Spectrum of mutations in the gene encoding the adrenoleukodystrophy protein

X-linked adrenoleukodystrophy (ALD) has been associated with mutations in a gene encoding an ATP-binding transporter, which is located in the peroxisomal membrane. Deficiency of the gene leads to impaired peroxisomal beta-oxidation. Systematic analysis of the open reading frame of the ALD gene, using reverse transcriptase-PCR, followed by direct sequencing, revealed mutations in all 28 unrelated kindreds analyzed. No entire gene deletions or drastic promoter mutations were detected. In only one kindred did the mutation involve multiple exons. The other mutations were small alterations leading to missense (13 of 28) or nonsense mutations, a single amino acid deletion, frameshifts, or splice acceptor-site defects. Mutations affecting a single amino acid were concentrated in the region between the third and fourth putative transmembrane domains and in the ATP-binding domain. Mutations were detected in all investigated ALD kindreds, suggesting that this gene is the only gene responsible for X-linked ALD. This overview of mutations is useful in the determination of structurally and functionally important regions and provides an efficient screening strategy for identification of mutations in the ALD gene.