Ceramidase Deficiency in Farber's Disease (Lipogranulomatosis)

Sugita, Mutsumi; Dulaney, John T.; Moser, Hugo W.

doi:10.1126/science.178.4065.1100

Cited by 194 publications

(91 citation statements)

References 20 publications

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“…Farber disease is a rare autosomal recessive lysosomal storage disorder caused by the inherited de®ciency of acidic ceramidase. Due to the accumulation of ceramide in various tissues, patients have a short life-span (Sugita et al, 1972;Moser et al, 1969). However, patients do not display overt developmental defects that should be the consequence of impaired apoptosis.…”

Section: Discussionmentioning

confidence: 99%

The role of ceramide in receptor- and stress-induced apoptosis studied in acidic ceramidase-deficient Farber disease cells

et al. 2001

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The activation of sphingomyelinases leading to the generation of ceramide has been implicated in various apoptotic pathways. However, the role of ceramide as an essential death mediator remains highly controversial. In the present study, we investigated the functional relevance of ceramide in a genetic model by using primary cells from a Farber disease patient. These cells accumulate ceramide as the result of an inherited deficiency of acidic ceramidase. We demonstrate that Farber disease lymphocytes and fibroblasts underwent apoptosis induced by various stress stimuli, including staurosporine, anticancer drugs and gamma -irradiation, equally as normal control cells. In addition, caspase activation by these proapoptotic agents occurred rather similarly in Farber disease and control fibroblasts. Interestingly, Farber disease lymphoid cells underwent apoptosis induced by the CD95 death receptor more rapidly than control cells. Our data therefore suggest that ceramide does not play an essential role as a second messenger in stress-induced apoptosis. However, in accordance with a role in lipid-rich microdomains, ceramide by altering membrane composition may function as an amplifier in CD95-mediated apoptosis

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Section: Discussionmentioning

confidence: 99%

The role of ceramide in receptor- and stress-induced apoptosis studied in acidic ceramidase-deficient Farber disease cells

et al. 2001

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“…Allogeneic BMT Acid ceramidase deficiency (lipogranulomatosis) is an uncommon autosomal recessive lysosomal storage disease with several phenotypes, all of which are characterized by accumulation of the sphingolipid ceramide in cells and tissues. 1,2 Acid ceramidase has been purified, 3 and the gene encoding this hydrolase has been cloned 4 and mapped to chromosomal region 8p21.3-p22. 5 Molecular analyses have identified specific mutations of the acid ceramidase gene among the different disease phenotypes.…”

Section: Discussionmentioning

confidence: 99%

Bone marrow transplantation for infantile ceramidase deficiency (Farber disease)

Yeager

Uhas

Coles

et al. 2000

Bone Marrow Transplant

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Summary:Infantile ceramidase deficiency (Farber disease) is an uncommon, progressive lysosomal storage disease characterized by multiple ceramide-containing nodules (lipogranulomata) in the subcutaneous tissue and upper aerodigestive tract, painful periarticular swelling, psychomotor retardation, and varying degrees of ocular, pulmonary or hepatic involvement. Management of Farber disease has been limited to symptomatic supportive care, and few affected infants survive beyond 5 years of age. We performed an allogeneic bone marrow transplant (BMT) from an HLA-identical heterozygous sister in a 9.5-month-old female with minimally symptomatic Farber disease who received a pre-transplant regimen of busulfan and cyclophosphamide. Ceramidase activity in peripheral blood leukocytes increased from 6% before transplant to 44% (donor heterozygote level) by 6 weeks after BMT. By 2 months after transplant, the patient's subcutaneous lipogranulomata, pain on joint motion, and hoarseness had resolved. Despite modest gains in cognitive and language development, hypotonia and delayed motor skills persisted. Gradual loss of circulating donor cells with autologous hematopoietic recovery occurred; VNTR analyses showed 50% donor DNA in peripheral blood cells at 8.5 months after BMT and only 1% at 21 months after transplant. Interestingly, leukocyte ceramidase activity consistently remained in the heterozygous range despite attrition of donor cells in peripheral blood. This novel observation indicates ongoing hydrolase production by non-circulating donor cells, possibly in the mononuclear phagocytic system, and uptake by recipient leukocytes. Although lipogranulomata and hoarseness did not recur, the patient's neurological and neurocognitive status progressively declined. She died 28 months after BMT (age 37.5 months) with pulmonary insufficiency caused by recurrent aspiration pneumonias. Allogeneic BMT

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“…Acid CDase is a lysosomal enzyme, a defect in which underlies the human disorder Farber's disease (disseminated lipogranulomatosis) [4]. This enzyme has a pH optimum of 4-5, is glycosylated, has an apparent molecular mass of 50 kDa and it prefers ceramide as a substrate over dhCer (dihydroceramide).…”

Section: Introductionmentioning

confidence: 99%

Identification of a novel amidase motif in neutral ceramidase

Galadari

Mao

et al. 2006

Biochemical Journal

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Neutral CDases (ceramidases) are newly identified enzymes with important roles in cell regulation, but little is known about their catalytic mechanisms. In the present study the full-length human neutral CDase was cloned and expressed in the yeast doubleknockout strain ∆ypc1∆ydc1, which lacks the yeast CDases YPC1p and YDC1p. Biochemical characterization of the human neutral CDase showed that the enzyme exhibited classical Michaelis-Menten kinetics, with an optimum activity at pH 7.5. Activity was enhanced by Na + and Ca 2+ . Mg 2+ and Mn 2+ were somewhat stimulatory, but Zn 2+ , Cu 2+ and Fe 2+ inhibited the enzyme. Dithiothreitol and 2-mercaptoethanol dose-dependently inhibited neutral CDase. In order to identify which amino acids were involved in the catalytic action of neutral CDase, the purified enzyme was subjected to chemical modifications. It was observed that the serine residue modifier di-isopropyl fluorophosphate dose-dependently inhibited activity, implicating a serine residue in the catalytic action. From an alignment of the sequences of the neutral CDases from different species, all conserved serine residues were selected for site-directed mutagenesis. Of the six aligned serine residues that were mutated to alanine, only the S354A mutant lost its activity totally. Ser 354 falls within a very highly conserved hexapeptide sequence GDVSPN, which itself was in the middle of a larger conserved sequence, namely NXGDVSPNXXG P / X XC. Moreover, mutations of Asp 352 and Cys 362 in the consensus sequence to alanine resulted in loss of activity of neutral CDase. Hence the present study identified a novel amidase sequence containing a critical serine residue that may function as a nucleophile in the hydrolytic attack on the amide bond present in ceramide.

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Ceramidase Deficiency in Farber's Disease (Lipogranulomatosis)

Cited by 194 publications

References 20 publications

The role of ceramide in receptor- and stress-induced apoptosis studied in acidic ceramidase-deficient Farber disease cells

The role of ceramide in receptor- and stress-induced apoptosis studied in acidic ceramidase-deficient Farber disease cells

Bone marrow transplantation for infantile ceramidase deficiency (Farber disease)

Identification of a novel amidase motif in neutral ceramidase

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