection against cell death.
The actions or reactions of an adult relating to the progression of that organism along the ground by the process of lifting and setting down each leg.
Any process that results in a change in state or activity of a cell or an organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of oxidative stress, a state often resulting from exposure to high levels of reactive oxygen species, where the change varies according to the age of the cell or organism.
Any biological process that results in permanent cessation of all vital functions of a cell. A cell should be considered dead when any one of the following molecular or morphological criteria is met: (1) the cell has lost the integrity of its plasma membrane; (2) the cell, including its nucleus, has undergone complete fragmentation into discrete bodies (frequently referred to as \
A family of membrane-associated proteins related to yeast Lag1p and mammalian TRAM has been identified. The family includes the protein product of CLN8, a gene mutated in progressive epilepsy with mental retardation. Mouse CLN8 is also mutated in the mnd/mnd mouse, a model for neuronal ceroid lipofuscinoses. The identification of these homologues has potential implications for our understanding of ceramide synthesis, lipid regulation and protein translocation in the endoplasmic reticulum.
Progressive epilepsy with mental retardation, EPMR, belongs to a group of inherited neurodegenerative disorders, the neuronal ceroid lipofuscinoses. The CLN8 gene that underlies EPMR encodes a novel transmembrane protein that localizes to the endoplasmic reticulum (ER) and ER-Golgi intermediate compartment. Recently, CLN8 was linked to a large eukaryotic protein family of TLC (TRAM, Lag1, CLN8) domain homologues with postulated functions in lipid synthesis, transport or sensing. By using liquid chromatography/mass spectrometry we analysed molecular species of major phosholipid and simple sphingolipid classes from cerebral samples of two EPMR patients representing a progressive and advanced state of the disease. The progressive state brain showed reduced levels of ceramide, galactosyl- and lactosylceramide and sulfatide as well as a decrease in long fatty acyl chain containing molecular species within these classes. Among glycerophospholipid classes, an increase in species containing polyunsaturated acyl chains was detected especially in phosphatidylserines and phosphatidylethanolamines. By contrast, saturated and monounsaturated species were overrepresented among phosphatidylserine, phosphatidylethanolamine and phosphatidylinositol classes in the advanced state sample. The observed changes in brain sphingo- and phospholipid molecular profiles may result in altered membrane stability, lipid peroxidation, vesicular trafficking or neurotransmission and thus may contribute to the progression of the molecular pathogenesis of EPMR.
The chemical reactions and pathways involving cholesterol, cholest-5-en-3 beta-ol, the principal sterol of vertebrates and the precursor of many steroids, including bile acids and steroid hormones. It is a component of the plasma membrane lipid bilayer and of plasma lipoproteins and can be found in all animal tissues.
Evidence
1:
Inferred from Mutant PhenotypeUniProtKB
Progressive epilepsy with mental retardation, EPMR, belongs to a group of inherited neurodegenerative disorders, the neuronal ceroid lipofuscinoses. The CLN8 gene that underlies EPMR encodes a novel transmembrane protein that localizes to the endoplasmic reticulum (ER) and ER-Golgi intermediate compartment. Recently, CLN8 was linked to a large eukaryotic protein family of TLC (TRAM, Lag1, CLN8) domain homologues with postulated functions in lipid synthesis, transport or sensing. By using liquid chromatography/mass spectrometry we analysed molecular species of major phosholipid and simple sphingolipid classes from cerebral samples of two EPMR patients representing a progressive and advanced state of the disease. The progressive state brain showed reduced levels of ceramide, galactosyl- and lactosylceramide and sulfatide as well as a decrease in long fatty acyl chain containing molecular species within these classes. Among glycerophospholipid classes, an increase in species containing polyunsaturated acyl chains was detected especially in phosphatidylserines and phosphatidylethanolamines. By contrast, saturated and monounsaturated species were overrepresented among phosphatidylserine, phosphatidylethanolamine and phosphatidylinositol classes in the advanced state sample. The observed changes in brain sphingo- and phospholipid molecular profiles may result in altered membrane stability, lipid peroxidation, vesicular trafficking or neurotransmission and thus may contribute to the progression of the molecular pathogenesis of EPMR.
