On this page
SKI
SKI proto-oncogene
The SKI gene provides instructions for making a protein that regulates cellular growth, division, and differentiation, primarily by modulating the transforming growth factor beta (TGF-β) signalling pathway. The SKI proto-oncogene encodes a protein crucial for various cellular processes, including growth, differentiation, and movement.
SKI is located on the short (p) arm of chromosome 1, at band 1p36.33-p36.32. Arm ratio per GRCh38 - banding schematic.
Explore chromosome 1 in the library →Available at Jeen Health
Clinical tests that include this
Overview
The SKI gene, also known as SKI proto-oncogene, plays a vital role in cellular regulation and development across the human body. It provides the genetic blueprint for a protein involved in a critical signalling pathway known as the transforming growth factor beta (TGF-β) pathway.
This pathway is fundamental for transmitting chemical signals from the cell's exterior to its nucleus, thereby influencing processes such as cell growth, proliferation, differentiation, and programmed cell death. Dysregulation of the SKI gene or its protein can therefore impact fundamental biological functions and contribute to various developmental conditions.
What the gene does
The SKI protein primarily functions as a regulator of the transforming growth factor beta (TGF-β) signalling pathway, a crucial system for cellular communication. This pathway allows external environmental signals to dictate how a cell produces proteins, thereby controlling essential mechanisms like cell growth, division (proliferation), maturation into specialised cells (differentiation), cell movement (motility), and programmed cell death (apoptosis).
Within this pathway, the SKI protein influences the activity of a group of proteins called the SMAD complex. When activated, the SMAD complex typically translocates to the cell nucleus, where it binds to specific DNA regions to regulate the activity of target genes. The SKI protein controls this process by binding directly to certain SMAD proteins, which then interrupts the signalling cascade. This binding can prevent the SMAD complex from entering the nucleus and activating genes.
Alternatively, if the SMAD complex does reach the nucleus and binds to DNA, the SKI protein can recruit other proteins known as co-repressors. These co-repressors then block the SMAD complex's ability to activate genes. The SKI protein is widely distributed throughout the body and is believed to contribute significantly to the development of various tissues, including the skull, other bones, skin, and the brain.
Video: Genetics 101
Chromosome location
The SKI gene is situated on the short arm of chromosome 1, specifically within the region designated 1p36.33-p36.32. This genomic location indicates its position on the human genome. The gene encodes a protein that is 728 amino acids in length.
Protein structure
The SKI protein comprises several distinct functional regions essential for its regulatory roles. It contains two identified disordered regions. One disordered region spans amino acids 321-357, and another is located between amino acids 452-542. Additionally, the protein features a coiled-coil domain, which is a structural motif often involved in protein-protein interactions, found between amino acids 536-710. These domains are crucial for the SKI protein's interaction with other cellular components, particularly SMAD proteins, to modulate the TGF-β signalling pathway.
Key variants
Genetic variants in the SKI gene can lead to alterations in the structure or function of the encoded protein, potentially disrupting its regulatory role in the TGF-β signalling pathway. These variants can include changes to single protein building blocks (amino acids), insertions, deletions, or other modifications that impact protein stability or interaction capabilities. The consequence of a specific variant depends on its location within the gene and its effect on the protein's overall function and domain integrity.
