SOX10 (SRY (sex determining region Y)-box 10)

2010-04-01   Michael Wegner  

Institut fuer Biochemie, Emil-Fischer-Zentrum, Universitaet Erlangen-Nuernberg, 91054 Erlangen, Germany

Identity

HGNC
LOCATION
22q13.1
LOCUSID
ALIAS
DOM,PCWH,WS2E,WS4,WS4C
FUSION GENES

DNA/RNA

Note

SOX10 was first identified as a gene mutated in patients suffering from Waardenburg syndrome type 4C (WS4C). SOX10 mutations also cause Waardenburg syndrome type 2E (WS2E) with or without neurologic involvement, Yemenite deaf-blind hypopigmentation syndrome and PCWH syndrome. They usually occur in the heterozygous state and can be either sporadic or familial.
Atlas Image
The SOX10 gene with its 5 exons. The open reading frame (orange) is split between exons 3-5. The 5 untranslated region is generated from exons 1-3 and the 3 untranslated region corresponds to the hind part of exon 5.

Description

DNA size: 12.22kb; 5 Exons.

Transcription

mRNA size: 2882 nucleotides.

Proteins

Note

The SOX10 protein belongs to subgroup E of the SOX protein family. All 20 human members of this protein family possess a high-mobility-group (HMG) domain with three alpha-helical regions and close similarity to the one found in the male sex determining factor SRY. SOX10 functions as transcription factor and structural protein in chromatin. SOX9 and SOX8 are its closest relatives among human SOX proteins.
Atlas Image
Human SOX10 and its domains including the DNA-dependent dimerization domain (Dim), the DNA-binding HMG domain, the context-dependent transactivation domain K2 and the main transactivation domain (TA). Numbers indicate amino acid positions. The bottom shows the exact amino acid sequence of the HMG domain with its three alpha-helices, the 2 nuclear localization signals (NLS1, NLS2) and the nuclear export sequence (NES).

Description

SOX10 consists of 466 amino acids. The following domains exist (from amino terminal to carboxy terminal): DNA-dependent dimerization domain (amino acids 61-101), DNA-binding HMG-domain (amino acids 101-180), context-dependent transactivation domain K2 (amino acids 233-306) and main transactivation domain TA (amino acids 400-462). SOX10 possesses two nuclear localization signals (NLS) at the beginning and the end of the HMG domain and a nuclear export sequence (NES in the middle).

Expression

SOX10 expression is first detected during embryonic development in the emerging neural crest and continues transiently or permanently in many non-ectomesenchymal derivates of the neural crest including melanocytes, adrenal medulla and the developing peripheral nervous system. Within the developing central nervous system SOX10 marks cells of the oligodendrocyte lineage. In the adult, SOX10 is predominantly found in oligodendrocytes, peripheral glial cells, melanocytes and adult neural crest stem cell populations.

Localisation

SOX10 is predominantly found in the nucleus as expected for a transcription factor but possesses the ability to shuttle between cytoplasm and nucleus because of the presence of both NLS and NES in the protein.

Function

SOX10 has multiple roles during development. In neural crest stem cells, SOX10 is needed for self-renewal, survival and maintenance of pluripotency. SOX10 is furthermore required for specification of melanocytes and peripheral glia from the neural crest. After specification, SOX10 continues to be essential for lineage progression and maintenance of identity in peripheral glia. Terminal differentiation of oligodendrocytes also depends on SOX10. SOX10 exerts these functions through interactions with different sets of transcription factors. SOX10 probably shares further roles with its close relatives SOX9 and SOX8 with which it is co-expressed in several cell types and functions in a partly redundant manner.

Homology

SOX10 is highly conserved among vertebrates. Human SOX10 shares 98% identity with Mus musculus Sox10, 97% identity with Sox10 from Rattus norvegicus and Canis lupus familiaris, 96% identity with Bos taurus Sox10 and 82% identity with Gallus gallus Sox10.

Mutations

Note

SOX10 mutations have so far primarily been identified as a cause for neurocristopathies including WS4C, WS2E with or without neurologic involvement, PCWH syndrome and Yemenite deaf-bling hypopigmentation syndrome.

Germinal

Missense mutations: S135T, A157V, Q174P.
Nonsense mutations: R43X, T83X, T173X, E189X, T207X, Q234X, Q250X, S251X, T313X, S346X, Q364X, Q372X, S376X, Q377X.
Insertions: (L160 R161) dup.
Carboxy terminal extensions: X467C ext82, X467L ext86, X467T ext86.
Frameshift mutations: S17C fsX17, E57S fsX57, A110L fsX2, P169R fsX117, R215P fsX64, R261A fsX25, G266A fsX20, I271S fsX15, H283L fsX11, H306T fsX5, G308A fsX3, V350C fsX52, A354P fsX3, E359D fsX42, Q399V fsX2.
Splice mutations: int3 pos.428 +2T>G, int4 pos.698 -2A>C.

Somatic

Missense mutations: R43Q, Q125X, A361V, G413S, G413D, H414Y, A424V.
Frameshift mutations: P14P fsX10, S449S fsX66.

