Human Molecular Genetics Advance Access originally published online on March 30, 2005
Human Molecular Genetics 2005 14(10):1293-1303; doi:10.1093/hmg/ddi140
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Decreased expression of ABCD4 and BG1 genes early in the pathogenesis of X-linked adrenoleukodystrophy
1Institut National de la Santé et de la Recherche Médicale U561, Hôpital Saint-Vincent de Paul, 75014 Paris, France, 2Laboratoire de Génétique Moléculaire-UPRES EA 3618, Faculté des Sciences Pharmaceutiques et Biologiques, Université Paris V, Paris, France, 3The Kennedy Krieger Institute, Baltimore, MD 21205, USA and 4Faculty of Pharmacy, Paris V University, Department of Biochemistry, Groupe Hospitalier Pitié-Salpétrière, 47-83 Boulevard de l'Hôpital, 75651 Paris Cedex 13, France
* To whom correspondence should be addressed at: INSERM U561, Hôpital Saint-Vincent de Paul, 82 Avenue Denfert-Rochereau, 75014 Paris, France. Tel: +33 140488074; Fax: +33 140488340; Email: aubourg{at}paris5.inserm.fr
Received January 15, 2005; Revised March 22, 2005; Accepted March 22, 2005
Childhood cerebral adrenoleukodystrophy (CCER), adrenomyeloneuropathy (AMN) and AMN with cerebral demyelination (AMN-C) are the main phenotypic variants of X-linked adrenoleukodystrophy (ALD). It is caused by mutations in the ABCD1 gene encoding a half-size peroxisomal transporter that has to dimerize to become functional. The biochemical hallmark of ALD is the accumulation of very-long-chain fatty acids (VLCFA) in plasma and tissues. However, there is no correlation between the ALD phenotype and the ABCD1 gene mutations or the accumulation of VLCFA in plasma and fibroblast from ALD patients. The absence of genotype–phenotype correlation suggests the existence of modifier genes. To elucidate the mechanisms underlying the phenotypic variability of ALD, we studied the expression of ABCD1, three other peroxisomal transporter genes of the same family (ABCD2, ABCD3 and ABCD4) and two VLCFA synthetase genes (VLCS and BG1) involved in VLCFA metabolism, as well as the VLCFA concentrations in the normal white matter (WM) from ALD patients with CCER, AMN-C and AMN phenotypes. This study shows that: (1) ABCD1 gene mutations leading to truncated ALD protein are unlikely to cause variation in the ALD phenotype; (2) accumulation of saturated VLCFA in normal-appearing WM correlates with ALD phenotype and (3) expression of the ABCD4 and BG1, but not of the ABCD2, ABCD3 and VLCS genes, tends to be correlated with the severity of the disease, acting early in the pathogenesis of ALD.
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