Wegner M (2007)
Publication Type: Journal article, Original article
Publication year: 2007
Publisher: Oxford University Press (OUP): Policy B - Oxford Open Option B
Pages Range: 3037-3046
Journal Issue: 16
DOI: 10.1093/hmg/ddm262
Peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome and Hirschsprung disease (PCWH) is a complex neurocristopathy caused by SOX10 mutations. Most PCWH - associated SOX10 mutations result in premature termination codons (PTCs), for which the molecular mechanism has recently been delineated. However, the first mutation reported to cause PCWH was a disruption of the native stop codon that by conceptual translation extends the protein into the 3′ untranslated region (3′-UTR) for an additional 82 residues. In this study, we sought to determine the currently unknown molecular pathology for the SOX10 extension mutation using in vitro functional assays. Despite the wild-type SOX10 coding sequence remaining intact, the extension mutation led to severely diminished transcription and DNA-binding activities. Nevertheless, it showed no dominant-negative interference with wild-type SOX10 in vitro. Within the 82-amino acid tail, an 11-amino acid region (termed the WR domain) was responsible primarily for the deleterious properties of the extension. The WR domain, presumably forming an α-helix structure, inhibited SOX10 transcription activities if inserted in the carboxyl-terminal half of the protein. The WR domain can also affect other transcription factors with a graded effect when fused to the carboxyl termini, suggesting that it probably elicits a toxic functional activity. Together, molecular pathology for the SOX10 extension mutation is distinct from that of more common PTC mutations. Failure to properly terminate SOX10 translation causes the generation of a deleterious functional domain that occurs because of translation of the normal 3′-UTR; the mutant fusion protein causes a severe neurological disease. © The Author 2007. Published by Oxford University Press. All rights reserved.
APA:
Wegner, M. (2007). Translation of SOX10 3' untranslated region causes a complex severe neurocristopathy by generation of a deleterious functional domain. Human Molecular Genetics, 16, 3037-3046. https://doi.org/10.1093/hmg/ddm262
MLA:
Wegner, Michael. "Translation of SOX10 3' untranslated region causes a complex severe neurocristopathy by generation of a deleterious functional domain." Human Molecular Genetics 16 (2007): 3037-3046.
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