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PPM1D gene
URL of this page: https://medlineplus.gov/genetics/gene/ppm1d/

PPM1D gene

protein phosphatase, Mg2+/Mn2+ dependent 1D

Normal Function

The PPM1D gene provides instructions for making an enzyme called protein phosphatase 1D. This enzyme plays an essential role in cell division, immune cell development, gene expression, and the process by which cells create energy from food (metabolism). This enzyme is present in many of the body's tissues, including the developing brain. 

Protein phosphatase 1D belongs to a group of enzymes known as the PP2C phosphatases, which help regulate cell development in response to environmental stress. The PP2C phosphatases turn on (activate) after attaching (binding) to charged molecules (ions) of manganese or magnesium. The activated enzyme can then regulate the activity of other proteins by removing a cluster of oxygen and phosphorous atoms (phosphate group) from that protein. This regulation helps repair DNA damage and return the cell to its normal state.

Protein phosphatase 1D specifically regulates tumor suppressors, such as tumor protein p53. Tumor suppressors are proteins that keep cells from growing and dividing too fast or in an uncontrolled way. By stopping cells with damaged DNA from dividing, tumor suppressors help prevent the development of tumors. Protein phosphatase 1D turns off proteins such as tumor protein p53 when they are no longer needed, which allows cells to continue growing and dividing. 

Protein phosphatase 1D is also thought to play a role in regulating areas of tightly packed DNA called heterochromatin. Because gene expression is lower when DNA is tightly packed than when DNA is loosely packed, protein phosphatase 1D helps to turn off (silence) regions of DNA that are not needed.

Health Conditions Related to Genetic Changes

Jansen-de Vries syndrome

Certain variants (sometimes called mutations) in the PPM1D gene can cause Jansen-de Vries syndrome, a developmental disorder that affects many parts of the body. The variants that cause Jansen-de Vries syndrome occur in particular segments of the PPM1D gene known as exon 5 or exon 6. These variants disrupt the gene's instructions, resulting in an enzyme that does not function as it should. Research suggests that this enzyme is not able to reach the cell's nucleus. Without enough functional enzyme, heterochromatin regulation is disrupted, which likely alters gene expression. Altered gene expression may affect the early development of the brain. Researchers are trying to learn exactly how variants in the PPM1D gene affect the early development of the brain and other body systems to cause the signs and symptoms of Jansen-de Vries syndrome. 

More About This Health Condition

Other Disorders

Variants in the PPM1D gene have been found in the tissues of people with various cancers, including breast cancer. These gene variants are known as somatic variants and are acquired during a person's lifetime. The variants are not inherited and are present only in certain cells. Variants in the PPM1D gene that are associated with cancer increase the activity of protein phosphatase 1D, which decreases the activity of tumor protein p53 and allows cancer cells to grow and divide. 

Other Names for This Gene

  • PP2C-DELTA
  • protein phosphatase 1D, magnesium-dependent, delta isoform
  • protein phosphatase 2C, delta isoform
  • wild-type p53-induced phosphatase 1
  • WIP1

