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 subtype of neuronal ceroid lipofuscinosis (NCL) is well recognized which has a clinical course consistent with juvenile NCL (JNCL) but the ultrastructural characteristics of infantile NCL (INCL): granular osmiophilic deposits (GROD). Evidence supporting linkage of this phenotype, designated vJNCL/GROD, to the INCL region of chromosome 1p32 was demonstrated (pairwise lod score with D1S211 , Z max = 2.63, straight theta = 0.00). The INCL gene, palmitoyl-protein thioesterase (PPT ; CLN1), was therefore screened for mutations in 11 vJNCL/GROD families. Five mutations in the PPT gene were identified: three missense mutations, Thr75Pro, Asp79Gly, Leu219Gln, and two nonsense mutations, Leu10STOP and Arg151STOP. The missense mutation Thr75Pro accounted for nine of the 22 disease chromosomes analysed and the nonsense mutation Arg151STOP for seven. Nine out of 11 patients were shown to combine a missense mutation on one disease chromosome with a nonsense mutation on the other. Mutations previously identified in INCL were not observed in vJNCL/GROD families. Thioesterase activity in peripheral blood lymphoblast cells was found to be markedly reduced in vJNCL/GROD patients compared with controls. These results demonstrate that this subtype of JNCL is allelic to INCL and further emphasize the correlation which exists between genetic basis and ultrastructural changes in the NCLs.
Hum Mol Genet 1998 Feb
PMID:Mutations in the palmitoyl-protein thioesterase gene (PPT; CLN1) causing juvenile neuronal ceroid lipofuscinosis with granular osmiophilic deposits. 942 37

The infantile form of neuronal ceroid lipofuscinosis (NCL) has been well studied in Finland, where there is a high carrier frequency (1:70) for a single mutation in the causative gene, CLN1, or PPT. We have recently studied a group of 29 NCL subjects in the United States with palmitoyl-protein thioesterase (PPT) deficiency and described 19 different CLN1/PPT mutations in our population. In this report, we present a review of our previous findings, including a more detailed analysis of phenotype-genotype correlations, and present previously unpublished data concerning the clinical manifestations of the disorder in children of families with multiple affected members. Our studies indicate that about half of PPT-deficient patients in the United States are very similar to Finnish infants with INCL, but that a different mutation (R151X) accounts for 40% of U.S. alleles. The Finnish mutation (R122W) is rare in the United States. The other half of U.S. PPT-deficient patients develop symptoms after the age of 2 years, much later than Finnish patients. One common mutation (the "Scottish" allele, T75P) accounts for 13% of alleles and results in a juvenile-onset phenotype that is clinically indistinguishable from JNCL with CLN3 mutations. Other rare mutations were also associated with JNCL phenotypes, such as D79G and G250V. A preliminary expression study of two of these mutant enzymes supports the conclusion that juvenile-onset NCL (JNCL with GROD) is caused by missense mutations in the PPT gene that result in mutated enzymes with residual PPT enzyme activity.
Mol Genet Metab 1999 Apr
PMID:Genotype-phenotype correlations in neuronal ceroid lipofuscinosis due to palmitoyl-protein thioesterase deficiency. 1019 Nov 7

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

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

Deficiency in a recently characterized lysosomal enzyme, palmitoyl-protein thioesterase (PPT), leads to a severe neurodegenerative disorder of children, infantile neuronal ceroid lipofuscinosis (NCL). Over 36 different mutations in the PPT gene have been described, and missense mutations have been interpreted in the light of the recently solved X-ray crystallographic structure of PPT. In the current study, we assessed the biochemical impact of mutations through the study of cells derived from patients and from the expression of recombinant PPT enzymes in COS and Sf9 cells. All missense mutations associated with infantile NCL showed no residual enzyme activity, whereas mutations associated with late-onset phenotypes showed up to 2.15% residual activity. Two mutations increased the K(m) of the enzyme for palmitoylated substrates and were located in positions that would distort the palmitate-binding pocket. An initiator methionine mutation (ATG-->ATA) in two late-onset patients was expressed at a significant level in COS cells, suggesting that the ATA codon may be utilized to a clinically important extent in vivo. The most common PPT nonsense mutation, R151X, was associated with an absence of PPT mRNA. Mannose 6-phosphate modification of wild-type and mutant PPT enzymes was grossly normal at the level of the phosphotransferase reaction. However, mutant PPT enzymes did not bind to mannose 6-phosphate receptors in a blotting assay. This observation was related to the failure of the mutant expressed enzymes to gain access to 'uncovering enzyme' (N-acetylglucosamine-1-phosphodiester alpha-N-acetyl glucosaminidase), presumably due to a block in transit out of the endoplasmic reticulum, where mutant enzymes are degraded.
Hum Mol Genet 2001 Jun 15
PMID:Biochemical analysis of mutations in palmitoyl-protein thioesterase causing infantile and late-onset forms of neuronal ceroid lipofuscinosis. 1144 Sep 96

