Adrenoleukodystrophy Gene: Unexpected Homology to a Protein Involved in Peroxisome Biogenesis

Adrenoleukodystrophy (ALD) is an X-linked peroxisomal disorder characterized by a progressive demyelination of the central nervous system and adrenal insufficiency. Clinical phenotypes of different severity are frequently observed within the same kindred. ALD is characterized biochemically by the accumulation of very-long-chain fatty acids (VLCFA) due to an impairment in the beta-oxidation of these fatty acids in peroxisome. From the observation that oxidation of VLCFA-CoA is normal in fibroblasts from patients with ALD, it was concluded that the gene coding for VLCFA-CoA synthetase was a candidate gene for ALD. Using positional cloning strategies, we have identified a gene which was found partially deleted in 7% of 85 independent patients with ALD. The predicted protein (ALDP) sequence shows significant homology to the 70-kDa peroxisomal membrane protein which is involved in peroxisome biogenesis and belongs to the 'ATP binding' superfamily of transporters. ALDP thus encodes a putative peroxisomal transporter molecule which may be involved in the import or anchoring of VLCFA-CoA synthetase.