Characterization of a novel mutation in exon 10 of the adrenoleukodystrophy gene.

We have detected a novel mutation in the adrenoleukodystrophy (ALD) gene in skin fibroblasts in primary culture derived from a patient suffering from the adrenocortical insufficiency-only-phenotype of ALD. This nonsense mutation (C2400T/Q672X) is the only mutation reported to date affecting exon 10. It leads to a translation product lacking the 74 C-terminal amino acids. As a consequence of the loss of this region, which immediately follows the putative nucleotide binding domain, the ALD protein (ALDP) was not detectable at all by ALDP-specific monoclonal antibodies. Since ALDP-specific mRNA was readily detected in these fibroblasts, the loss of protein is probably not attributable to RNA instability but may be explained by protein instability. If the Q672X mutation leads in fact to an unstable translation product this would be consistent with the hypothesis that the C-terminus is crucial for ALDP stability.