Get access

Identification and functional analysis of SOX10 missense mutations in different subtypes of waardenburg syndrome

Authors

  • Asma Chaoui,

    1. INSERM U955, Hôpital Henri Mondor, Créteil, France
    2. Université Paris Est, Faculté de Médecine, Créteil, France
    Search for more papers by this author
    • Both authors contributed equally to this work.

  • Yuli Watanabe,

    1. INSERM U955, Hôpital Henri Mondor, Créteil, France
    2. Université Paris Est, Faculté de Médecine, Créteil, France
    Search for more papers by this author
    • Both authors contributed equally to this work.

  • Renaud Touraine,

    1. CHU-Hôpital Nord, Service de Génétique, Saint Etienne, France
    Search for more papers by this author
  • Viviane Baral,

    1. INSERM U955, Hôpital Henri Mondor, Créteil, France
    2. Université Paris Est, Faculté de Médecine, Créteil, France
    Search for more papers by this author
  • Michel Goossens,

    1. INSERM U955, Hôpital Henri Mondor, Créteil, France
    2. Université Paris Est, Faculté de Médecine, Créteil, France
    3. AP-HP, Hôpital H. Mondor - A. Chenevier, Service de Biochimie et Génétique, Créteil, France
    Search for more papers by this author
  • Veronique Pingault,

    1. INSERM U955, Hôpital Henri Mondor, Créteil, France
    2. Université Paris Est, Faculté de Médecine, Créteil, France
    3. AP-HP, Hôpital H. Mondor - A. Chenevier, Service de Biochimie et Génétique, Créteil, France
    Search for more papers by this author
  • Nadege Bondurand

    Corresponding author
    1. INSERM U955, Hôpital Henri Mondor, Créteil, France
    2. Université Paris Est, Faculté de Médecine, Créteil, France
    • INSERM U955, Equipe 11, Hôpital Henri Mondor, 51 Avenue du Maréchal de Lattre de Tassigny, 94010 Créteil, France
    Search for more papers by this author

  • Communicated by Arnold Munnich

Abstract

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.

Get access to the full text of this article

Ancillary