Location, Location, Location

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Science  19 Mar 2004:
Vol. 303, Issue 5665, pp. 1731
DOI: 10.1126/science.303.5665.1731b

One of the notable advances in biomedical research has been the application of recombinant DNA techniques to establish the association of human diseases and genetic mutations, beginning with the mapping of the Huntington's disease gene to chromosome 4 two decades ago. On the other hand, filling in the causal links between a nucleotide change (or insertion or deletion) and the outward manifestation of dysfunction has not always been as rapid as anticipated. In particular, it has been challenging to explain how different mutations in the same gene can yield distinct phenotypes.

Inoue et al. describe how the location of mutation within the gene SOX10, which encodes a transcription factor, dictates whether the less severe Waardenburg syndrome 4 (WS4) or the more severe PCWH disorder (encompassing peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome, and Hirschsprung disease) ensues. Many of these mutations (nonsense) introduce premature termination codons (PTCs) and hence would result in truncated protein products. As predicted, all of the mutant proteins display dominant negative effects on wild-type SOX10 transcriptional activity in vitro, but with about equal potency. There is, however, a surveillance mechanism for PTCs called nonsense-mediated decay (NMD), a process in which messenger RNAs (mRNAs) that contain a termination codon lying upstream of an intron are recognized as faulty and are degraded. The intron requirement explains why mutations in exon 5, the last exon and only one in SOX10 not followed by an intron, produce mRNAs that apparently escape the NMD pathway and are translated into aberrant proteins with severe consequences. — GJC

Nature Genet. 36, 361 (2004).

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