The chemical reactions and pathways resulting in the formation of lipids, compounds soluble in an organic solvent but not, or sparingly, in an aqueous solvent.
A family of membrane-associated proteins related to yeast Lag1p and mammalian TRAM has been identified. The family includes the protein product of CLN8, a gene mutated in progressive epilepsy with mental retardation. Mouse CLN8 is also mutated in the mnd/mnd mouse, a model for neuronal ceroid lipofuscinoses. The identification of these homologues has potential implications for our understanding of ceramide synthesis, lipid regulation and protein translocation in the endoplasmic reticulum.
The directed movement of lipids into, out of or within a cell, or between cells, by means of some agent such as a transporter or pore. Lipids are compounds soluble in an organic solvent but not, or sparingly, in an aqueous solvent.
A family of membrane-associated proteins related to yeast Lag1p and mammalian TRAM has been identified. The family includes the protein product of CLN8, a gene mutated in progressive epilepsy with mental retardation. Mouse CLN8 is also mutated in the mnd/mnd mouse, a model for neuronal ceroid lipofuscinoses. The identification of these homologues has potential implications for our understanding of ceramide synthesis, lipid regulation and protein translocation in the endoplasmic reticulum.
A process that is carried out at the cellular level which results in the assembly, arrangement of constituent parts, or disassembly of a lysosome. A lysosome is a cytoplasmic, membrane-bounded organelle that is found in most animal cells and that contains a variety of hydrolases.
A process that is carried out at the cellular level which results in the assembly, arrangement of constituent parts, or disassembly of a mitochondrial membrane, either of the lipid bilayer surrounding a mitochondrion.
A family of membrane-associated proteins related to yeast Lag1p and mammalian TRAM has been identified. The family includes the protein product of CLN8, a gene mutated in progressive epilepsy with mental retardation. Mouse CLN8 is also mutated in the mnd/mnd mouse, a model for neuronal ceroid lipofuscinoses. The identification of these homologues has potential implications for our understanding of ceramide synthesis, lipid regulation and protein translocation in the endoplasmic reticulum.
Any process that stops or reduces the rate of transferase activity, the catalysis of the transfer of a group, e.g. a methyl group, glycosyl group, acyl group, phosphorus-containing, or other groups, from a donor compound to an acceptor.
The neuronal ceroid lipofuscinoses (NCLs) are a genetically heterogeneous group of progressive neurodegenerative disorders characterized by the accumulation of autofluorescent lipopigment in various tissues. Progressive epilepsy with mental retardation (EPMR, MIM 600143) was recently recognized as a new NCL subtype (CLN8). It is an autosomal recessive disorder characterized by onset of generalized seizures between 5 and 10 years, and subsequent progressive mental retardation. Here we report the positional cloning of a novel gene, CLN8, which is mutated in EPMR. It encodes a putative transmembrane protein. EPMR patients were homozygous for a missense mutation (70C-->G, R24G) that was not found in homozygosity in 433 controls. We also cloned the mouse Cln8 sequence. It displays 82% nucleotide identity with CLN8, conservation of the codon harbouring the human mutation and is localized to the same region as the motor neuron degeneration mouse, mnd, a naturally occurring mouse NCL (ref. 4). In mnd/mnd mice, we identified a homozygous 1-bp insertion (267-268insC, codon 90) predicting a frameshift and a truncated protein. Our data demonstrate that mutations in these orthologous genes underlie NCL phenotypes in human and mouse, and represent the first description of the molecular basis of a naturally occurring animal model for NCL.
A process that is carried out at the cellular level which results in the assembly, arrangement of constituent parts, or disassembly of cytoskeletal structures comprising neurofilaments and their associated proteins.
