Human Molecular Genetics, 2003, Vol. 12, No. 10 1145-1154
DOI: 10.1093/hmg/ddg126
© 2003 Oxford University Press
A very long-chain acyl-CoA synthetase-deficient mouse and its relevance to X-linked adrenoleukodystrophy
1The Kennedy Krieger Institute, 2Department of Pediatrics, 3Department of Neurology and 4Institute of Genetic Medicine, The Johns Hopkins School of Medicine, Baltimore, MD 21205, USA, 5Fu Jen Catholic University, School of Medicine, Hsinchung Hsih, Taipei Hsien, Taiwan, Republic of China, 6Laboratory of Genetic Metabolic Diseases, Emma Children's Hospital, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands and 7Departments of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA
Received January 7, 2003; Accepted March 14, 2003
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 ß-oxidation. It has been hypothesized that ABCD1, which has no demonstrable VLCS activity itself, has an indirect effect on peroxisomal VLCS activity and VLCFA ß-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 ß-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 ß-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.
* To whom correspondence should be addressed at: RM 400A Kennedy Krieger Institute, 707 North Broadway, Baltimore, MD 21205, USA. Tel: +1 4439232751; Fax: +1 4439232775; Email: smithk{at}jhmi.edu
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