Infantile and classical late infantile neuronal ceroid lipofuscinoses (NCL) are two recent additions to the expanding spectrum of lysosomal storage disorders caused by deficiencies in lysosomal hydrolases. They are latecomers to the lysosomal storage disorders, probably because of the heterogeneous nature of the storage material, which precluded meaningful biochemical analysis. Infantile NCL is caused by deficiency in palmitoyl-protein thioesterase, an enzyme that hydrolyzes fatty acids from cysteine residues in lipid-modified proteins. Classical late-infantile NCL is caused by a deficiency in tripeptidyl amino peptidase-I, a lysosomal peptidase that removes three amino acids from the free amino terminus of peptides or small proteins. Late-onset forms of these disorders have been described. The clinical, biochemical, and molecular genetic aspects of these two latest lysosomal storage disorders are discussed in this review. In addition, approaches to treatment and future directions for research are examined.
Curr Mol Med 2002 Aug
PMID:Neuronal ceroid lipofuscinoses caused by defects in soluble lysosomal enzymes (CLN1 and CLN2). 1212 8

Infantile neuronal ceroid lipofuscinosis (INCL) is an autosomal recessive disease that results from deficiency of palmitoyl-protein thioesterase-1 (PPT1). INCL leads to retinal blindness, neurodegeneration, and early death. We studied the clinical features and electroretinogram (ERG) in three patients and histopathologic and immunofluorescence analyses of the retina in the third patient, who died at 3 years 2 months of age. The ERGs for the 2 youngest patients (ages 1.7 and 2.3 years) showed normal scotopic bright flash a-wave amplitudes with severe loss of b-wave (electronegative ERG), indicating dysfunction at or proximal to the photoreceptor inner segments. The third patient at 2.9 years of age showed subnormal a-wave amplitudes and even greater loss of b-wave amplitudes. Histopathology revealed reduced cell numbers in all retinal layers, including the inner nuclear layer (INL), and a central epiretinal membrane. Autofluorescent lipofuscin granules were present in all neuronal cell types in the retina. Cones and rods in the parafoveal area were labeled with a cone cytoplasmic marker, mAb 7G6, and anti-rhodopsin, respectively, and had extremely short outer segments. The periphery showed better preservation but photoreceptor outer segments were short. Immunofluorescence revealed degenerate rods and cones throughout the retina with better preservation in the periphery. Autofluorescent lipofuscin was found in all cell types, including cone inner segments, to a greater degree than seen in normal ageing. The ERG findings support the existence early in the disease of a relative pre- or post-synaptic block of effective neurotransmission from photoreceptor inner segments to the second order bipolar neurons.
Mol Genet Metab
PMID:Electroretinographic and clinicopathologic correlations of retinal dysfunction in infantile neuronal ceroid lipofuscinosis (infantile Batten disease). 1546 27

The infantile neuronal ceroid lipofuscinosis (INCL), a rare (one in 100 000 births) but one of the most lethal inherited neurodegenerative storage disorders of childhood, is caused by inactivating mutations in the palmitoyl-protein thioesterase-1 (PPT1) gene. PPT1 cleaves thioester linkages in s-acylated (palmitoylated) proteins and facilitates their degradation and/or recycling. Thus, PPT1-deficiency leads to an abnormal intracellular accumulation of s-acylated proteins causing INCL pathogenesis. Although neuronal apoptosis is the suggested cause of neurodegeneration in this disease, the molecular mechanism(s) remains poorly understood. We recently reported that one of the major pathways of neuronal apoptosis in PPT1-knockout (PPT1-KO) mice that mimic INCL, is mediated by endoplasmic reticulum (ER) stress-induced caspase-12 activation. ER stress also increases the production of reactive oxygen species (ROS), disrupts Ca(2+) homeostasis and increases the potential for destabilizing mitochondrial membrane. Mitochondrial membrane destabilization activates caspase-9 present in this organelle, and can mediate apoptosis. We report here that the levels of superoxide dismutase (SOD), most likely induced by ROS, in human INCL as well as PPT1-KO mouse brain tissues are markedly elevated. Moreover, we demonstrate that activated caspase-3 and cleaved-PARP, indicative of apoptosis, are also increased in these tissues. Using cultured neurospheres from PPT1-KO and wild-type mouse fetuses, we further demonstrate that the levels of ROS, SOD-2, cleaved-caspase-9, activated caspase-3 and cleaved-PARP are elevated. We propose that: (i) ER stress due to PPT1-deficiency increases ROS and disrupts calcium homeostasis activating caspase-9 and (ii) caspase-9 activation mediates caspase-3 activation and apoptosis contributing to rapid neurodegeneration in INCL.
Hum Mol Genet 2006 May 15
PMID:Palmitoyl-protein thioesterase-1 deficiency leads to the activation of caspase-9 and contributes to rapid neurodegeneration in INCL. 1657


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