Translation of SOX10 3' untranslated region causes a complex severe neurocristopathy by generation of a deleterious functional domain

Hum Mol Genet. 2007 Dec 15;16(24):3037-46. doi: 10.1093/hmg/ddm262. Epub 2007 Sep 13.


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 alpha-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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions / metabolism
  • 3' Untranslated Regions / physiology*
  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • COS Cells
  • Cells, Cultured
  • Chlorocebus aethiops
  • DNA-Binding Proteins / antagonists & inhibitors
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / physiology*
  • Demyelinating Diseases / genetics*
  • Genes, Dominant
  • High Mobility Group Proteins / antagonists & inhibitors
  • High Mobility Group Proteins / chemistry
  • High Mobility Group Proteins / genetics*
  • High Mobility Group Proteins / physiology*
  • Hirschsprung Disease / genetics*
  • Humans
  • Molecular Sequence Data
  • Mutant Proteins / chemistry
  • Mutant Proteins / physiology
  • Octamer Transcription Factor-6 / antagonists & inhibitors
  • Protein Biosynthesis / physiology
  • Protein Structure, Tertiary / genetics
  • Protein Structure, Tertiary / physiology
  • SOX9 Transcription Factor
  • SOXC Transcription Factors
  • SOXE Transcription Factors
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / chemistry
  • Transcription Factors / genetics*
  • Transcription Factors / physiology*
  • Transcriptional Activation / genetics
  • Waardenburg Syndrome / genetics*


  • 3' Untranslated Regions
  • DNA-Binding Proteins
  • High Mobility Group Proteins
  • Mutant Proteins
  • POU3F1 protein, human
  • SOX10 protein, human
  • SOX11 protein, human
  • SOX9 Transcription Factor
  • SOX9 protein, human
  • SOXC Transcription Factors
  • SOXE Transcription Factors
  • Transcription Factors
  • Octamer Transcription Factor-6