Insertional Mutagenesis of the Mouse Acid Ceramidase Gene Leads to Early Embryonic Lethality in Homozygotes and Progressive Lipid Storage Disease in Heterozygotes

Park, Jae Ho; Simonaro, Calogera M.; He, Xu; Gordon, Ronald E.; Friedman, Adriana-Haimovitz; Ehleiter, Desiree; Pâris, François; Manova, Katia; Hepbildikler, Stefan; Fuks, Zvi; Sandhoff, Konrad; Kolesnick, Richard; Schuchman, Edward H.

doi:10.1006/geno.2002.6788

Cited by 21 publications

(23 citation statements)

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“…Consistent with the notion that AC has a protective role in cell survival, knockout of the mouse AC was found to lead to the death of embryos at a very early stage [130,131]. Addition of exogenous S1P delays the death of embryos, suggesting that inhibition of the generation of S1P is in part responsible for early embryo death caused by knockout of AC [131].…”

Section: Acid Ceramidasesupporting

confidence: 61%

Ceramidases: regulators of cellular responses mediated by ceramide, sphingosine, and sphingosine-1-phosphate

Mao

Obeid

2008

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

354

328

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Section: Acid Ceramidasesupporting

confidence: 61%

Ceramidases: regulators of cellular responses mediated by ceramide, sphingosine, and sphingosine-1-phosphate

Mao

Obeid

2008

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

354

328

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“…The AC-deficient mouse (Asah1 Ϫ / Ϫ ) undergoes apoptotic death at the 2-cell stage (E1; Fig. 4 ) because of excessive ceramide accumulation ( 39,102 ), demonstrating that AC is expressed in the embryo and that ceramide degradation is essential for survival beyond the 2-cell stage (E1) ( 102 ). In addition to increasing ceramide pools, loss of AC activity is thought to concurrently reduce pools of sphingosine and sphingosine-1-phosphate, two lipids known to promote cell growth and differentiation ( 103 ).…”

Section: Disorders Of Ceramide Degradationmentioning

confidence: 99%

“…Recently, alterations of autophagy pathways in several LSDs, e.g., NPC1 and Batten disease ( 257 ), suggest that impairment of the autophagosome system that can lead to neuron death by as-yet-undetermined mechanisms. Altered calcium homeostasis was described in NPC1 disease ( 195 ), ASM knockout mice ( 102,109 ), Sandhoff mice ( 258 ) and GM1 gangliosidosis mice ( 254,259 ). A mechanistic link among GSL accumulation, Ca 2+ homeostasis, and neuronal cell death may be of signifi cance for delineating the neuronal degeneration in GSL disorder diseases.…”

Section: Neuronal Degenerationmentioning

confidence: 99%

Multi-system disorders of glycosphingolipid and ganglioside metabolism

Xu¹,

Barnes²,

Sun³

et al. 2010

Journal of Lipid Research

142

121

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important to a variety of cellular functions. GSLs and gangliosides are synthesized at the endoplasmic reticulum (ER) and are remodeled during transit from cis to trans Golgi by a series of glycosyl-and sialyl-transferases. These are then transported to the intracellular compartments and the plasma membrane where they become enriched in microdomains and membrane bilayers. During plasma membrane turnover, GSLs and gangliosides can be internalized and partially or completely degraded in the endosomal/lysosomal system to sphingosine and free fatty acids that are then transported or fl ipped across late endosomal and lysosomal membranes for recycling or for use as signaling molecules ( 2, 3 ). GSL metabolic pathwaysGSL biosynthesis begins with condensation of serine and palmitoyl-CoA catalyzed by serine-palmitoyltransferase (SPT) on the cytoplasmic face of the ER, leading to de novo biosynthesis of ceramide, the core of GSLs (

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“…Viral episomal vectors carrying HSV-1 and EBV amplicons can deliver and express full-length genes as large as approximately 150 kb in size (1, 2). However, several concerns limit the use of HSV-1 and EBV viral vectors: absence of strong copy number control, undesired immunological responses, and occasional integration into the host genome, causing insertional mutagenesis and gene silencing (6).…”

mentioning

confidence: 99%

Human artificial chromosome (HAC) vector with a conditional centromere for correction of genetic deficiencies in human cells

Kim¹,

Кононенко²,

Erliandri³

et al. 2011

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

135

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Human artificial chromosome (HAC)-based vectors offer a promising system for delivery and expression of full-length human genes of any size. HACs avoid the limited cloning capacity, lack of copy number control, and insertional mutagenesis caused by integration into host chromosomes that plague viral vectors. We previously described a synthetic HAC that can be easily eliminated from cell populations by inactivation of its conditional kinetochore. Here, we demonstrate the utility of this HAC, which has a unique gene acceptor site, for delivery of full-length genes and correction of genetic deficiencies in human cells. A battery of functional tests was performed to demonstrate expression of NBS1 and VHL genes from the HAC at physiological levels. We also show that phenotypes arising from stable gene expression can be reversed when cells are "cured" of the HAC by inactivating its kinetochore in proliferating cell populations, a feature that provides a control for phenotypic changes attributed to expression of HAC-encoded genes. This generation of human artificial chromosomes should be suitable for studies of gene function and therapeutic applications.

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Insertional Mutagenesis of the Mouse Acid Ceramidase Gene Leads to Early Embryonic Lethality in Homozygotes and Progressive Lipid Storage Disease in Heterozygotes

Cited by 21 publications

References 0 publications

Ceramidases: regulators of cellular responses mediated by ceramide, sphingosine, and sphingosine-1-phosphate

Ceramidases: regulators of cellular responses mediated by ceramide, sphingosine, and sphingosine-1-phosphate

Multi-system disorders of glycosphingolipid and ganglioside metabolism

Human artificial chromosome (HAC) vector with a conditional centromere for correction of genetic deficiencies in human cells

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