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)

A deficiency of palmitoyl-protein thioesterase (PPT) was recently shown to be the primary defect in infantile neuronal ceroid lipofuscinosis (INCL). The available enzyme assays are complicated and impractical for diagnostic use. We have recently developed a new, fluorometric assay for PPT based on the sensitive fluorochrome 4-methylumbelliferone, requiring an overnight incubation to measure PPT. Now we have synthesized an analogue of this substrate which allows PPT determinations in 1 h. This improved PPT assay is simple, sensitive, and robust and will facilitate the definition of the full clinical spectrum associated with a deficiency of PPT. PPT activity was readily detectable in fibroblasts, leukocytes, amniotic fluid cells, chorionic villi, plasma, and cerebrospinal fluid from controls. PPT activity was profoundly deficient in these tissues and fluids from INCL patients. Similarly, a deficiency of PPT activity was demonstrated in patients with the variant juvenile NCL with GROD. These results show the feasibility of rapid pre- and postnatal diagnosis of INCL and its variants.
Mol Genet Metab 1999 Apr
PMID:A rapid fluorogenic palmitoyl-protein thioesterase assay: pre- and postnatal diagnosis of INCL. 1019 Nov 8

Two distinct clinical subtypes of neuronal ceroid lipofuscinosis caused by mutations in the PPT gene, INCL and vJNCL/GROD, occur at a high frequency in the central region of Scotland. In this paper we summarize the clinical details and the molecular basis underlying the disease in the Scottish patients. Comparison of the combination of mutations in the different clinical types reveals a clear genotype-phenotype correlation.
Mol Genet Metab 1999 Apr
PMID:The molecular basis of GROD-storing neuronal ceroid lipofuscinoses in Scotland. 1019 Nov 9

This study describes the phenotype/genotype analyses of 56 probands with a juvenile onset, some of which had atypical features of neuronal ceroid lipofuscinosis, collected at the New York State Institute for Basic Research (IBR). In this group, we found probands with abundant curvilinear profiles in lysosomal storage material, deficiency of pepstatin-insensitive peptidase, and mutations in the CLN2 gene, as well as patients with a predominance of granular osmiophilic deposits in the lysosomal storage material, deficiency of palmitoyl-protein thioesterase, and mutations in the CLN1 gene. We have divided the probands into two categories: typical (or classic) and atypical. Most of the typical and atypical probands had onset of symptoms about or after 4 years of age. Interfamiliar and intrafamiliar variations were found, especially in the speed of becoming practically blind. Thus, our study indicates that some mutations in the CLN1, CLN2, and CLN3 genes may be associated with late onset of the disease process, may have a more benign clinical course, and clinic overlap with other forms of neuronal ceroid lipofuscinosis.
Mol Genet Metab 1999 Apr
PMID:Reevaluation of neuronal ceroid lipofuscinoses: atypical juvenile onset may be the result of CLN2 mutations. 1019 Nov 10

Juvenile neuronal ceroid lipofuscinosis (Batten disease) is a progressive neurologic disorder which results from mutations in the CLN3 gene, which normally produces a 48-kDa polypeptide of unknown function. To help characterize the CLN3 protein, we have studied its tissue distribution and subcellular localization in human tissues using three epitope-specific polyclonal antibodies to human CLN3 by immunoblot, immunocytochemical, and immunoelectron microscopic analysis. The most abundant CLN3 protein expression was in the gray matter of the brain, where it was localized to astrocytes, capillary endothelium, and neurons. CLN3 was also evident in peripheral nerve, in pancreatic islet cells, and within the seminiferous tubules in the testis. Staining was generally diffuse within the cytoplasm with some nuclear reactivity. Subcellular localization identified the CLN3 protein within the nucleus and along cell membranes. These results were contrasted with the cellular distribution of palmitoyl-protein thioesterase (PPT), the enzyme whose deficiency is responsible for infantile neuronal ceroid lipofuscinosis (CLN1). PPT was most abundant in brain and visceral macrophages where it displayed a coarse granular staining pattern typical of lysosomal distribution. Immunoelectron microscopy confirmed that PPT immunoreactivity was limited to lysosomes.
Mol Genet Metab 1999 Apr
PMID:Tissue expression and subcellular localization of CLN3, the Batten disease protein. 1019 Nov 16

