Disruption of PPT2 in mice causes an unusual lysosomal storage disorder with neurovisceral features

Praveena Gupta, Abigail A. Soyombo, John M. Shelton, Ian G. Wilkofsky, Krystyna E. Wisniewski, James A. Richardson, Sandra L. Hofmann

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)12325-12330
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume100
Issue number21
DOIs
StatePublished - Oct 14 2003

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Neuronal Ceroid-Lipofuscinoses
Pancreas
Bone Marrow
Macrophages
Extramedullary Hematopoiesis
Histiocytosis
Lysosomal Storage Diseases
Lipofuscin
Foam Cells
Equidae
Splenomegaly
Giant Cells
Ataxia
Islets of Langerhans
Neurodegenerative Diseases
Electron Microscopy
Chromosomes
palmitoyl-protein thioesterase
Phenotype
Membranes

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Disruption of PPT2 in mice causes an unusual lysosomal storage disorder with neurovisceral features. / Gupta, Praveena; Soyombo, Abigail A.; Shelton, John M.; Wilkofsky, Ian G.; Wisniewski, Krystyna E.; Richardson, James A.; Hofmann, Sandra L.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 100, No. 21, 14.10.2003, p. 12325-12330.

Research output: Contribution to journalArticle

Gupta, Praveena ; Soyombo, Abigail A. ; Shelton, John M. ; Wilkofsky, Ian G. ; Wisniewski, Krystyna E. ; Richardson, James A. ; Hofmann, Sandra L. / Disruption of PPT2 in mice causes an unusual lysosomal storage disorder with neurovisceral features. In: Proceedings of the National Academy of Sciences of the United States of America. 2003 ; Vol. 100, No. 21. pp. 12325-12330.
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abstract = "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.",
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