Peripheral neuropathy with hypomyelination, chronic intestinal pseudo-obstruction and deafness: A developmental ?neural crest syndrome? related to a SOX10 mutation

Pingault, Véronique; Guiochon‐Mantel, Anne; Bondurand, Nadège; Fauré, Christophe; Lacroix, Catherine; Lyonnet, Stanislas; Goossens, Michel; Landrieu, P.

doi:10.1002/1531-8249(200010)48:4<671::aid-ana17>3.0.co;2-8

Cited by 87 publications

(24 citation statements)

References 17 publications

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“…The patient described had characteristics of hypopigmentation, but not all the features of Waardenburg syndrome nor intestinal aganglionosis. In another case, a single nucleotide deletion (795delG) in the SOX10 gene has been reported in a patient with peripheral neuropathy, hypomyelination, deafness, and chronic intestinal pseudo-obstruction, which are not features of WS4 21. WS4 patients who have SOX10 mutations also displayed different severity in the extent of intestinal aganglionosis.…”

Section: Discussionmentioning

confidence: 98%

Novel mutations of SOX10 suggest a dominant negative role in Waardenburg-Shah syndrome

Sham

2001

Journal of Medical Genetics

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Section: Discussionmentioning

confidence: 98%

Novel mutations of SOX10 suggest a dominant negative role in Waardenburg-Shah syndrome

Sham

2001

Journal of Medical Genetics

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“…PCWH phenotypes include moderate (CMT1-like) or severe (CHN-like) demyelinating neuropathies (Inoue et al, 2004, 2002, 1999; Pingault et al, 2000; Verheij et al, 2006), but SOX10 mutations have not been identified in non-syndromic CMT (Pingault et al, 2001). SOX10 alterations are typically nonsense mutations that produce premature termination and dose-dependent effects suggesting toxic gain-of-function.…”

Section: Mechanismsmentioning

confidence: 99%

Molecular mechanisms of inherited demyelinating neuropathies

Scherer

Wrabetz

2008

Glia

151

116

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The past 15 years have witnessed the identification of more than 25 genes responsible for inherited neuropathies in humans, many associated with primary alterations of the myelin sheath. A remarkable body of work in patients, as well as animal and cellular models, has defined the clinical and molecular genetics of these illnesses and shed light on how mutations in associated genes produce the heterogeneity of dysmyelinating and demyelinating phenotypes. Here, we review selected recent developments from work on the molecular mechanisms of these disorders and their implications for treatment strategies. V

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“…1). A number of the patients with total or long segment HSCR also exhibited additional signs of deficiency in myelinating Schwann cells of the peripheral nervous system and oligodendrocytes of the central nervous system [Inoue et al, 1999; Pingault et al, 2000, 2001; Touraine et al, 2000]. There are other SOX10 mutations identified in patients without full clinical features of WS4.…”

Section: Summary Of the Sox10 Mutations And The Associated Phenotypesmentioning

confidence: 99%

“…A SOX10 mis‐sense mutation (S135T) has been reported in a case of Yemenite deaf‐blind hypopigmentation syndrome [Bondurand et al, 1999], the patient described had characteristics of hypopigmentation, but not all the features of Waardenburg syndrome nor intestinal aganglionosis. In another case, a single nucleotide deletion (795delG) in the SOX10 gene has been reported in a patient with peripheral neuropathy, hypopigmentation, deafness, and chronic intestinal pseudo‐obstruction, which are not clinical features of WS4 [Pingault et al, 2000].…”

Section: Summary Of the Sox10 Mutations And The Associated Phenotypesmentioning

confidence: 99%

Analysis of SOX10 mutations identified in Waardenburg‐Hirschsprung patients: Differential effects on target gene regulation

Chan

Wong

Lui

et al. 2003

J of Cellular Biochemistry

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SOX10 is a member of the SOX gene family related by homology to the high-mobility group (HMG) box region of the testis-determining gene SRY. Mutations of the transcription factor gene SOX10 lead to Waardenburg-Hirschsprung syndrome (Waardenburg-Shah syndrome, WS4) in humans. A number of SOX10 mutations have been identified in WS4 patients who suffer from different extents of intestinal aganglionosis, pigmentation, and hearing abnormalities. Some patients also exhibit signs of myelination deficiency in the central and peripheral nervous systems. Although the molecular bases for the wide range of symptoms displayed by the patients are still not clearly understood, a few target genes for SOX10 have been identified. We have analyzed the impact of six different SOX10 mutations on the activation of SOX10 target genes by yeast one-hybrid and mammalian cell transfection assays. To investigate the transactivation activities of the mutant proteins, three different SOX target binding sites were introduced into luciferase reporter gene constructs and examined in our series of transfection assays: consensus HMG domain protein binding sites; SOX10 binding sites identified in the RET promoter; and Sox10 binding sites identified in the P0 promoter. We found that the same mutation could have different transactivation activities when tested with different target binding sites and in different cell lines. The differential transactivation activities of the SOX10 mutants appeared to correlate with the intestinal and/or neurological symptoms presented in the patients. Among the six mutant SOX10 proteins tested, much reduced transactivation activities were observed when tested on the SOX10 binding sites from the RET promoter. Of the two similar mutations X467K and 1400del12, only the 1400del12 mutant protein exhibited an increase of transactivation through the P0 promoter. While the lack of normal SOX10 mediated activation of RET transcription may lead to intestinal aganglionosis, overexpression of genes coding for structural myelin proteins such as P0 due to mutant SOX10 may explain the dysmyelination phenotype observed in the patients with an additional neurological disorder.

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Peripheral neuropathy with hypomyelination, chronic intestinal pseudo-obstruction and deafness: A developmental ?neural crest syndrome? related to a SOX10 mutation

Cited by 87 publications

References 17 publications

Novel mutations of SOX10 suggest a dominant negative role in Waardenburg-Shah syndrome

Novel mutations of SOX10 suggest a dominant negative role in Waardenburg-Shah syndrome

Molecular mechanisms of inherited demyelinating neuropathies

Analysis of SOX10 mutations identified in Waardenburg‐Hirschsprung patients: Differential effects on target gene regulation

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