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A very long-chain acyl-CoA synthetase-deficient mouse and its relevance to X-linked adrenoleukodystrophy.

X-linked adrenoleukodystrophy (X-ALD) is a neurodegenerative and endocrine disorder resulting from mutations in ABCD1 which encodes a peroxisomal membrane protein in the ATP binding cassette superfamily. The biochemical signature of X-ALD is increased levels of saturated very long-chain fatty acids (VLCFA; carbon chains of 22 or more) in tissues and plasma that has been associated with decreased peroxisomal very long-chain acyl-CoA synthetase (VLCS) activity and decreased peroxisomal VLCFA beta-oxidation. It has been hypothesized that ABCD1, which has no demonstrable VLCS activity itself, has an indirect effect on peroxisomal VLCS activity and VLCFA beta-oxidation by transporting fatty acid substrates, VLCS protein or some required co-factor into peroxisomes. Here we report the characterization of a Vlcs knockout mouse that exhibits decreased peroxisomal VLCS activity and VLCFA beta-oxidation but does not accumulate VLCFA. The XALD/Vlcs double knockout mouse has the biochemical abnormalities observed in the individual knockout mice but does not display a more severe X-ALD phenotype. These data lead us to conclude that (1) VLCFA levels are independent of peroxisomal fatty acid beta-oxidation, (2) there is no ABCD1/VLCS interaction and (3) the common severe forms of X-ALD cannot be modeled by decreasing peroxisomal VLCS activity in the XALD mouse.

Pubmed ID: 12719378


  • Heinzer AK
  • Watkins PA
  • Lu JF
  • Kemp S
  • Moser AB
  • Li YY
  • Mihalik S
  • Powers JM
  • Smith KD


Human molecular genetics

Publication Data

May 15, 2003

Associated Grants


Mesh Terms

  • ATP-Binding Cassette Transporters
  • Adrenoleukodystrophy
  • Animals
  • Brain
  • Coenzyme A Ligases
  • Fatty Acids
  • Humans
  • Kidney
  • Liver
  • Mice
  • Mice, Knockout
  • Repressor Proteins
  • Saccharomyces cerevisiae Proteins