Mutations in the gene ABCD1 can cause either adrenoleukodystrophy (ALD) or adrenomyeloneuropathy (AMN), neurodegenerative disorders inherited in an X-linked pattern, with a mutant allele frequency greater than 1:17,000. These diseases represent distinct pathological processes. ALD is caused by an immune mediated demyelination of the cerebral cortex and typically manifests in childhood. AMN is a late-onset axonopathy, characterized by spastic paraperesis, and degeneration of the axons in the corticospinal and spino-cerebellar tracts. While the pathologies diverge, they share a common biochemical defect: accumulation of by very-long chain fatty acids. Intriguingly, there is no genotype to phenotype correlation, with the same mutation resulting in either phenotype, even within identical genetic contexts. One exception is a recently identified mutation, in which 23 basepairs, encompassing the start codon of ABCD1, are deleted. In this family, AMN is inherited in a dominant pattern, and there is no indication of cerebral demyelination. The mutant gene, although lacking a traditional start codon, produces a truncated protein product. The protein is too large to be initiated at the next down-stream methionine, suggesting it is one of a minority of proteins translated from a non-AUG codon. In our experiments, we will test the hypothesis that this truncated form of ABCDI acts a dominant negative. We will identify the sequence of the ABCDI protein in the patients, and make transgenic mice that over-express the wildtype or mutant form. These mice will be crossed to existing ABCD1 knock-out mice. The ABCD1 knock-out mice, while they accumulate very long chain fatty acids, do not undergo neuronal degeneration, limiting their value as an animal model for AMN. The progeny of the knock-out and transgenic mouse crosses will be characterized for behavioral, morphological, and electrophysiological changes. In addition, we will quantify changes in their myelin's lipid composition. We will also compare the lipid profiles to those of human ALD and AMN spinal cord myelin. The results of this project will demonstrate the relevance of alternative initiation to disease and could provide valuable reagents for further inquiry into the disease pathobiology.
| McCampbell, Alexander; Truong, David; Broom, Daniel C et al. (2005) Mutant SPTLC1 dominantly inhibits serine palmitoyltransferase activity in vivo and confers an age-dependent neuropathy. Hum Mol Genet 14:3507-21 |
