SOX10 mutations in patients with Waardenburg-Hirschsprung disease

Pingault, Véronique; Bondurand, Nadège; Kuhlbrodt, Kirsten; Goerich, Derk E.; Prehu, Marie-Odette; Puliti, Aldamaria; Herbarth, Beate; Hermans‐Borgmeyer, Irm; Legius, Eric; Matthijs, Gert; Amiel, Jeanne; Lyonnet, Stanislas; Ceccherini, Isabella; Romeo, Giovanni; Smith, Jill; Read, Andrew P.; Wegner, Michael; Goossens, Michel

doi:10.1038/ng0298-171

Cited by 751 publications

(526 citation statements)

References 27 publications

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“…SOX10 mutations in humans are responsible for the WS4 in part characterized by pigmentary defects (69). SOX10 has been shown to increase the MITF promoter activity (70).…”

Section: Regulation Of Mitf Expressionmentioning

confidence: 99%

Cyclic AMP a Key Messenger in the Regulation of Skin Pigmentation

Buscà

Ballotti

2000

Pigment Cell Research

734

640

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In humans, stimulation of skin pigmentation over the basal constitutive level, which we commonly call tanning, is physiologically stimulated by ultraviolet (UV) radiation of the solar light. UV-induced skin darkening involves an increase in the melanocyte number as well as a stimulation of melanin neosynthesis and melanocyte dendricity, a crucial morphological feature required for melanin transfer to keratinocytes. These events, corresponding to the final steps of melanocyte differentiation, play a central role in the tanning response and are subjected to an accurate research which aims to understand the precise mechanisms governing their regulation. In the present review, we will mainly focus our attention on the molecular processes involved in the regulation of melanogenesis.

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“…SOX10 mutations in humans are responsible for the WS4 in part characterized by pigmentary defects (69). SOX10 has been shown to increase the MITF promoter activity (70).…”

Section: Regulation Of Mitf Expressionmentioning

confidence: 99%

Cyclic AMP a Key Messenger in the Regulation of Skin Pigmentation

Buscà

Ballotti

2000

Pigment Cell Research

734

640

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“…1c). To determine the generality of this correlation between the location of the mutation in SOX10 and phenotype, we examined a wider data set obtained from previous studies on people with SOX10 mutations 1,2,[9][10][11]14,[16][17][18][19] . We identified several individuals possessing clinical features that resembled PCWH but that were not well defined by objective electrophysiological (NCV) and imaging (MRI) studies.…”

Section: ′ and 3′ Sox10 Mutations Convey Distinct Phenotypesmentioning

confidence: 99%

“…10,19 and data not shown). Notably, the most 3′ mutation (1076delGA), which generates the longest truncated protein, causes no measurable dysmyelinating phenotype 9 .…”

Section: Polarity Of Truncating Mutations Causing Pcwhmentioning

confidence: 99%

“…SOX10 is essential for the development of cells in the neural crest lineage, including melanocytes and enteric ganglia neurons 4,5 ; it also controls the proliferation and differentiation of Schwann cells and oligodendrocytes [6][7][8] . Notably, some mutations in SOX10 also cause a distinct and more restricted disease that does not involve either the peripheral (PNS) or the central (CNS) nervous systems [9][10][11] . This less complicated neurocristopathy, called WS4, combines Waardenburg and Hirschsprung diseases 12 .…”

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confidence: 99%

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Molecular mechanism for distinct neurological phenotypes conveyed by allelic truncating mutations

