NM_006941.3(SOX10):c.1400_*10delAAAGGGGGCCCT (p.*467Cysext*82) AND Peripheral demyelinating neuropathy, central dysmyelination, Waardenburg syndrome, and Hirschsprung disease

Clinical significance:Pathogenic (Last evaluated: Dec 15, 2007)

Review status:(0/4) 0 stars out of maximum of 4 stars

no assertion criteria provided

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000007824.4

Allele description

NM_006941.3(SOX10):c.1400_*10delAAAGGGGGCCCT (p.*467Cysext*82)

Genes:
POLR2F:RNA polymerase II subunit F [Gene - OMIM - HGNC]
SOX10:SRY-box 10 [Gene - OMIM - HGNC]
Variant type:
Deletion
Cytogenetic location:
22q13.1
Genomic location:
Preferred name:
NM_006941.3(SOX10):c.1400_*10delAAAGGGGGCCCT (p.*467Cysext*82)
HGVS:
  • NC_000022.11:g.37973485_37973496delAGGGCCCCCTTT
  • NG_007948.1:g.16037_16048delAAAGGGGGCCCT
  • NM_006941.3:c.1400_*10delAAAGGGGGCCCT
  • NP_008872.1:p.*467Cysext*82
  • LRG_271t1:c.1400_*10delAAAGGGGGCCCT
  • LRG_271:g.16037_16048delAAAGGGGGCCCT
  • LRG_271p1:p.*467Cysext*82
  • NC_000022.10:g.38369492_38369503delAGGGCCCCCTTT
  • NM_006941.3:c.1400_1411del12
Links:
OMIM: 602229.0008; dbSNP: rs397515368
NCBI 1000 Genomes Browser:
rs397515368

Condition(s)

Name:
Peripheral demyelinating neuropathy, central dysmyelination, Waardenburg syndrome, and Hirschsprung disease (PCWH)
Synonyms:
WAARDENBURG-SHAH SYNDROME, NEUROLOGIC VARIANT
Identifiers:
MedGen: C1836727; Orphanet: 163746; OMIM: 609136

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000028029OMIMno assertion criteria providedPathogenic
(Dec 15, 2007)
germlineliterature only

PubMed (2)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only

Citations

PubMed

Myelin deficiencies in both the central and the peripheral nervous systems associated with a SOX10 mutation.

Inoue K, Tanabe Y, Lupski JR.

Ann Neurol. 1999 Sep;46(3):313-8.

PubMed [citation]
PMID:
10482261

Translation of SOX10 3' untranslated region causes a complex severe neurocristopathy by generation of a deleterious functional domain.

Inoue K, Ohyama T, Sakuragi Y, Yamamoto R, Inoue NA, Yu LH, Goto Y, Wegner M, Lupski JR.

Hum Mol Genet. 2007 Dec 15;16(24):3037-46. Epub 2007 Sep 13. Erratum in: Hum Mol Genet. 2008 Jun 1;17(11):1705. Li-Hua, Yu [corrected to Yu, Li-Hua].

PubMed [citation]
PMID:
17855451

Details of each submission

From OMIM, SCV000028029.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (2)

Description

Inoue et al. (1999) described a patient presenting with a neurologic variant of Waardenburg-Shah syndrome (PCWH; 609136) characterized by severe dysmyelination compatible with Pelizaeus-Merzbacher disease (see 312080) and peripheral neuropathy consistent with Charcot-Marie-Tooth disease type I (see 118200), in addition to Waardenburg-Hirschsprung syndrome (277580). In the patient, Inoue et al. (1999) identified a novel heterozygous 12-bp deletion in exon 5 of the SOX10 gene that did not disrupt the coding region, but extended the peptide and hence was thought to act as a dominant-negative allele. There was a 6-bp direct repeat in the wildtype SOX10 sequence that flanked the deletion, suggesting that the deletion may have been mediated by DNA polymerase slippage between these direct repeats. The healthy parents and sibs did not have this deletion, indicating that this was a de novo mutation. Deletion started at the second nucleotide of the TAA stop codon, resulting in disruption of the stop codon, and, by conceptual translation, an extension of 82 amino acids on the carboxy terminus without any other alterations in the putative SOX10 protein. The 12-bp deletion converted the carboxy-terminal codon from TAA (stop) to TGT (cys).

By in vitro functional expression assays, Inoue et al. (2007) showed that the 12-bp deletion led to severely diminished transcription and DNA-binding activity of SOX10. However, the mutant protein did not show dominant-negative interference with wildtype SOX10 in vitro. Within the additional 82-amino acid tail, an 11-amino acid region (termed the WR domain) presumably formed an alpha-helix structure and inhibited SOX10 transcription activity if inserted in the C-terminal half of the protein. The WR domain also affected other transcription factors with a graded effect when fused to the C terminus, suggesting that it elicited a toxic functional activity. Inoue et al. (2007) concluded that the molecular pathology caused by the 12-bp deletion and its resulting extension was distinct from that of more common premature termination mutations. Failure to properly terminate SOX10 translation resulted in the generation of a deleterious functional domain and a gain-of-function effect.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jul 21, 2018