Structure of the Human Palmitoyl-Protein Thioesterase-2 Gene (PPT2) in the Major Histocompatibility Complex on Chromosome 6p21.3

Soyombo, Abigail A.; Yi, Won; Hofmann, Sandra L.

doi:10.1006/geno.1998.5703

Cited by 16 publications

(9 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In contrast, PPT2 expression (Fig. 4 D-F) was more diffuse throughout the brain and its expression level lower as compared to PPT1, a finding that is supported by previous work (18). PPT2 expression in the Purkinje cells was similar to that in the granular layer, with the result that the dramatic Purkinje cell definition seen for PPT1 was lost.…”

Section: Resultssupporting

confidence: 86%

Disruption ofPPT1orPPT2causes neuronal ceroid lipofuscinosis in knockout mice

Gupta

Soyombo

Atashband

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

267

303

View full text Add to dashboard Cite

PPT1 and PPT2 encode two lysosomal thioesterases that catalyze the hydrolysis of long chain fatty acyl CoAs. In addition to this function, PPT1 (palmitoyl-protein thioesterase 1) hydrolyzes fatty acids from modified cysteine residues in proteins that are undergoing degradation in the lysosome. PPT1 deficiency in humans causes a neurodegenerative disorder, infantile neuronal ceroid lipofuscinosis (also known as infantile Batten disease). In the current work, we engineered disruptions in the PPT1 and PPT2 genes to create ''knockout'' mice that were deficient in either enzyme. Both lines of mice were viable and fertile. However, both lines developed spasticity (a ''clasping'' phenotype) at a median age of 21 wk and 29 wk, respectively. Motor abnormalities progressed in the PPT1 knockout mice, leading to death by 10 mo of age. In contrast, the majority of PPT2 mice were alive at 12 mo. Myoclonic jerking and seizures were prominent in the PPT1 mice. Autofluorescent storage material was striking throughout the brains of both strains of mice. Neuronal loss and apoptosis were particularly prominent in PPT1-deficient brains. These studies provide a mouse model for infantile neuronal ceroid lipofuscinosis and further suggest that PPT2 serves a role in the brain that is not carried out by PPT1.

show abstract

Section: Resultssupporting

confidence: 86%

Disruption ofPPT1orPPT2causes neuronal ceroid lipofuscinosis in knockout mice

Gupta

Soyombo

Atashband

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

267

303

View full text Add to dashboard Cite

show abstract

“…It is important to note that the location of the PPT2 gene on human chromosome 6p21.3 (8) does not correspond to any previously described human disease gene locus. Mouse models of the lysosomal storage diseases have tended to reproduce many features of the corresponding human disorders (18,19), with some exceptions (20).…”

Section: Discussionmentioning

confidence: 90%

“…The PPT1 or CLN1 gene underlies the most severe form of the disease, and it encodes a thioesterase enzyme that removes palmitate or other fatty acids from cysteine residues in proteins (4)(5)(6). The enzyme encoded by PPT2 is a second lysosomal thioesterase with a substrate specificity that overlaps that of PPT1 (7)(8)(9).…”

mentioning

confidence: 99%

Disruption ofPPT2in mice causes an unusual lysosomal storage disorder with neurovisceral features