et al. 2004

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Different mutations in the same gene often cause distinct disease phenotypes in humans. Generally, such variations in the clinical phenotypes have been considered to be a consequence of the function or dysfunction of mutant proteins. Thus, a primary emphasis in genotype-phenotype correlation studies has been placed on determining the unique functional properties of encoded mutant proteins. But in vitro functional assays of mutant proteins often show discordance between predicted protein function and clinical outcome. Little is known about the many factors that are potentially involved in this discrepancy, but loss-of-function versus gain-of-function effects are often invoked as a possible mechanism.We previously identified two unrelated individuals with an unusual phenotype that combined four distinct syndromesperipheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome and Hirschsprung disease-that are characterized by deficiencies of Schwann cells, oligodendrocytes, melanocytes and enteric ganglia neurons, respectively 1,2 . Here we describe four more individuals and propose that this complex disorder is a newly described neurocristopathy called PCWH.We previously identified mutations in SOX10 in all affected individuals 1,2 . SOX10 is a transcription factor that contains a central high mobility group (HMG) DNA-binding domain and a transactivation domain at its C terminus 3 . SOX10 is essential for the development of cells in the neural crest lineage, including melanocytes and enteric ganglia neurons 4,5 ; it also controls the proliferation and differentiation of Schwann cells and oligodendrocytes [6][7][8] . Notably, some mutations in SOX10 also cause a distinct and more restricted disease that does not involve either the peripheral (PNS) or the central (CNS) nervous systems 9-11 . This less complicated neurocristopathy, called WS4, combines Waardenburg and Hirschsprung diseases 12 . Most SOX10 disease-associated mutations, regardless of whether they cause PCWH or WS4, result in premature termination codons (PTCs).As in SOX10, different mutations in MPZ are responsible for distinct neurological diseases, which each affect the myelin of the PNS. These neuropathies include early onset congenital hypomyelinating neuropathy (CHN; OMIM 605253), Dejerine-Sottas neuropathy (DSN; OMIM 145900) and the less severe, adult onset Charcot-MarieTooth disease type 1B (CMT1B; OMIM 118200; ref. 13). It has been suggested that the severity of alleles in CHN and DSN is due to dominant-negative effects, whereas the reduced severity of alleles in CMT1B is due to loss of function. But although some nonsense and frameshift alleles cause CMT1B, several truncating mutations have been reported that convey either a CHN or a DSN phenotype.We investigated the molecular mechanisms underlying the neurological phenotypes of the PCWH and WS4 neurocristopathies resulting from allelic SOX10 truncating mutations, as well as those underlying the CHN, DSN and CMT1B myelinopathies caused by allelic MPZ truncatin...

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“…Its absence results in multiple neural crest-derived defects, including aganglionosis of the whole gut [10][11][12] . Haploinsufficiency of SOX10 in mice and individuals with HSCR results in aganglionosis of the hindgut [10][11][12][13][14][15] . Both Sox10 and Ednrb are expressed in migrating ENS precursors (Fig.…”

Section: E T T E R Smentioning

confidence: 99%

Spatiotemporal regulation of endothelin receptor-B by SOX10 in neural crest–derived enteric neuron precursors

et al. 2004

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Hirschsprung disease (HSCR) is a multigenic, congenital disorder that affects 1 in 5,000 newborns and is characterized by the absence of neural crest-derived enteric ganglia in the colon 1 . One of the primary genes affected in HSCR encodes the G protein-coupled endothelin receptor-B (EDNRB) 2,3 . The expression of Ednrb is required at a defined time period during the migration of the precursors of the enteric nervous system (ENS) into the colon 4 . In this study, we describe a conserved spatiotemporal ENS enhancer of Ednrb. This 1-kb enhancer is activated as the ENS precursors approach the colon, and partial deletion of this enhancer at the endogenous Ednrb locus results in pigmented mice that die postnatally from megacolon. We identified binding sites for SOX10, an SRY-related transcription factor associated with HSCR 5 , in the Ednrb ENS enhancer, and mutational analyses of these sites suggested that SOX10 may have multiple roles in regulating Ednrb in the ENS.Mice and individuals with HSCR with mutations in the EDNRB-mediated pathway have megacolon because of the absence of enteric neurons in the distal gut 1 . This regional specificity of aganglionosis could be explained by a temporal requirement for Ednrb between embryonic day (E) 11 and E12.5 (ref. 4), when vagal neural crest-derived ENS progenitors are populating the hindgut during mouse embryogenesis, such that in the absence of EDNRB the migratory wavefront is delayed near the ileocecal junction (Fig. 1a) [6][7][8] . To elucidate the molecular mechanisms for Ednrb expression in the ENS, we dissected the Ednrb genomic region. We isolated a 78-kb P1 genomic clone encompassing Ednrb (Fig. 1b) and used it to create four independent transgenic lines. When we crossed the individual transgenic lines into the Ednrb-null mice, all the lines rescued postnatal death from megacolon (Fig. 1c). Although three of the lines did not rescue the melanocyte defect in the Ednrb-null mice (Fig. 1c), one line (when homozygous with respect to the transgene) partially rescued the pigmentation defect that resembles the hypomorphic Ednrb s allele 9 (data not shown). These results suggested that the P1 clone contained the necessary information for expression of Ednrb in ENS progenitors. In addition, we mapped a main transcription start site Ednrb -/-Tg P5

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SOX10 mutations in patients with Waardenburg-Hirschsprung disease

Cited by 751 publications

References 27 publications

Cyclic AMP a Key Messenger in the Regulation of Skin Pigmentation

Cyclic AMP a Key Messenger in the Regulation of Skin Pigmentation

Molecular mechanism for distinct neurological phenotypes conveyed by allelic truncating mutations

Spatiotemporal regulation of endothelin receptor-B by SOX10 in neural crest–derived enteric neuron precursors

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