Any process that an organism uses to control its balance, the orientation of the organism (or the head of the organism) in relation to the source of gravity. In humans and animals, balance is perceived through visual cues, the labyrinth system of the inner ears and information from skin pressure receptors and muscle and joint receptors.
Progressive epilepsy with mental retardation, EPMR, belongs to a group of inherited neurodegenerative disorders, the neuronal ceroid lipofuscinoses. The CLN8 gene that underlies EPMR encodes a novel transmembrane protein that localizes to the endoplasmic reticulum (ER) and ER-Golgi intermediate compartment. Recently, CLN8 was linked to a large eukaryotic protein family of TLC (TRAM, Lag1, CLN8) domain homologues with postulated functions in lipid synthesis, transport or sensing. By using liquid chromatography/mass spectrometry we analysed molecular species of major phosholipid and simple sphingolipid classes from cerebral samples of two EPMR patients representing a progressive and advanced state of the disease. The progressive state brain showed reduced levels of ceramide, galactosyl- and lactosylceramide and sulfatide as well as a decrease in long fatty acyl chain containing molecular species within these classes. Among glycerophospholipid classes, an increase in species containing polyunsaturated acyl chains was detected especially in phosphatidylserines and phosphatidylethanolamines. By contrast, saturated and monounsaturated species were overrepresented among phosphatidylserine, phosphatidylethanolamine and phosphatidylinositol classes in the advanced state sample. The observed changes in brain sphingo- and phospholipid molecular profiles may result in altered membrane stability, lipid peroxidation, vesicular trafficking or neurotransmission and thus may contribute to the progression of the molecular pathogenesis of EPMR.
The chemical reactions and pathways resulting in the breakdown of a protein by the destruction of the native, active configuration, with or without the hydrolysis of peptide bonds.
J. Neurosci. Res. 60, 133-140 (2000)[PubMed:10740217]
Neuronal ceroid lipofuscinosis (Batten disease) encompasses a group of 8 or more inherited lysosomal storage diseases, with an overall frequency of 1 in 12,500 births. All are characterized by progressive blindness and dementia and were initially classified on the basis of age of onset, clinical phenotype and ultrastructural characterization of the storage material as granular osmiophilic deposits, curvilinear bodies or fingerprint bodies. Recent research has shown that the various forms of Batten disease result from mutations in at least 8 genes which code for proteins involved in different aspects of lysosomal protein catabolism. These include palmitoyl:protein thioesterase 1 (CLN1), tripeptidylpeptidase 1 (CLN2), cathepsin D (CLN8), and two membrane proteins of unknown function (CLN3 and CLN5). Biochemically, Batten disease is characterized by the accumulation in neurons and other cells of an autofluorescent pigment which has resisted many attempts at analysis. In this review we attempt to relate our current understanding of the nature of the storage material in Batten disease with this genetic information. We conclude that the 8 genes probably code for proteins which facilitate the degradation of post-translationally modified proteins in lysosomes, suggesting that the turnover of these proteins is highest in cortical neurons.
The process whose specific outcome is the progression of the retina over time, from its formation to the mature structure. The retina is the innermost layer or coating at the back of the eyeball, which is sensitive to light and in which the optic nerve terminates.
The process in which neuroepithelial cells in the neural tube acquire specialized structural and/or functional features of somatic motor neurons. Somatic motor neurons innervate skeletal muscle targets and are responsible for transmission of motor impulses from the brain to the periphery. Differentiation includes the processes involved in commitment of a cell to a specific fate.
A reference proteome is a set of protein sequences derived from a complete proteome which constitutes a defined standard for a particular user community. Reference proteomes are manually defined according to a number of criteria. They cover the proteomes of well- studied model organisms and other proteomes of interest for biomedical and biotechnological research. Reference proteomes have been selected to provide broad coverage of the tree of life, and constitute a representative cross-section of the taxonomic diversity to be found within UniProtKB.
My favorites 
My labels 
Login
