Neurological Phenotype in Waardenburg Syndrome Type 4 Correlates with Novel SOX10 Truncating Mutations and Expression in Developing Brain

{ "0" : "Département de Génétique et Unité de Recherches sur les Handicaps Génétiques de l'Enfant, Hôpital Necker-Enfants Malades, Paris" , "1" : "Centre de Génétique, Hôpital d'Enfants, Dijon, France" , "2" : "Kinderkrankenhaus, Kliniken der Stadt Köln" , "3" : "Institut für Genetik, Universität zu Köln, Cologne, Germany" , "4" : "Unité de Génétique Médicale et Foetopathologie, Hôpital Arnaud de Villeneuve, Montpellier, France" , "5" : "Génétique Moléculaire et Physiopathologie, Hôpital Henri Mondor, Créteil, France" , "7" : "Ataxia" , "8" : "Dysautonomia" , "9" : "Hirschsprung disease" , "10" : "Neuroscristopathy" , "11" : "Waardenburg syndrome"}
The American Journal of Human Genetics (Impact Factor: 10.93). 06/2000; 66(5):1496-1503. DOI: 10.1086/302895
Source: PubMed


Waardenburg syndrome type 4 (WS4), also called Shah-Waardenburg syndrome, is a rare neurocristopathy that results from the absence of melanocytes and intrinsic ganglion cells of the terminal hindgut. WS4 is inherited as an autosomal recessive trait attributable to EDN3 or EDNRB mutations. It is inherited as an autosomal dominant condition when SOX10 mutations are involved. We report on three unrelated WS4 patients with growth retardation and an as-yet-unreported neurological phenotype with impairment of both the central and autonomous nervous systems and occasionally neonatal hypotonia and arthrogryposis. Each of the three patients was heterozygous for a SOX10 truncating mutation (Y313X in two patients and S351X in one patient). The extended spectrum of the WS4 phenotype is relevant to the brain expression of SOX10 during human embryonic and fetal development. Indeed, the expression of SOX10 in human embryo was not restricted to neural-crest–derived cells but also involved fetal brain cells, most likely of glial origin. These data emphasize the important role of SOX10 in early development of both neural-crest–derived tissues, namely melanocytes, autonomic and enteric nervous systems, and glial cells of the central nervous system.

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    • "The earlier the mutation in the last exon, the more severe the phenotype as the result of a stronger dominant negative effect. In agreement, mutations located in the first part of the last exon (Gln234X, Gln250X, Ser251X) result in severe symptoms ranging from neonatal distress at birth, coma, hypoventilation/respiratory failure, and death in the postnatal period [Inoue et al., 2002; Pingault et al., 2002; Touraine et al., 2000]. The reasons why SOX10 deletions resulting in haploinsufficiency lead to PCW/ PCWH in some patients are not explained in this model [Bondurand et al., 2007]. "
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    ABSTRACT: Waardenburg syndrome (WS) is characterized by the association of pigmentation abnormalities, including depigmented patches of the skin and hair, vivid blue eyes or heterochromia irides, and sensorineural hearing loss. However, other features such as dystopia canthorum, musculoskeletal abnormalities of the limbs, Hirschsprung disease, or neurological defects are found in subsets of patients and used for the clinical classification of WS. Six genes are involved in this syndrome: PAX3 (encoding the paired box 3 transcription factor), MITF (microphthalmia-associated transcription factor), EDN3 (endothelin 3), EDNRB (endothelin receptor type B), SOX10 (encoding the Sry bOX10 transcription factor), and SNAI2 (snail homolog 2), with different frequencies. In this review we provide an update on all WS genes and set up mutation databases, summarize molecular and functional data available for each of them, and discuss the applications in diagnostics and genetic counseling. Hum Mutat 31, 1–16, 2010. © 2010 Wiley-Liss, Inc.
    Human Mutation 04/2010; 31(4):391 - 406. DOI:10.1002/humu.21211 · 5.14 Impact Factor
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    • "The annotated literature section is categorized by gene; currently presented is SOX10, a transcription factor that is crucial for the development of melanocyte and glial lineages (12–14). Mutation of human SOX10 results in Waardenburg syndrome type 4 and PCWH (peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome and Hirschsprung disease), disorders that result from abnormal development of neural crest-derived melanocytes, enteric neurons and glia, Schwaan cells and oligodendrocytes (15–17). SOX10 mutations are seen in melanoma as well (18). "
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    ABSTRACT: We describe the creation of a specialized web-accessible database named the Pigment Cell Gene Resource, which contains information on the genetic pathways that regulate pigment cell development and function. This manually curated database is comprised of two sections, an annotated literature section and an interactive transcriptional network diagram. Initially, this database focuses on the transcription factor SOX10, which has essential roles in pigment cell development and function, but the database has been designed with the capacity to expand in the future, allowing inclusion of many more pigmentation genes. Database URL:
    Database The Journal of Biological Databases and Curation 01/2010; 2010:baq025. DOI:10.1093/database/baq025 · 3.37 Impact Factor
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    • "All genes tested were, therefore, expressed by other tissues, notably by the source neuroepithelium, in addition to hNCC at C13. As in animals, SOX10 (24) and FOXD3 (Fig. 3) appeared to be more expressed by early postmigratory hNCC than the neural tube. "
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    ABSTRACT: The fields of both developmental and stem cell biology explore how functionally distinct cell types arise from a self-renewing founder population. Multipotent, proliferative human neural crest cells (hNCC) develop toward the end of the first month of pregnancy. It is assumed that most differentiate after migrating throughout the organism, although in animal models neural crest stem cells reportedly persist in postnatal tissues. Molecular pathways leading over time from an invasive mesenchyme to differentiated progeny such as the dorsal root ganglion, the maxillary bone or the adrenal medulla are altered in many congenital diseases. To identify additional components of such pathways, we derived and maintained self-renewing hNCC lines from pharyngulas. We show that, unlike their animal counterparts, hNCC are able to self-renew ex vivo under feeder-free conditions. While cross species comparisons showed extensive overlap between human, mouse and avian NCC transcriptomes, some molecular cascades are only active in the human cells, correlating with phenotypic differences. Furthermore, we found that the global hNCC molecular profile is highly similar to that of pluripotent embryonic stem cells when compared with other stem cell populations or hNCC derivatives. The pluripotency markers NANOG, POU5F1 and SOX2 are also expressed by hNCC, and a small subset of transcripts can unambiguously identify hNCC among other cell types. The hNCC molecular profile is thus both unique and globally characteristic of uncommitted stem cells.
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