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SOX9
SRY-box transcription factor 9
The SOX9 gene provides instructions for a transcription factor protein essential for embryonic development, particularly in skeletal formation and sex determination. The SOX9 gene codes for a protein that acts as a transcription factor, regulating other genes involved in critical developmental processes.
SOX9 is located on the long (q) arm of chromosome 17, at band 17q24.3. Arm ratio per GRCh38 - banding schematic.
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Overview
The SOX9 gene, or SRY-box transcription factor 9, plays a pivotal role in human embryonic development. It provides the genetic blueprint for a protein that governs the activity of many other genes. This regulatory function is especially important for the formation of the skeleton and for the processes that determine sex in a developing embryo.
Disruptions in the SOX9 gene can lead to a range of developmental abnormalities, underscoring its critical role in these complex biological pathways.
What the gene does
The SOX9 protein operates as a transcription factor, meaning it binds to specific regions of DNA to control the expression of other genes. This regulatory action is fundamental for proper skeletal development, influencing the differentiation and maturation of cartilage and bone cells. Furthermore, SOX9 is a key regulator in sex determination, particularly in the development of male characteristics in an embryo. It initiates a cascade of genetic events necessary for the formation of testes.
By modulating the activity of target genes, SOX9 orchestrates complex developmental programmes, ensuring the correct formation of tissues and organs during embryogenesis.
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Chromosome location
The SOX9 gene is located on chromosome 17, specifically at position 17q24.3. This precise genomic address helps in understanding the gene's organisation within the human genome and its proximity to other genes that may be involved in related biological processes.
Protein structure
The SOX9 protein is 509 amino acids long and features several distinct domains. It contains multiple Disordered regions: amino acids 1-67, 160-273, 330-415, and 479-509. A Dimerization (DIM) region and a PQA region are found between amino acids 63-103. A crucial HMG box (DNA binding) domain is located from amino acids 105-173, responsible for its transcription factor activity. The protein also includes two Transactivation domains, TAM (amino acids 224-307) and TAC (amino acids 394-509), which contain 9aaTAD 1 (amino acids 275-284), 9aaTAD 2 (amino acids 290-298), and 9aaTAD 3 (amino acids 460-468) motifs.
Key variants
Genetic changes, or variants, within the SOX9 gene can alter the function of the SOX9 protein. These alterations can range from small changes in the DNA sequence to larger deletions or duplications. The impact of these variants varies, potentially leading to reduced protein function or, in some cases, a complete absence of the protein. The clinical consequences depend on the specific nature and location of the variant.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1018C>T | p.Gln340Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Camptomelic dysplasia |
c.1069C>T | p.Gln357Ter | Pathogenic | ★★☆☆ | Camptomelic dysplasia |
c.1180C>T | p.Arg394Ter | Pathogenic | ★★☆☆ | Camptomelic dysplasia |
c.1320C>A | p.Tyr440Ter | Pathogenic | ★★☆☆ | Camptomelic dysplasia |
c.1320C>G | p.Tyr440Ter | Pathogenic | ★★☆☆ | CAMPOMELIC DYSPLASIA WITH AUTOSOMAL SEX REVERSAL |
c.331G>A | p.Ala111Thr | Pathogenic/Likely pathogenic | ★★☆☆ | Inborn genetic diseases |
c.337A>G | p.Met113Val | Pathogenic | ★★☆☆ | not provided |
c.432-2A>T | - | Pathogenic | ★★☆☆ | Camptomelic dysplasia |
c.442G>T | p.Glu148Ter | Pathogenic | ★★☆☆ | Camptomelic dysplasia |
c.455G>C | p.Arg152Pro | Pathogenic/Likely pathogenic | ★★☆☆ | Camptomelic dysplasia |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Variants in the SOX9 gene are associated with several inherited conditions, primarily Campomelic dysplasia, a severe disorder affecting skeletal development and sex determination. Other conditions linked to SOX9 variants include isolated Pierre Robin sequence, characterised by specific craniofacial anomalies, and certain forms of differences in sex development, such as 46,XX testicular difference of sex development and Swyer syndrome.