Gupta

Soyombo

Shelton

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

The palmitoyl protein thioesterase-2 (PPT2) gene encodes a lysosomal thioesterase homologous to PPT1, which is the enzyme defective in the human disorder called infantile neuronal ceroid lipofuscinosis. In this article, we report that PPT2 deficiency in mice causes an unusual form of neuronal ceroid lipofuscinosis with striking visceral manifestations. All PPT2-deficient mice displayed a neurodegenerative phenotype with spasticity and ataxia by 15 mo. The bone marrow was infiltrated by brightly autofluorescent macrophages and multinucleated giant cells, but interestingly, the macrophages did not have the typical appearance of foam cells commonly associated with other lysosomal storage diseases. Marked splenomegaly caused by extramedullary hematopoiesis was observed. The pancreas was grossly orange to brown as a result of massive storage of lipofuscin pigments in the exocrine (but not islet) cells. Electron microscopy showed that the storage material consisted of multilamellar membrane profiles (''zebra bodies''). In summary, PPT2 deficiency in mice manifests as a neurodegenerative disorder with visceral features. Although PPT2 deficiency has not been described in humans, manifestations would be predicted to include neurodegeneration with bone marrow histiocytosis, visceromegaly, brown pancreas, and linkage to chromosome 6p21.3 in affected families. P almitoyl protein thioesterase (PPT) 2 is a lysosomal thioesterase that is 27% identical to PPT1, a lysosomal enzyme defective in a neurodegenerative disorder called infantile neuronal ceroid lipofuscinosis, or infantile Batten disease (1). The neuronal ceroid lipofuscinosis (NCLs) are a group of neurodegenerative disorders of children characterized by the accumulation of autofluorescent storage material in the brain and other tissues, cognitive and motor deterioration, visual failure, and seizures. Notable is the absence of functionally significant manifestations outside the central nervous system (2, 3). The NCLs are caused by defects in at least eight genes (of which six have been identified), and different forms of the disease have a distinct storage ultrastructure (2). The PPT1 or CLN1 gene underlies the most severe form of the disease, and it encodes a thioesterase enzyme that removes palmitate or other fatty acids from cysteine residues in proteins (4-6). The enzyme encoded by PPT2 is a second lysosomal thioesterase with a substrate specificity that overlaps that of PPT1 (7-9).Recently, we disrupted both PPT1 and PPT2 genes in mice and showed that homozygous PPT1 knockout mice have a neurodegenerative disorder that closely parallels infantile Batten disease (10). Most PPT1 knockout mice are terminal by 10 mo of age. Preliminary analysis of homozygous PPT2 knockout mice at 10 mo had shown the development of scant autofluorescent storage material in the brain and a neurological phenotype in a proportion of the animals. In the current article, we have extended the observation of these PPT2 knockout mice throughout their natural lifespan and analyzed their behavio...

show abstract

“…CLN1 is similar to a gene in the yeast Schizosaccharomyces pombe (AL023634) (although it has not been found in Saccharomyces cerevisiae), to a gene in the nematode worm Caenorhabditis elegans (U50313) and to one in the plant Arabidopsis thaliana (Z97343). A human homologue, PPT2, has also been characterised [Soyombo et al, 1997[Soyombo et al, , 1999. CLN2 is similar to two bacterial carboxypeptidases (D37970, D83740), to a gene in the slime mould Dictyostelium discoideum (U27540) and other distant species (Y08256, X64708, L76740), but has no similar gene in either S. pombe or S. cerevisiae.…”

Section: The Ncl Genesmentioning

confidence: 99%

Molecular basis of the neuronal ceroid lipofuscinoses: Mutations in CLN1, CLN2, CLN3, and CLN5

1999

View full text Add to dashboard Cite

The neuronal ceroid lipofuscinoses (NCLs), also referred to as Batten disease, are a group of neurodegenerative disorders characterised by the accumulation of an autofluorescent lipopigment in many cell types. Different NCL types are distinguished according to age of onset, clinical phenotype, ultrastructural characterisation of the storage material, and chromosomal location of the disease gene. At least eight genes underlie the NCLs, of which four have been isolated and mutations characterised: CLN1, CLN2, CLN3, CLN5. Two of these genes encode lysosomal enzymes, and two encode transmembrane proteins, at least one of which is likely to be in the lysosomal membrane. The basic defect in the NCLs appears to be associated with lysosomal function. Hum Mutat 14:199-215, 1999.

show abstract

Structure of the Human Palmitoyl-Protein Thioesterase-2 Gene (PPT2) in the Major Histocompatibility Complex on Chromosome 6p21.3

Cited by 16 publications

References 31 publications

Disruption ofPPT1orPPT2causes neuronal ceroid lipofuscinosis in knockout mice

Disruption ofPPT1orPPT2causes neuronal ceroid lipofuscinosis in knockout mice

Disruption ofPPT2in mice causes an unusual lysosomal storage disorder with neurovisceral features

Molecular basis of the neuronal ceroid lipofuscinoses: Mutations in CLN1, CLN2, CLN3, and CLN5

Contact Info

Product

Resources

About