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

Sham, Mai Har

doi:10.1136/jmg.38.9.e30

Cited by 52 publications

(36 citation statements)

References 22 publications

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“…Similar to the four individuals with PCWH, most of these previously studied individuals had nonsense mutations or frameshift mutations that resulted in PTCs in the last exon of SOX10 (e.g., Y313X, Q234X, S251X, 778delG, S376X, Q377X and X467K; refs. 10,11,16,17,19; Fig. 1c).…”

Section: ′ and 3′ Sox10 Mutations Convey Distinct Phenotypesmentioning

confidence: 95%

“…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%

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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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Section: ′ and 3′ Sox10 Mutations Convey Distinct Phenotypesmentioning

confidence: 95%

Section: ′ and 3′ Sox10 Mutations Convey Distinct Phenotypesmentioning

confidence: 99%

Molecular mechanism for distinct neurological phenotypes conveyed by allelic truncating mutations

et al. 2004

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“…Four missense or small in frame insertions are described in the HMG domain. Remarkably, there is a significant number of nonstop mutations (i.e., mutations of the stop codon that lengthen the protein), which are thought to exert a dominant negative effect due to the extended tail [Chan et al, 2003;Inoue et al, 1999;Sham et al, 2001]. Partial or full gene deletions represent a significant proportion of SOX10 mutations [Bondurand et al, 2007].…”

Section: Sox10mentioning

confidence: 99%

Review and update of mutations causing Waardenburg syndrome

et al. 2010

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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.

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“…Autosomal recessive forms are caused by mutations in the homozygous state in EDN3 or EDNRB [Puffenberger et al, 1994;Atti e et al, 1995;Edery et al, 1996;Hofstra et al, 1996;Bidaud et al, 1997;Boardman et al, 2001;Verheij et al, 2002;Sangkhathat et al, 2005], but some heterozygous carriers show part of the clinical features of the syndrome. Autosomal dominant forms are caused by mutations in the heterozygous state in EDN3, EDNRB, or SOX10 [Pingault et al, 1998[Pingault et al, , 2001[Pingault et al, , 2002Southard-Smith et al, 1999;Syrris et al, 1999;Sham et al, 2001;Mor ın et al, 2008]. Mutations affecting SOX10 result in a great phenotypic variability, including not only the canonical WS4, but ranging from the more severe PCWH phenotype (Peripheral demyelinating neuropathy, Central dysmyelinating leukodystrophy, and Waardenburg-Hirschsprung features, OMIM 609136) [Inoue et al, 1999[Inoue et al, , 2002[Inoue et al, , 2004Pingault et al, 2000;Touraine et al, 2000;Verheij et al, 2006] to milder forms with only pigmentary abnormalities and sensorineural hearing impairment, but no Hirschsprung disease [Bondurand et al, 1999[Bondurand et al, , 2007Iso et al, 2008].…”

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confidence: 99%

Genetic and phenotypic heterogeneity in two novel cases of Waardenburg syndrome type IV

Viñuela

Morín

Villamar

et al. 2009

American J of Med Genetics Pt A

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

Cited by 52 publications

References 22 publications

Molecular mechanism for distinct neurological phenotypes conveyed by allelic truncating mutations

Molecular mechanism for distinct neurological phenotypes conveyed by allelic truncating mutations

Review and update of mutations causing Waardenburg syndrome

Genetic and phenotypic heterogeneity in two novel cases of Waardenburg syndrome type IV

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