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.100G>A | p.Gly34Ser | Pathogenic/Likely pathogenic | ★★☆☆ | Inborn genetic diseases |
c.100G>T | p.Gly34Cys | Pathogenic | ★★☆☆ | Inborn genetic diseases |
c.101G>T | p.Gly34Val | Pathogenic | ★★☆☆ | Shprintzen-Goldberg syndrome |
c.103C>T | p.Pro35Ser | Pathogenic | ★★☆☆ | Familial thoracic aortic aneurysm and aortic dissection |
c.265C>T | p.Pro89Ser | Pathogenic | ★★☆☆ | Shprintzen-Goldberg syndrome |
c.347G>A | p.Gly116Glu | Pathogenic/Likely pathogenic | ★★☆☆ | Shprintzen-Goldberg syndrome |
c.349G>A | p.Gly117Ser | Pathogenic/Likely pathogenic | ★★☆☆ | Shprintzen-Goldberg syndrome |
c.349G>C | p.Gly117Arg | Pathogenic/Likely pathogenic | ★★☆☆ | Shprintzen-Goldberg syndrome |
c.539C>A | p.Thr180Lys | Pathogenic/Likely pathogenic | ★★☆☆ | Disproportionate tall stature |
c.539C>T | p.Thr180Met | Pathogenic/Likely pathogenic | ★★☆☆ | Familial thoracic aortic aneurysm and aortic dissection |
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 SKI gene are associated with several inherited conditions, reflecting its crucial role in development and cellular regulation. One notable condition linked to SKI gene variants is Shprintzen-Goldberg syndrome. This syndrome is characterised by distinctive facial features, skeletal abnormalities, and intellectual disability. Many of the identified variants in SKI that cause Shprintzen-Goldberg syndrome affect the protein region responsible for binding to SMAD proteins, thereby impairing its ability to modulate the TGF-β pathway.
UK clinical status
The SKI gene is relevant within the UK National Health Service (NHS) Genomic Medicine Service (GMS) pathways, as evidenced by its inclusion in several diagnostic panels. It is listed in NHS England's PanelApp for conditions such as Arthrogryposis (R83), Clefting, Ehlers Danlos syndrome with a likely monogenic cause (R101), Foetal anomalies (R21), Hydrocephalus (R86), Intellectual disability (R29), Rare syndromic craniosynostosis or isolated multisuture synostosis (R100), Skeletal dysplasia (R104), and Thoracic aortic aneurysm or dissection (R125).
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Diet & lifestyle considerations
Research suggests that general healthy lifestyle practices, including a balanced diet and regular physical activity, contribute to overall well-being. However, there is no conclusive evidence to suggest that specific lifestyle interventions can prevent or directly mitigate the effects of conditions associated with SKI gene variants. For individuals with genetic predispositions, lifestyle choices are generally aimed at promoting overall health and may be part of a broader health management plan developed in consultation with a healthcare provider.
Supplement considerations
Currently, there is no conclusive scientific evidence indicating that specific nutritional supplements can prevent or treat conditions associated with variants in the SKI gene. While a balanced diet is important for overall health, individuals should always consult with a healthcare professional before considering any new supplements, especially in the context of a genetic condition. This ensures that any choices made are safe and appropriate for their individual health needs.
Frequently asked questions
What is the primary function of the SKI gene?
The SKI gene provides instructions for making a protein that primarily regulates the transforming growth factor beta (TGF-β) signalling pathway, influencing cell growth, division, differentiation, and programmed cell death.
What is Shprintzen-Goldberg syndrome?
Shprintzen-Goldberg syndrome is an inherited condition characterised by distinctive facial features, skeletal abnormalities, and intellectual disability, often linked to variants in the SKI gene.
How does the SKI protein affect the SMAD complex?
The SKI protein binds to SMAD proteins, either preventing them from entering the cell nucleus or, once in the nucleus, recruiting other proteins to block their ability to activate target genes.
Is the SKI gene associated with cancer?
The SKI gene is classified as a proto-oncogene, meaning that under certain circumstances, alterations could potentially contribute to uncontrolled cell growth, a hallmark of cancer. However, its primary association discussed here is with developmental conditions.
Where is the SKI gene located?
The SKI gene is located on the short arm of chromosome 1, specifically within the region 1p36.33-p36.32.
References
- Doyle AJ, Doyle JJ, Bessling SL. Mutations in the TGF-β repressor SKI cause Shprintzen-Goldberg syndrome with aortic aneurysm. Nature genetics. 2012. PMID: 23023332
- Carmignac V, Thevenon J, Adès L. In-frame mutations in exon 1 of SKI cause dominant Shprintzen-Goldberg syndrome. American journal of human genetics. 2012. PMID: 23103230
- Deheuninck J, Luo K. Ski and SnoN, potent negative regulators of TGF-beta signaling. Cell research. 2009. PMID: 19114989
- Suzuki H, Yagi K, Kondo M. c-Ski inhibits the TGF-beta signaling pathway through stabilization of inactive Smad complexes on Smad-binding elements. Oncogene. 2004. PMID: 15107821