Mutations in a palmitoyl-protein thioesterase (PPT) gene cause infantile neuronal ceroid lipofuscinosis (INCL). INCL is characterized by an extreme and selective neuronal loss in cerebral cortex and retina. Using reverse transcriptase PCR we show that PPT expression is developmentally regulated in rat brain and eyes but not in spleen. The changes in the expression coincide with developmental events in the brain. These data indicate that PPT has an important role in the development of the CNS.
Mol Genet Metab 1999 Apr
PMID:The expression of palmitoyl-protein thioesterase is developmentally regulated in neural tissues but not in nonneural tissues. 1019 Nov 17

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

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

Neuronal ceroid lipofuscinosis (NCL) is one of the most common inherited neurological diseases in childhood. It occurs every 12,500 births in northern-European populations. Mental retardation, visual impairment, and seizures are common symptoms. The prevalence of NCL is variable depending upon the races or countries. Although a wealth information is available in Caucasian populations, there is little information about NCL in Asian people. Because a nationwide survey in Japanese patients with NCL has never been performed, we pursued an epidemiological survey. We identified 36 NCL patients in Japan. Patients with infantile, late infantile, juvenile, and adult type accounted for 2, 15, 15, and 4 cases, respectively. Seizures were a major initial symptom in the late infantile type. In the juvenile type, visual failure was present in 73% at onset. Recently, the juvenile NCL (Batten disease) gene has been isolated. Studies of the mutations in this gene demonstrated that a 1.02-kb deletion was the most prevalent mutation among Caucasian patients, accounting for 81% of total alleles. To determine the prevalence of this 1.02-kb deletion in Japanese patients, we performed a rapid allele-specific polymerase chain reaction test. No 1.02-kb major deletion was detected in 5 Japanese juvenile NCL cases. These data suggest that the distribution of NCL and clinical findings are similar to those of Caucasian subjects; however, prevalence of mutations in Japanese patients with NCL would be distinct from that observed in Caucasians.
Mol Genet Metab 1999 Apr
PMID:Clinical and molecular analysis of Japanese patients with neuronal ceroid lipofuscinosis. 1019 Nov 27

Since the last, 6th, International Congress on Neuronal Ceroid-Lipofuscinoses, neuropathological advances in neuronal ceroid lipofuscinoses (NCL) have been made in several areas: (1) In adult NCL (ANCL) lipopigments have now been repeatedly confirmed to contain subunit c of mitochondrial ATP synthase and even sphingolipid activators (saposins). ANCL lipopigments have also been confirmed in extracerebral tissues including skin, skeletal muscle, and spleen, but not yet lymphocytes (2). Among circulating blood cells not only B cells and subclasses of T lymphocytes, i.e., CD4(+), CD8(+), and CD56 cells, but also monocytes have been found to contain NCL lipopigments, indicating that this precursor cell in the digesting macrophage system also has an impaired metabolic catabolism for lipopigments (3). Immunohistochemical studies indicate that microglial reaction in NCL brain is limited to resident microglia without contribution by circulating monocytes (4). The granular osmiophilic deposit (GROD) type of NCL has now been established not only in infantile, but also in late-infantile, juvenile, and protracted-juvenile NCL (5). A European Tissue Registry established within the framework of a European Concerted Action on Neuronal Ceroid-Lipofuscinosis may form the basis for additional collaborative studies on NCL, including both biopsy and autopsy tissues.
Mol Genet Metab 1999 Apr
PMID:Progress in neuropathology of the neuronal ceroid lipofuscinoses. 1019 Nov 30

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


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