MED12 Gene

mediator complex subunit 12

genes

1. Introduction

Normal Function

The MED12 gene provides instructions for making a protein called mediator complex subunit 12. As its name suggests, this protein forms one part (subunit) of the mediator complex, which is a group of about 25 proteins that work together to regulate gene activity. The mediator complex physically links transcription factors, which are proteins that influence whether genes are turned on or off, with an enzyme called RNA polymerase II. Once transcription factors are attached, this enzyme initiates gene transcription, the process by which information stored in a gene's DNA is used to build proteins.

Researchers believe that the MED12 protein is involved in many aspects of early development, including the development of nerve cells (neurons) in the brain. The MED12 protein is part of several chemical signaling pathways within cells. These pathways help direct a broad range of cellular activities, such as cell growth, cell movement (migration), and the process by which cells mature to carry out specific functions (differentiation).

Researchers believe that the MED12 protein is involved in many aspects of early development, including the development of nerve cells (neurons) in the brain. The MED12 protein is part of several chemical signaling pathways within cells. These pathways help direct a broad range of cellular activities, such as cell growth, cell movement (migration), and the process by which cells mature to carry out specific functions (differentiation).

2. Health Conditions Related to Genetic Changes

2.1.

FG syndrome

At least two mutations in the MED12 gene have been found to cause FG syndrome, which is characterized by intellectual disability, behavioral problems, and physical abnormalities including weak muscle tone (hypotonia) and obstruction of the anal opening (imperforate anus).

The mutations that cause FG syndrome each change a single protein building block (amino acid) in the MED12 protein. One mutation replaces the amino acid arginine with the amino acid tryptophan at protein position 961 (written as Arg961Trp or R961W). The other replaces the amino acid glycine with the amino acid glutamic acid at protein position 958 (written as Gly958Glu or G958E). These mutations alter the structure of the MED12 protein, which likely disrupts its ability to regulate gene activity during development. However, it is unclear how the genetic changes lead to intellectual disability and the other features of FG syndrome.

2.2.

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Lujan syndrome

At least one mutation in the MED12 gene causes Lujan syndrome, a disorder characterized by intellectual disability, behavioral problems, and physical features including tall stature and a long, narrow face. This mutation is different than the genetic changes associated with FG syndrome (described above); the Lujan syndrome mutation replaces the amino acid asparagine with the amino acid serine at position 1007 of the MED12 protein (written as Asn1007Ser or N1007S). The mutation alters the structure of the MED12 protein and likely disrupts its ability to regulate gene activity, but it is not known how these changes affect development and lead to the specific features of Lujan syndrome.

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At least one mutation in the MED12 gene causes Lujan syndrome, a disorder characterized by intellectual disability, behavioral problems, and physical features including tall stature and a long, narrow face. This mutation is different than the genetic changes associated with FG syndrome (described above); the Lujan syndrome mutation replaces the amino acid asparagine with the amino acid serine at position 1007 of the MED12 protein (written as Asn1007Ser or N1007S). The mutation alters the structure of the MED12 protein and likely disrupts its ability to regulate gene activity, but it is not known how these changes affect development and lead to the specific features of Lujan syndrome.

Ohdo syndrome, Maat-Kievit-Brunner type

At least three MED12 gene mutations have been found to cause the Maat-Kievit-Brunner type of Ohdo syndrome, which is a rare condition characterized by intellectual disability and distinctive facial features. The mutations that cause this disorder change single amino acids in the MED12 gene, although they are not the same genetic changes that cause FG syndrome or Lujan syndrome (described above). The mutations that result in the Maat-Kievit-Brunner type of Ohdo syndrome change the structure of the MED12 gene, impairing its ability to control gene activity. It is unclear how these changes lead to the particular cognitive and physical features of the disorder.

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3. Ohdo syndrome, Maat-Kievit-Brunner type

Prostate cancer

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At least three MED12 gene mutations have been found to cause the Maat-Kievit-Brunner type of Ohdo syndrome, which is a rare condition characterized by intellectual disability and distinctive facial features. The mutations that cause this disorder change single amino acids in the MED12 gene, although they are not the same genetic changes that cause FG syndrome or Lujan syndrome (described above). The mutations that result in the Maat-Kievit-Brunner type of Ohdo syndrome change the structure of the MED12 gene, impairing its ability to control gene activity. It is unclear how these changes lead to the particular cognitive and physical features of the disorder.

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3.1.

Tumors

Some gene mutations are acquired during a person's lifetime and are present only in certain cells. These changes, which are known as somatic mutations, are not inherited. Somatic mutations in the MED12 gene have been found in several types of tumors, both noncancerous and cancerous.

Some gene mutations are acquired during a person's lifetime and are present only in certain cells. These changes, which are known as somatic mutations, are not inherited. Somatic mutations in the MED12 gene have been found in several types of tumors, both noncancerous and cancerous.