Inheritance pattern
Conditions caused by pathogenic SOX9 variants typically follow autosomal dominant inheritance.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
UK clinical status
SOX9 is recognised in the UK by the NHS Genomic Medicine Service. It is featured on several national germline genetic testing panels, including those for Clefting, DDG2P, Differences in sex development (R146), Foetal anomalies (R21), and Skeletal dysplasia (R104), all of which are categorised as 'green', indicating they are routinely evaluated for clinical sequencing.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main function of the SOX9 gene?
The SOX9 gene provides instructions for making a protein that acts as a transcription factor, which means it regulates the activity of other genes. It is crucial for embryonic development, especially for skeletal formation and sex determination.
Which conditions are associated with SOX9 gene variants?
Variants in the SOX9 gene are primarily associated with Campomelic dysplasia, a severe developmental disorder. They can also be linked to isolated Pierre Robin sequence and certain differences in sex development, such as 46,XX testicular difference of sex development and Swyer syndrome.
How does SOX9 influence sex determination?
The SOX9 protein plays a key role in sex determination by initiating the developmental cascade that leads to the formation of male characteristics, specifically the development of the testes, in an embryo.
References
- Alankarage D, Lavery R, Svingen T. SOX9 regulates expression of the male fertility gene Ets variant factor 5 (ETV5) during mammalian sex development. The international journal of biochemistry & cell biology. 2016. PMID: 27498191
- Gordon CT, Attanasio C, Bhatia S. Identification of novel craniofacial regulatory domains located far upstream of SOX9 and disrupted in Pierre Robin sequence. Human mutation. 2014. PMID: 24934569
- Mead TJ, Wang Q, Bhattaram P. A far-upstream (-70 kb) enhancer mediates Sox9 auto-regulation in somatic tissues during development and adult regeneration. Nucleic acids research. 2013. PMID: 23449223
- Amarillo IE, Dipple KM, Quintero-Rivera F. Familial microdeletion of 17q24.3 upstream of SOX9 is associated with isolated Pierre Robin sequence due to position effect. American journal of medical genetics. Part A. 2013. PMID: 23532965
- Fonseca AC, Bonaldi A, Bertola DR. The clinical impact of chromosomal rearrangements with breakpoints upstream of the SOX9 gene: two novel de novo balanced translocations associated with acampomelic campomelic dysplasia. BMC medical genetics. 2013. PMID: 23648064
- Benko S, Fantes JA, Amiel J. Highly conserved non-coding elements on either side of SOX9 associated with Pierre Robin sequence. Nature genetics. 2009. PMID: 19234473
- Leipoldt M, Erdel M, Bien-Willner GA. Two novel translocation breakpoints upstream of SOX9 define borders of the proximal and distal breakpoint cluster region in campomelic dysplasia. Clinical genetics. 2007. PMID: 17204049
- Bien-Willner GA, Stankiewicz P, Lupski JR. SOX9cre1, a cis-acting regulatory element located 1.1 Mb upstream of SOX9, mediates its enhancement through the SHH pathway. Human molecular genetics. 2007. PMID: 17409199
- Hill-Harfe KL, Kaplan L, Stalker HJ. Fine mapping of chromosome 17 translocation breakpoints > or = 900 Kb upstream of SOX9 in acampomelic campomelic dysplasia and a mild, familial skeletal dysplasia. American journal of human genetics. 2005. PMID: 15717285
- Velagaleti GV, Bien-Willner GA, Northup JK. Position effects due to chromosome breakpoints that map approximately 900 Kb upstream and approximately 1.3 Mb downstream of SOX9 in two patients with campomelic dysplasia. American journal of human genetics. 2005. PMID: 15726498
- Kobayashi A, Chang H, Chaboissier MC. Sox9 in testis determination. Annals of the New York Academy of Sciences. 2005. PMID: 16467253