SOX10 mutations in chronic intestinal pseudo-obstruction suggest a complex physiopathological mechanism

Pingault, Véronique; Girard, Mathilde; Bondurand, Nadège; Dorkins, Huw; Maldergem, Lionel Van; Mowat, David; Shimotake, Takashi; Verma, Ishwar C.; Baumann, Clarisse; Goossens, Michel

doi:10.1007/s00439-002-0765-8

Cited by 123 publications

(104 citation statements)

References 43 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: 94%

“…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%

“…Specifically, the Q234X, Q250X and S251X mutations are associated with a lethal phenotype 2,11,16 , whereas the 847insT, Y313X and Q364X mutations are associated with infantile-or juvenile-onset myelin deficiencies that cause only modest neurological disabilities (Fig. 1c).…”

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 .…”

mentioning

confidence: 99%

“…In particular, the involvement of both the PNS and the CNS is a distinguishing characteristic of PCWH. These neurological findings predominate in determining the degree of disability in individuals and also significantly influence the prognosis: severe hypomyelination in the PNS and CNS has even resulted in early death in some cases 2,11,16 . Second, PCWH is unique because so far it is known only to be caused by a single gene, whereas WS4 is associated with at least two other genes, EDN3 and EDNRB (refs 9,39,40).…”

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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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Section: ′ and 3′ Sox10 Mutations Convey Distinct Phenotypesmentioning

confidence: 94%