Somatic MED12 gene mutations are present in most uterine leiomyomas, which are noncancerous growths also known as uterine fibroids. Uterine leiomyomas are common in adult women. These growths can cause pelvic pain and abnormal bleeding, and, in some cases, lead to an inability to have biological children (infertility). Somatic MED12 gene mutations have also been identified in some cancerous uterine tumors, including leiomyosarcomas and smooth muscle tumors of uncertain malignant potential (STUMP), and in some prostate and colorectal cancers.

Somatic MED12 gene mutations are present in most uterine leiomyomas, which are noncancerous growths also known as uterine fibroids. Uterine leiomyomas are common in adult women. These growths can cause pelvic pain and abnormal bleeding, and, in some cases, lead to an inability to have biological children (infertility). Somatic MED12 gene mutations have also been identified in some cancerous uterine tumors, including leiomyosarcomas and smooth muscle tumors of uncertain malignant potential (STUMP), and in some prostate and colorectal cancers.

Studies suggest that somatic MED12 gene mutations alter the function of the MED12 protein, which likely disrupts normal cell signaling and impairs regulation of cell growth and other cell functions. As a result, certain cells may become able to divide in an uncontrolled way, leading to the growth of a tumor.

Studies suggest that somatic MED12 gene mutations alter the function of the MED12 protein, which likely disrupts normal cell signaling and impairs regulation of cell growth and other cell functions. As a result, certain cells may become able to divide in an uncontrolled way, leading to the growth of a tumor.

4. Other Names for This Gene

  • CAGH45
  • HOPA
  • KIAA0192
  • MED12_HUMAN
  • mediator of RNA polymerase II transcription, subunit 12 homolog
  • OKS
  • OPA-containing protein
  • OPA1
  • thyroid hormone receptor-associated protein, 230 kDa subunit
  • TNRC11
  • TRAP230

References

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  3. Je EM, Kim MR, Min KO, Yoo NJ, Lee SH. Mutational analysis of MED12 exon 2 in uterine leiomyoma and other common tumors. Int J Cancer. 2012 Sep15;131(6):E1044-7. doi: 10.1002/ijc.27610.
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  5. Lyons MJ. MED12-Related Disorders. 2008 Jun 23 [updated 2016 Aug 11]. In: AdamMP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle;1993-2020. Available from http://www.ncbi.nlm.nih.gov/books/NBK1676/
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  7. Philibert RA, Bohle P, Secrest D, Deaderick J, Sandhu H, Crowe R, Black DW.The association of the HOPA(12bp) polymorphism with schizophrenia in the NIMHGenetics Initiative for Schizophrenia sample. Am J Med Genet B NeuropsychiatrGenet. 2007 Sep 5;144B(6):743-7.
  8. Philibert RA, Madan A. Role of MED12 in transcription and human behavior.Pharmacogenomics. 2007 Aug;8(8):909-16. Review.
  9. Philibert RA. A meta-analysis of the association of the HOPA12bp polymorphism and schizophrenia. Psychiatr Genet. 2006 Apr;16(2):73-6.
  10. Pérot G, Croce S, Ribeiro A, Lagarde P, Velasco V, Neuville A, Coindre JM,Stoeckle E, Floquet A, MacGrogan G, Chibon F. MED12 alterations in both humanbenign and malignant uterine soft tissue tumors. PLoS One. 2012;7(6):e40015. doi:10.1371/journal.pone.0040015.
  11. Risheg H, Graham JM Jr, Clark RD, Rogers RC, Opitz JM, Moeschler JB, PeifferAP, May M, Joseph SM, Jones JR, Stevenson RE, Schwartz CE, Friez MJ. A recurrent mutation in MED12 leading to R961W causes Opitz-Kaveggia syndrome. Nat Genet.2007 Apr;39(4):451-3.
  12. Rump P, Niessen RC, Verbruggen KT, Brouwer OF, de Raad M, Hordijk R. A novelmutation in MED12 causes FG syndrome (Opitz-Kaveggia syndrome). Clin Genet. 2011 Feb;79(2):183-8. doi: 10.1111/j.1399-0004.2010.01449.x.
  13. Schwartz CE, Tarpey PS, Lubs HA, Verloes A, May MM, Risheg H, Friez MJ,Futreal PA, Edkins S, Teague J, Briault S, Skinner C, Bauer-Carlin A, SimensenRJ, Joseph SM, Jones JR, Gecz J, Stratton MR, Raymond FL, Stevenson RE. Theoriginal Lujan syndrome family has a novel missense mutation (p.N1007S) in theMED12 gene. J Med Genet. 2007 Jul;44(7):472-7.
  14. Vulto-van Silfhout AT, de Vries BB, van Bon BW, Hoischen A,Ruiterkamp-Versteeg M, Gilissen C, Gao F, van Zwam M, Harteveld CL, van Essen AJ,Hamel BC, Kleefstra T, Willemsen MA, Yntema HG, van Bokhoven H, Brunner HG, BoyerTG, de Brouwer AP. Mutations in MED12 cause X-linked Ohdo syndrome. Am J HumGenet. 2013 Mar 7;92(3):401-6. doi: 10.1016/j.ajhg.2013.01.007.
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