Human Molecular Genetics Advance Access published online on September 13, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm262
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Translation of SOX10 3’ untranslated region causes a complex severe neurocristopathy by generation of a deleterious functional domain
1 Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo 187-8502, Japan 2 Department of Molecular and Human Genetics, Houston 77030, TX 3 Institut für Biochemie, Emil-Fischer-Zentrum, Universität Erlangen, Erlangen D-91054, Germany 4 Department of Pediatrics, Baylor College of Medicine, Houston 77030, TX 5 Texas Children's Hospital, Houston 77030, TX
* Corresponding to: Ken Inoue, M.D., Ph.D. Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry 4-1-1 Ogawahigashi-cho, Kodaira, Tokyo 187-8502, Japan. Phone: +81-42-346-1713, FAX: +81-42-346-1743, Email: kinoue{at}ncnp.go.jp
Received June 11, 2007; Revised September 7, 2007; Accepted September 7, 2007
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 
-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.