Both authors contributed equally to this work.
Identification and functional analysis of SOX10 missense mutations in different subtypes of waardenburg syndrome†
Article first published online: 19 SEP 2011
© 2011 Wiley-Liss, Inc.
Volume 32, Issue 12, pages 1436–1449, December 2011
How to Cite
Chaoui, A., Watanabe, Y., Touraine, R., Baral, V., Goossens, M., Pingault, V. and Bondurand, N. (2011), Identification and functional analysis of SOX10 missense mutations in different subtypes of waardenburg syndrome. Hum. Mutat., 32: 1436–1449. doi: 10.1002/humu.21583
Communicated by Arnold Munnich
- Issue published online: 14 NOV 2011
- Article first published online: 19 SEP 2011
- Accepted manuscript online: 24 AUG 2011 11:50AM EST
- Manuscript Accepted: 28 JUL 2011
- Manuscript Received: 16 MAR 2011
- Institut National de la Santé et de la Recherche Médicale (INSERM)
- Agence Nationale de la Recherche (ANR-JCJC)
- neural crest;
- enteric nervous system;
Waardenburg syndrome (WS) is a rare disorder characterized by pigmentation defects and sensorineural deafness, classified into four clinical subtypes, WS1–S4. Whereas the absence of additional features characterizes WS2, association with Hirschsprung disease defines WS4. WS is genetically heterogeneous, with six genes already identified, including SOX10. About 50 heterozygous SOX10 mutations have been described in patients presenting with WS2 or WS4, with or without myelination defects of the peripheral and central nervous system (PCWH, Peripheral demyelinating neuropathy-Central dysmyelinating leukodystrophy-Waardenburg syndrome-Hirschsprung disease, or PCW, PCWH without HD). The majority are truncating mutations that most often remove the main functional domains of the protein. Only three missense mutations have been thus far reported. In the present study, novel SOX10 missense mutations were found in 11 patients and were examined for effects on SOX10 characteristics and functions. The mutations were associated with various phenotypes, ranging from WS2 to PCWH. All tested mutations were found to be deleterious. Some mutants presented with partial cytoplasmic redistribution, some lost their DNA-binding and/or transactivation capabilities on various tissue-specific target genes. Intriguingly, several mutants were redistributed in nuclear foci. Whether this phenomenon is a cause or a consequence of mutation-associated pathogenicity remains to be determined, but this observation could help to identify new SOX10 modes of action. 32:1436–1449, 2011. ©2011 Wiley Periodicals, Inc.