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Normal Function
The SKI gene provides instructions for making a protein involved in a signaling pathway that transmits chemical signals from the cell surface to the nucleus. This pathway, called the transforming growth factor beta (TGF-β) pathway, allows the environment outside the cell to affect how the cell produces other proteins. It helps regulate cell growth and division (proliferation), the process by which cells mature to carry out special functions (differentiation), cell movement (motility), and the self-destruction of cells (apoptosis). Through this pathway, a group of proteins called the SMAD complex is turned on (activated). The activated SMAD protein complex moves to the cell nucleus and attaches (binds) to specific areas of DNA to control the activity of particular genes, which help regulate various cellular processes.
The SKI protein controls the activity of the TGF-β pathway by binding to certain SMAD proteins, which interrupts signaling through the pathway. SKI protein binding within the cell can keep the SMAD protein complex from entering the nucleus, so it is unable to activate genes. Binding of the SKI protein can also occur in the nucleus. Although the SMAD complex binds to DNA, the SKI protein attracts other proteins (corepressors) that block its ability to turn genes on.
The SKI protein is found in many cell types throughout the body and appears to play a role in the development of many tissues, including the skull, other bones, skin, and brain.
Health Conditions Related to Genetic Changes
Shprintzen-Goldberg syndrome
At least 10 mutations in the SKI gene have been found in people with Shprintzen-Goldberg syndrome, a condition characterized by distinctive facial features, skeletal abnormalities, and intellectual disability. Most of these mutations change single protein building blocks (amino acids) in the SKI protein. Many of the mutations alter the region of the SKI protein that binds to SMAD proteins. It is thought that altered SKI proteins are unable to attach to SMAD proteins, which allows TGF-β signaling to continue uncontrolled. Excess TGF-β signaling changes the regulation of gene activity and likely disrupts development of many body systems, including the bones and brain, resulting in the wide range of signs and symptoms of Shprintzen-Goldberg syndrome.
More About This Health ConditionOther Names for This Gene
- proto-oncogene c-Ski
- ski oncogene
- ski oncoprotein
- SKI_HUMAN
- v-ski avian sarcoma viral oncogene homolog
- v-ski sarcoma viral oncogene homolog (avian)
Additional Information & Resources
Tests Listed in the Genetic Testing Registry
Scientific Articles on PubMed
Catalog of Genes and Diseases from OMIM
References
- Carmignac V, Thevenon J, Ades L, Callewaert B, Julia S, Thauvin-Robinet C, Gueneau L, Courcet JB, Lopez E, Holman K, Renard M, Plauchu H, Plessis G, De Backer J, Child A, Arno G, Duplomb L, Callier P, Aral B, Vabres P, Gigot N, Arbustini E, Grasso M, Robinson PN, Goizet C, Baumann C, Di Rocco M, Sanchez Del Pozo J, Huet F, Jondeau G, Collod-Beroud G, Beroud C, Amiel J, Cormier-Daire V, Riviere JB, Boileau C, De Paepe A, Faivre L. In-frame mutations in exon 1 of SKI cause dominant Shprintzen-Goldberg syndrome. Am J Hum Genet. 2012 Nov 2;91(5):950-7. doi: 10.1016/j.ajhg.2012.10.002. Epub 2012 Oct 25. Citation on PubMed or Free article on PubMed Central
- Deheuninck J, Luo K. Ski and SnoN, potent negative regulators of TGF-beta signaling. Cell Res. 2009 Jan;19(1):47-57. doi: 10.1038/cr.2008.324. Citation on PubMed or Free article on PubMed Central
- Doyle AJ, Doyle JJ, Bessling SL, Maragh S, Lindsay ME, Schepers D, Gillis E, Mortier G, Homfray T, Sauls K, Norris RA, Huso ND, Leahy D, Mohr DW, Caulfield MJ, Scott AF, Destree A, Hennekam RC, Arn PH, Curry CJ, Van Laer L, McCallion AS, Loeys BL, Dietz HC. Mutations in the TGF-beta repressor SKI cause Shprintzen-Goldberg syndrome with aortic aneurysm. Nat Genet. 2012 Nov;44(11):1249-54. doi: 10.1038/ng.2421. Epub 2012 Sep 30. Citation on PubMed or Free article on PubMed Central
- Suzuki H, Yagi K, Kondo M, Kato M, Miyazono K, Miyazawa K. c-Ski inhibits the TGF-beta signaling pathway through stabilization of inactive Smad complexes on Smad-binding elements. Oncogene. 2004 Jun 24;23(29):5068-76. doi: 10.1038/sj.onc.1207690. Citation on PubMed
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