Implicated in

Entity name
Melanoma
Note
SOX10 is expressed homogenously in primary and metastatic melanoma and was identified as a melanoma tumor antigen. It is often co-expressed with its relative SOX9. Somatic SOX10 mutations occur in early stage melanoma. SOX10 upregulates MITF, MET and Nestin expression in melanoma and responds to Wnt signals. Its nuclear localization is controlled by the Tam tyrosine receptor kinase Tyro3 and its activity is modulated by the transcription factor SOX5. In sentinel lymph nodes, SOX10 is a reliable marker for metastatic melanoma.
Note
SOX10 is widely expressed in clear cell sarcoma where it cooperates with EWS-ATF1 fusions in MITF activation.
Entity name
Malignant nerve sheath tumor (MNST)
Note
SOX10 is present in MNST. Expression levels appear lower than the ones in plexiform neurofibromas from which MNST arise or in Schwann cells. SOX10 expression levels are positively correlated with ErbB3 levels and inversely correlated with SOX9 levels.
Entity name
Schwannoma
Note
Homogenous SOX10 expression has been detected throughout this neoplasm.
Entity name
Ganglioneuroma
Note
SOX10 expression has been detected. Levels decrease with increasing grade.
Entity name
Glioma
Note
SOX10 transcripts and protein were found in astrocytoma, oligodendroglioma and glioblastoma. Expression levels and number of expressing cells within the tumor usually diminish with advancing grade and malignant progression. SOX10 levels are particularly high in pilocytic astrocytoma. No correlation with 1p and 19q deletions has been detected. In a mouse model, SOX10 has been found to act synergistically with PDGF during glioma development, although it was not sufficient to induce gliomagenesis on its own.

Article Bibliography

Pubmed IDLast YearTitleAuthors

Other Information

Locus ID:

NCBI: 6663
MIM: 602229
HGNC: 11190
Ensembl: ENSG00000100146

Variants:

dbSNP: 6663
ClinVar: 6663
TCGA: ENSG00000100146
COSMIC: SOX10

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000100146ENST00000360880P56693
ENSG00000100146ENST00000360880A0A024R1N6
ENSG00000100146ENST00000396884P56693
ENSG00000100146ENST00000396884A0A024R1N6
ENSG00000100146ENST00000427770A6PVD3
ENSG00000100146ENST00000446929H0Y5N4
ENSG00000100146ENST00000651746A0A494C0R1

Protein levels (Protein atlas)

Not detected
Low
Medium
High

PharmGKB

Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA445204Ovarian NeoplasmsDiseaseClinicalAnnotationassociatedPD23963862
PA448803carboplatinChemicalClinicalAnnotationassociatedPD23963862
PA449383docetaxelChemicalClinicalAnnotationassociatedPD23963862
PA450761paclitaxelChemicalClinicalAnnotationassociatedPD23963862

References

Pubmed IDYearTitleCitations
378472392024SOX10 Loss Sensitizes Melanoma Cells to Cytokine-Mediated Inflammatory Cell Death.1
382669202024SOX10-Internal Tandem Duplications and PLAG1 or HMGA2 Fusions Segregate Eccrine-Type and Apocrine-Type Cutaneous Mixed Tumors.0
384193872024A novel frameshift mutation in SOX10 gene induced Waardenburg syndrome type II.1
384930962024Aberrant SOX10 and RET expressions in patients with Hirschsprung disease.0
386590112024Waardenburg syndrome type 2 with a de novo variant of the SOX10 gene: a case report.0
378472392024SOX10 Loss Sensitizes Melanoma Cells to Cytokine-Mediated Inflammatory Cell Death.1
382669202024SOX10-Internal Tandem Duplications and PLAG1 or HMGA2 Fusions Segregate Eccrine-Type and Apocrine-Type Cutaneous Mixed Tumors.0
384193872024A novel frameshift mutation in SOX10 gene induced Waardenburg syndrome type II.1
384930962024Aberrant SOX10 and RET expressions in patients with Hirschsprung disease.0
386590112024Waardenburg syndrome type 2 with a de novo variant of the SOX10 gene: a case report.0
366690742023Staged Excision of Lentigo Maligna of the Head and Neck: Assessing Surgical Excision Margins With Melan A, SOX10, and PRAME Immunohistochemistry.2
369748072023SOX10 Inhibits T Cell Recognition by Inducing Expression of the Immune Checkpoint Molecule PD-L1 in A375 Melanoma Cells.4
371623372023Gallbladder cancer-associated genetic variants rs1003349 and rs1004030 regulate MMP14 expression by altering SOX10- and MYB-binding sites.1
373365492023SOX10.0
374369632023Novel SOX10 indel mutations drive schwannomas through impaired transactivation of myelination gene programs.5

Citation

Michael Wegner

SOX10 (SRY (sex determining region Y)-box 10)

Atlas Genet Cytogenet Oncol Haematol. 2010-04-01

Online version: http://atlasgeneticsoncology.org/gene/43768/haematological-explorer/case-report-explorer/deep-insight-explorer/