title: Translation of SOX10 3' untranslated region causes a complex severe neurocristopathy by generation of a deleterious functional domain.
abstract: 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.
authors.affiliation: Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo 187-8502, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Inoue
authors.forename: Tomoko
authors.initials: T
authors.lastname: Ohyama
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Sakuragi
authors.forename: Ryoko
authors.initials: R
authors.lastname: Yamamoto
authors.forename: Naoko A
authors.initials: NA
authors.lastname: Inoue
authors.forename: Li-Hua
authors.initials: LH
authors.lastname: Yu
authors.forename: Yu
authors.initials: Y
authors.lastname: Li-Hua
authors.forename: Yu-ichi
authors.initials: Y
authors.lastname: Goto
authors.forename: Michael
authors.initials: M
authors.lastname: Wegner
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
mesh_terms: D020413:3' Untranslated Regions / Q000378:metabolism / Q000502:physiology*; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics* / Q000502:physiology*; D003711:Demyelinating Diseases / Q000235:genetics*; D005799:Genes, Dominant; D006609:High Mobility Group Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics* / Q000502:physiology*; D006627:Hirschsprung Disease / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry / Q000502:physiology; D050816:Octamer Transcription Factor-6 / Q000037:antagonists & inhibitors; D014176:Protein Biosynthesis / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000235:genetics / Q000502:physiology; D055758:SOX9 Transcription Factor; D055751:SOXC Transcription Factors; D055757:SOXE Transcription Factors; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics* / Q000502:physiology*; D015533:Transcriptional Activation / Q000235:genetics; D014849:Waardenburg Syndrome / Q000235:genetics*
chemical_list: D020413:3' Untranslated Regions; D004268:DNA-Binding Proteins; D006609:High Mobility Group Proteins; D050505:Mutant Proteins; C494178:POU3F1 protein, human; C527923:SOX10 protein, human; C097473:SOX11 protein, human; D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human; D055751:SOXC Transcription Factors; D055757:SOXE Transcription Factors; D014157:Transcription Factors; D050816:Octamer Transcription Factor-6