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

• Published in: Human molecular genetics Vol. 16; no. 24; pp. 3037 - 3046
• Main Authors: Inoue, Ken, Ohyama, Tomoko, Sakuragi, Yosuke, Yamamoto, Ryoko, Inoue, Naoko A., Li-Hua, Yu, Goto, Yu-ichi, Wegner, Michael, Lupski, James R.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 15-12-2007; Oxford Publishing Limited (England)
• Subjects: 3' Untranslated Regions - metabolism; 3' Untranslated Regions - physiology; Amino Acid Sequence; Animals; Base Sequence; Biological and medical sciences; Cells, Cultured; Cercopithecus aethiops; COS Cells; Demyelinating Diseases - genetics; DNA-Binding Proteins - antagonists & inhibitors; DNA-Binding Proteins - chemistry; DNA-Binding Proteins - genetics; DNA-Binding Proteins - physiology; Fundamental and applied biological sciences. Psychology; Genes, Dominant; Genetics of eukaryotes. Biological and molecular evolution; 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 and cellular biology; 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; Severe; Genetics; Neurocristopathy
• ISSN: 0964-6906; 1460-2083
• 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.