Additional Information & Resources

Tests Listed in the Genetic Testing Registry

Scientific Articles on PubMed

Catalog of Genes and Diseases from OMIM

Gene and Variant Databases

References

  • Andrysik Z, Sullivan KD, Kieft JS, Espinosa JM. PPM1D suppresses p53-dependent transactivation and cell death by inhibiting the Integrated Stress Response. Nat Commun. 2022 Dec 1;13(1):7400. doi: 10.1038/s41467-022-35089-5. Citation on PubMed
  • Bradshaw N, Levdikov VM, Zimanyi CM, Gaudet R, Wilkinson AJ, Losick R. A widespread family of serine/threonine protein phosphatases shares a common regulatory switch with proteasomal proteases. Elife. 2017 May 20;6:e26111. doi: 10.7554/eLife.26111. Citation on PubMed
  • Jansen S, Geuer S, Pfundt R, Brough R, Ghongane P, Herkert JC, Marco EJ, Willemsen MH, Kleefstra T, Hannibal M, Shieh JT, Lynch SA, Flinter F, FitzPatrick DR, Gardham A, Bernhard B, Ragge N, Newbury-Ecob R, Bernier R, Kvarnung M, Magnusson EA, Wessels MW, van Slegtenhorst MA, Monaghan KG, de Vries P, Veltman JA; Deciphering Developmental Disorders Study; Lord CJ, Vissers LE, de Vries BB. De Novo Truncating Mutations in the Last and Penultimate Exons of PPM1D Cause an Intellectual Disability Syndrome. Am J Hum Genet. 2017 Apr 6;100(4):650-658. doi: 10.1016/j.ajhg.2017.02.005. Epub 2017 Mar 23. Citation on PubMed
  • Kamada R, Kudoh F, Ito S, Tani I, Janairo JIB, Omichinski JG, Sakaguchi K. Metal-dependent Ser/Thr protein phosphatase PPM family: Evolution, structures, diseases and inhibitors. Pharmacol Ther. 2020 Nov;215:107622. doi: 10.1016/j.pharmthera.2020.107622. Epub 2020 Jul 7. Citation on PubMed
  • Kleiblova P, Shaltiel IA, Benada J, Sevcik J, Pechackova S, Pohlreich P, Voest EE, Dundr P, Bartek J, Kleibl Z, Medema RH, Macurek L. Gain-of-function mutations of PPM1D/Wip1 impair the p53-dependent G1 checkpoint. J Cell Biol. 2013 May 13;201(4):511-21. doi: 10.1083/jcb.201210031. Epub 2013 May 6. Citation on PubMed
  • Lu X, Nannenga B, Donehower LA. PPM1D dephosphorylates Chk1 and p53 and abrogates cell cycle checkpoints. Genes Dev. 2005 May 15;19(10):1162-74. doi: 10.1101/gad.1291305. Epub 2005 May 3. Citation on PubMed
  • Ruark E, Snape K, Humburg P, Loveday C, Bajrami I, Brough R, Rodrigues DN, Renwick A, Seal S, Ramsay E, Duarte Sdel V, Rivas MA, Warren-Perry M, Zachariou A, Campion-Flora A, Hanks S, Murray A, Ansari Pour N, Douglas J, Gregory L, Rimmer A, Walker NM, Yang TP, Adlard JW, Barwell J, Berg J, Brady AF, Brewer C, Brice G, Chapman C, Cook J, Davidson R, Donaldson A, Douglas F, Eccles D, Evans DG, Greenhalgh L, Henderson A, Izatt L, Kumar A, Lalloo F, Miedzybrodzka Z, Morrison PJ, Paterson J, Porteous M, Rogers MT, Shanley S, Walker L, Gore M, Houlston R, Brown MA, Caufield MJ, Deloukas P, McCarthy MI, Todd JA; Breast and Ovarian Cancer Susceptibility Collaboration; Wellcome Trust Case Control Consortium; Turnbull C, Reis-Filho JS, Ashworth A, Antoniou AC, Lord CJ, Donnelly P, Rahman N. Mosaic PPM1D mutations are associated with predisposition to breast and ovarian cancer. Nature. 2013 Jan 17;493(7432):406-10. doi: 10.1038/nature11725. Epub 2012 Dec 16. Citation on PubMed
  • Wojcik MH, Srivastava S, Agrawal PB, Balci TB, Callewaert B, Calvo PL, Carli D, Caudle M, Colaiacovo S, Cross L, Demetriou K, Drazba K, Dutra-Clarke M, Edwards M, Genetti CA, Grange DK, Hickey SE, Isidor B, Kury S, Lachman HM, Lavillaureix A, Lyons MJ, Marcelis C, Marco EJ, Martinez-Agosto JA, Nowak C, Pizzol A, Planes M, Prijoles EJ, Riberi E, Rush ET, Russell BE, Sachdev R, Schmalz B, Shears D, Stevenson DA, Wilson K, Jansen S, de Vries BBA, Curry CJ. Jansen-de Vries syndrome: Expansion of the PPM1D clinical and phenotypic spectrum in 34 families. Am J Med Genet A. 2023 Jul;191(7):1900-1910. doi: 10.1002/ajmg.a.63226. Epub 2023 May 14. Citation on PubMed

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