The PIK3R1 gene provides instructions for making a part (subunit) of an enzyme called phosphatidylinositol 3-kinase (PI3K). The primary function of the subunit is to regulate the enzyme's activity. Several slightly different versions of this regulatory subunit are produced from the PIK3R1 gene; the most abundant of these is called p85α.
PI3K is a kinase, which means that it adds a cluster of oxygen and phosphorus atoms (a phosphate group) to other proteins through a process called phosphorylation. PI3K phosphorylates certain signaling molecules, which triggers a series of additional reactions that transmit chemical signals within cells. PI3K signaling is important for many cell activities, including cell growth and division, movement (migration) of cells, production of new proteins, transport of materials within cells, and cell survival. Studies suggest that PI3K signaling may be involved in the regulation of several hormones, including insulin, which helps control blood sugar levels. PI3K signaling may also play a role in the maturation of fat cells (adipocytes).
Health Conditions Related to Genetic Changes
Short stature, hyperextensibility, hernia, ocular depression, Rieger anomaly, and teething delay
At least seven mutations in the PIK3R1 gene have been reported to cause a condition known as short stature, hyperextensibility, hernia, ocular depression, Rieger anomaly, and teething delay (often called SHORT syndrome). This condition is characterized by signs and symptoms affecting many parts of the body, including the skin, eyes, teeth, and joints. The most common mutation, which has been identified in at least 10 affected families, changes a single protein building block (amino acid) in the regulatory subunit of PI3K. Specifically, the amino acid arginine is replaced with the amino acid tryptophan at protein position 649 (written as Arg649Trp or R649W). Mutations in the PIK3R1 gene alter the structure of the subunit, which reduces the ability of PI3K to participate in cell signaling. Because the mutations reduce the enzyme's activity, they are described as "loss-of-function" mutations.
Researchers are working to determine how PIK3R1 gene mutations lead to the specific features of SHORT syndrome. PI3K's role in insulin activity may be related to insulin resistance and diabetes, which are problems with blood sugar regulation that are found in some people with SHORT syndrome. Abnormal adipocyte maturation might contribute to a lack of fatty tissue under the skin (lipoatrophy), which is another common feature of the condition. It is unclear how reduced PI3K signaling is associated with the other signs and symptoms of SHORT syndrome.More About This Health Condition
Some gene mutations are acquired during a person's lifetime and are present only in certain cells. These changes, which are called somatic mutations, are not inherited. Somatic PIK3R1 gene mutations have been identified in some cancers of the uterine lining (endometrial cancers) and in a form of brain cancer called glioblastoma. Less commonly, somatic mutations in the PIK3R1 gene have been found in cancers of the colon, ovary, and breast.
Cancer-associated changes in the PIK3R1 gene alter the regulatory subunit such that it can no longer control the activity of PI3K, which increases PI3K signaling dramatically. Because the genetic changes enhance the activity of the enzyme, they are classified as "gain-of-function" mutations. Increased PI3K signaling appears to promote the uncontrolled cell growth and division that is characteristic of cancerous tumors. It is unclear why these mutations seem to be more common in some types of cancer than in others.
Other Names for This Gene
- phosphatidylinositol 3-kinase 85 kDa regulatory subunit alpha
- phosphatidylinositol 3-kinase regulatory subunit alpha
- phosphatidylinositol 3-kinase, regulatory subunit, polypeptide 1 (p85 alpha)
- phosphatidylinositol 3-kinase-associated p-85 alpha
- phosphoinositide-3-kinase regulatory subunit
- phosphoinositide-3-kinase, regulatory subunit 1 (alpha)
- PI3-kinase subunit p85-alpha
- PI3K regulatory subunit alpha
- ptdIns-3-kinase regulatory subunit alpha
Additional Information & Resources
Tests Listed in the Genetic Testing Registry
Scientific Articles on PubMed
Catalog of Genes and Diseases from OMIM
- Chudasama KK, Winnay J, Johansson S, Claudi T, König R, Haldorsen I, Johansson B, Woo JR, Aarskog D, Sagen JV, Kahn CR, Molven A, Njølstad PR. SHORT syndrome with partial lipodystrophy due to impaired phosphatidylinositol 3 kinase signaling. Am J Hum Genet. 2013 Jul 11;93(1):150-7. doi: 10.1016/j.ajhg.2013.05.023. Epub 2013 Jun 27. Citation on PubMed or Free article on PubMed Central
- Dyment DA, Smith AC, Alcantara D, Schwartzentruber JA, Basel-Vanagaite L, Curry CJ, Temple IK, Reardon W, Mansour S, Haq MR, Gilbert R, Lehmann OJ, Vanstone MR, Beaulieu CL; FORGE Canada Consortium, Majewski J, Bulman DE, O'Driscoll M, Boycott KM, Innes AM. Mutations in PIK3R1 cause SHORT syndrome. Am J Hum Genet. 2013 Jul 11;93(1):158-66. doi: 10.1016/j.ajhg.2013.06.005. Epub 2013 Jun 27. Citation on PubMed or Free article on PubMed Central
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- Mellor P, Furber LA, Nyarko JN, Anderson DH. Multiple roles for the p85α isoform in the regulation and function of PI3K signalling and receptor trafficking. Biochem J. 2012 Jan 1;441(1):23-37. doi: 10.1042/BJ20111164. Review. Citation on PubMed
- Philp AJ, Campbell IG, Leet C, Vincan E, Rockman SP, Whitehead RH, Thomas RJ, Phillips WA. The phosphatidylinositol 3'-kinase p85alpha gene is an oncogene in human ovarian and colon tumors. Cancer Res. 2001 Oct 15;61(20):7426-9. Citation on PubMed
- Quayle SN, Lee JY, Cheung LW, Ding L, Wiedemeyer R, Dewan RW, Huang-Hobbs E, Zhuang L, Wilson RK, Ligon KL, Mills GB, Cantley LC, Chin L. Somatic mutations of PIK3R1 promote gliomagenesis. PLoS One. 2012;7(11):e49466. doi: 10.1371/journal.pone.0049466. Epub 2012 Nov 14. Citation on PubMed or Free article on PubMed Central
- Schroeder C, Riess A, Bonin M, Bauer P, Riess O, Döbler-Neumann M, Wieser S, Moog U, Tzschach A. PIK3R1 mutations in SHORT syndrome. Clin Genet. 2014 Sep;86(3):292-4. doi: 10.1111/cge.12263. Epub 2013 Oct 17. Citation on PubMed
- Thauvin-Robinet C, Auclair M, Duplomb L, Caron-Debarle M, Avila M, St-Onge J, Le Merrer M, Le Luyer B, Héron D, Mathieu-Dramard M, Bitoun P, Petit JM, Odent S, Amiel J, Picot D, Carmignac V, Thevenon J, Callier P, Laville M, Reznik Y, Fagour C, Nunes ML, Capeau J, Lascols O, Huet F, Faivre L, Vigouroux C, Rivière JB. PIK3R1 mutations cause syndromic insulin resistance with lipoatrophy. Am J Hum Genet. 2013 Jul 11;93(1):141-9. doi: 10.1016/j.ajhg.2013.05.019. Epub 2013 Jun 27. Citation on PubMed or Free article on PubMed Central
- Urick ME, Rudd ML, Godwin AK, Sgroi D, Merino M, Bell DW. PIK3R1 (p85α) is somatically mutated at high frequency in primary endometrial cancer. Cancer Res. 2011 Jun 15;71(12):4061-7. doi: 10.1158/0008-5472.CAN-11-0549. Epub 2011 Apr 8. Citation on PubMed or Free article on PubMed Central