The Human Acid Ceramidase Gene (ASAH): Structure, Chromosomal Location, Mutation Analysis, and Expression

Li, Chi Ming; Park, Jae Ho; He, Xingxing; Levy, Brynn; Chen, Fei; Arai, Koji; Adler, David A.; Distèche, Christine M.; Koch, J.; Sandhoff, Konrad; Schuchman, Edward H.

doi:10.1006/geno.1999.5940

Cited by 128 publications

(83 citation statements)

References 13 publications

(17 reference statements)

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“…Indeed, in hepatoma cell lines, a microarray-based comparative genomic hybridization described that most frequent DNA copy number gain/loss occurred on chromosomes 5, 11, 13, 14 and 17 but not on chromosomes 1 and 8 (Kawaguchi et al, 2005). Interestingly, acid CDase is located on chromosome 8 (Li et al, 1999), suggesting that the stimulation of acid CDase is unlikely related to chromosomal modifications. In addition to the decreased ceramide accumulation, acid CDase can protect cells by generating S1P.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological inhibition or small interfering RNA targeting acid ceramidase sensitizes hepatoma cells to chemotherapy and reduces tumor growth in vivo

et al. 2006

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Section: Discussionmentioning

confidence: 99%

Pharmacological inhibition or small interfering RNA targeting acid ceramidase sensitizes hepatoma cells to chemotherapy and reduces tumor growth in vivo

et al. 2006

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“…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. 4,5 The infantile phenotype of acid ceramidase deficiency bears the eponym Farber disease and is associated with painful swelling around joints, multiple subcutaneous nodules (lipogranulomata), hoarseness due to lipogranulomata in the upper respiratory tract, psychomotor retardation, and failure to thrive.…”

Section: Discussionmentioning

confidence: 99%

“…5 Molecular analyses have identified specific mutations of the acid ceramidase gene among the different disease phenotypes. 4,5 The infantile phenotype of acid ceramidase deficiency bears the eponym Farber disease and is associated with painful swelling around joints, multiple subcutaneous nodules (lipogranulomata), hoarseness due to lipogranulomata in the upper respiratory tract, psychomotor retardation, and failure to thrive. 6,7 Recurrent pulmonary infections, aspiration pneumonitis, swallowing difficulties and hepatomegaly are common.…”

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 ceramidase is a lysosomal enzyme whose main function is to degrade ceramide to sphingosine and free fatty acid (Gatt 1963). Li et al (1999) mapped the acid ceramidase gene (ASAH1) to chromosome 8p22-p21.3. Mutations in the ASAH1 gene have been shown to be the cause of Farber disease Koch et al 1996;Li et al 1999;Zhang et al 2000).…”

Section: Introductionmentioning

confidence: 99%

“…Li et al (1999) mapped the acid ceramidase gene (ASAH1) to chromosome 8p22-p21.3. Mutations in the ASAH1 gene have been shown to be the cause of Farber disease Koch et al 1996;Li et al 1999;Zhang et al 2000). In the present study, the disease was clinically identified by typical presentation, and by the presence of storage material in the nodules by histopathology, in two siblings from an Indian family presenting with the classical form of Farber disease.…”

Section: Introductionmentioning

confidence: 99%

Farber lipogranulomatosis: clinical and molecular genetic analysis reveals a novel mutation in an Indian family

et al. 2006

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Farber disease is a rare lysosomal storage disorder caused by a deficiency of the acid ceramidase enzyme, leading to the accumulation of ceramide in various tissues. It usually manifests within a few months after birth with a unique triad of symptoms, including painful and progressive deformed joints, progressive hoarseness and subcutaneous nodules. The disease is inherited as an autosomal recessive trait, and mutations in the N-acylsphingosine amidohydrolase (ASAH1) gene, which codes for the acid ceramidase enzyme, have been shown to cause the disease. In the current study, we report the identification of a novel diseasecausing mutation in the ASAH1 gene that results in Farber disease in an Indian family. The mutation was identified in the eighth exon and is a missense mutation resulting in replacement of Valine by Leucine at codon 182. Two affected siblings harboured the identical mutation. The possible mechanism(s) of disease caused by this mutation are discussed.

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The Human Acid Ceramidase Gene (ASAH): Structure, Chromosomal Location, Mutation Analysis, and Expression

Cited by 128 publications

References 13 publications

Pharmacological inhibition or small interfering RNA targeting acid ceramidase sensitizes hepatoma cells to chemotherapy and reduces tumor growth in vivo

Pharmacological inhibition or small interfering RNA targeting acid ceramidase sensitizes hepatoma cells to chemotherapy and reduces tumor growth in vivo

Bone marrow transplantation for infantile ceramidase deficiency (Farber disease)

Farber lipogranulomatosis: clinical and molecular genetic analysis reveals a novel mutation in an Indian family

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