Journal of Inherited Metabolic Disease

, Volume 25, Issue 7, pp 585–592 | Cite as

Mutation analysis of the acid ceramidase gene in Japanese patients with Farber disease

  • T. Muramatsu
  • N. Sakai
  • I. Yanagihara
  • M. Yamada
  • T. Nishigaki
  • C. Kokubu
  • H. Tsukamoto
  • M. Ito
  • K. Inui
Article

Abstract

Farber disease is a rare lysosomal storage disease, characterized by the accumulation of ceramide in tissues due to acid ceramidase deficiency. Here we report the identification of three novel mutations in the acid ceramidase gene from two Japanese patients. Patient 1 showed joint problems at around 10 months of age and the patient is now emaciated, with multiple nodules and mild neurological problems at 10 years of age. Patient 2 had consanguineous parents and showed joint contractures at around 8 months of age. He showed neurological symptoms around 2 years of age and died at 6 years owing to respiratory failure. The diagnosis was made clinically and was confirmed by enzymatic assay of acid ceramidase. Molecular analysis of cultured skin fibroblasts showed normal mRNA levels expressed in both patients. By direct sequencing of cDNA, missense mutations of V97E in exon 4 and G235R in exon 9 were detected in patient 1 and 96delV in exon 4 was homozygously identified in patient 2. These mutations were also confirmed in genomic DNA. Expression of mutated acid ceramidase cDNA in COS-1 cells showed acid ceramidase activity decreased to 35%, 2% and 37% of control value, respectively. We also found a new polymorphism V369I in exon 14 in the allele from the mother of patient 1. To date, 13 mutations, including our newly identified mutations, have been reported. All these mutations were genetically private and genotype–phenotype correlations could not be made.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

REFERENCES

  1. Bar J, Linke T, Ferlinz K, Neumann U, Schuchman EH, Sandhoff K (2001) Molecular analysis of acid ceramidase deficiency in patients with Farber disease. Hum Mut 17: 199-209.Google Scholar
  2. Furuya H, Kukita Y, Nagano S, et al (1997) Adult onset globoid cell leukodystrophy (Krabbe disease): analysis of galactosylceramidase cDNA from four Japanese patients. Hum Genet 100: 450-456.Google Scholar
  3. Ito M, Kurita T, Kita K, et al (1995) A novel enzyme that cleaves the N-acyl linkage of ceramides in various glycosphingolipids as well as sphingomyelin to produce their lyso forms. J Biol Chem 270: 24370-24374.Google Scholar
  4. Koch J, Gartner S, Li CM, et al (1996) Molecular cloning and characterization of a full-length complementary DNA encoding human acid ceramidase. J Biol Chem 271: 33110-33115.Google Scholar
  5. Kudoh T and Wenger DA (1982) Diagnosis of metachromatic leukodystrophy, Krabbe disease and Farber disease after uptake of fatty acid-labelled cerebroside sulfate into cultured skin fibroblasts. J Clin Invest 70: 89-97.Google Scholar
  6. Li CM, Hong SB, Kopal G, et al (1998) Cloning and characterization of the full-length cDNA and genomic sequences encoding murine acid ceramidase. Genomics 50: 267-274.Google Scholar
  7. Li CM, Park JH, He X, et al (1999) The human acid ceramidase gene (ASAH): structure, chromosomal location, mutation analysis, and expression. Genomics 62: 223-231.Google Scholar
  8. Moser HW (2001) Acid ceramidase deficiency: Farber lipogranulomatosis. In: Scriver CR, Beaudet AL, Valle D, Sly WS eds; Childs B, Kinzler KW, Vogelstein, assocr. eds. The Metabolic and Molecular Bases of Inherited Disease, 8th edn. New York: McGraw-Hill, 3573-3588.Google Scholar
  9. Mitsutake S, Katsuhiro K, Okino N, Ito M (1997) 14C Ceramide synthesis by sphingolipid ceramide N-deacylase: new assay for ceramidase activity detection. Anal Biochem 247: 52-57.Google Scholar
  10. van Echten-Deckert G, Klein A, Linke T, et al (1997) Turnover of endogenous ceramide in cultured normal and Farber fibroblasts. J Lipid Res 38: 2569-2579.Google Scholar
  11. Zhang Z, Mandal AK, Mital A, et al (2000) Human acid ceramidase gene: novel mutations in Farber disease. Mol Genet Metab 70: 301-309.Google Scholar

Copyright information

© Kluwer Academic Publishers 2002

Authors and Affiliations

  • T. Muramatsu
    • 1
  • N. Sakai
    • 1
  • I. Yanagihara
    • 1
  • M. Yamada
    • 1
  • T. Nishigaki
    • 1
  • C. Kokubu
    • 1
  • H. Tsukamoto
    • 1
  • M. Ito
    • 2
  • K. Inui
    • 1
  1. 1.Department of Developmental Medicine (Pediatrics)Osaka University Graduate School of MedicineOsaka
  2. 2.Department of Bioscience and Biotechnology, Graduate School of Bioresource and Bioenvironmental SciencesKyusyu UniversityFukuokaJapan

Personalised recommendations