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URL of this page: https://medlineplus.gov/genetics/gene/pitx1/

PITX1 gene

paired like homeodomain 1

Normal Function

The PITX1 gene provides instructions for making a protein that plays a critical role in the development of the legs and feet. The protein acts as a transcription factor, which means that it binds to specific regions of DNA and helps control the activity of particular genes. Specifically, the PITX1 protein regulates the activity of genes that direct the development of the bones and tissues in the legs, knees, ankles, and feet.

The PITX1 protein is also found in the embryonic structures called branchial arches that give rise to tissues in the face and neck and in the developing pituitary gland, which is a hormone-producing gland located at the base of the brain. Researchers suspect that the PITX1 protein may play a role in the formation of the pituitary gland and in the formation of certain tissues that are derived from the branchial arches, such as the roof of the mouth, the jaw, and parts of the inner ear.

Health Conditions Related to Genetic Changes

Liebenberg syndrome

Changes in the long arm (q) of chromosome 5 that affect the PITX1 gene cause Liebenberg syndrome. This condition is characterized by the abnormal development of the elbows, wrists, and hands. Affected individuals typically have joint deformities called contractures that limit the movement of these structures.

People with Liebenberg syndrome have deletions, insertions, or rearrangements of the long arm of chromosome 5 that affect regions of DNA known as regulatory elements. These regulatory elements help turn genes on (enhancers) or off (repressors) during development. The chromosome changes that cause Liebenberg syndrome typically move an enhancer that activates the genes that are involved in the development of the arms and hands closer to the PITX1 gene.

As a result of these changes, the PITX1 gene is abnormally active when the arms and hands are developing. Because the PITX1 protein normally directs the development of the legs and feet, the bones and tissues in the arms and hands develop more like those in the legs and feet.

More About This Health Condition

Other disorders

Changes in the PITX1 gene have been found to cause an inward- and upward-turning foot (clubfoot) with or without the absence or severe shortening of a bone in the lower leg called the tibia (tibial hemimelia). Some individuals also have extra toes (polydactyly) arranged such that the outer toes (normally the  shorter toes) are mirror images of the inner toes (normally the longer toes) This condition is called mirror-image polydactyly. Unlike in Liebenberg syndrome, these features are caused by changes in the PITX1 gene itself. These changes cause cells to produce fewer functional PITX1 proteins. This disrupts the normal development of the legs, feet, and toes.

Other Names for This Gene

  • BFT
  • paired-like homeodomain 1
  • paired-like homeodomain transcription factor 1
  • pituitary homeobox 1
  • pituitary otx-related factor
  • POTX
  • PTX1

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

  • Alvarado DM, McCall K, Aferol H, Silva MJ, Garbow JR, Spees WM, Patel T, Siegel M, Dobbs MB, Gurnett CA. Pitx1 haploinsufficiency causes clubfoot in humans and a clubfoot-like phenotype in mice. Hum Mol Genet. 2011 Oct 15;20(20):3943-52. doi: 10.1093/hmg/ddr313. Epub 2011 Jul 20. Citation on PubMed or Free article on PubMed Central
  • Bompadre O, Rouco R, Darbellay F, Rauseo A, Guerard-Millet F, Gentile C, Kmita M, Andrey G. Liebenberg syndrome severity arises from variations in Pitx1 locus topology and proportion of ectopically transcribing cells. Nat Commun. 2025 Jul 9;16(1):6321. doi: 10.1038/s41467-025-61615-2. Citation on PubMed
  • DeLaurier A, Schweitzer R, Logan M. Pitx1 determines the morphology of muscle, tendon, and bones of the hindlimb. Dev Biol. 2006 Nov 1;299(1):22-34. doi: 10.1016/j.ydbio.2006.06.055. Epub 2006 Jul 14. Citation on PubMed
  • Duboc V, Logan MP. Pitx1 is necessary for normal initiation of hindlimb outgrowth through regulation of Tbx4 expression and shapes hindlimb morphologies via targeted growth control. Development. 2011 Dec;138(24):5301-9. doi: 10.1242/dev.074153. Epub 2011 Nov 9. Citation on PubMed or Free article on PubMed Central
  • Infante CR, Park S, Mihala AG, Kingsley DM, Menke DB. Pitx1 broadly associates with limb enhancers and is enriched on hindlimb cis-regulatory elements. Dev Biol. 2013 Feb 1;374(1):234-44. doi: 10.1016/j.ydbio.2012.11.017. Epub 2012 Nov 27. Citation on PubMed or Free article on PubMed Central
  • Klopocki E, Kahler C, Foulds N, Shah H, Joseph B, Vogel H, Luttgen S, Bald R, Besoke R, Held K, Mundlos S, Kurth I. Deletions in PITX1 cause a spectrum of lower-limb malformations including mirror-image polydactyly. Eur J Hum Genet. 2012 Jun;20(6):705-8. doi: 10.1038/ejhg.2011.264. Epub 2012 Jan 18. Citation on PubMed or Free article on PubMed Central
  • Kragesteen BK, Brancati F, Digilio MC, Mundlos S, Spielmann M. H2AFY promoter deletion causes PITX1 endoactivation and Liebenberg syndrome. J Med Genet. 2019 Apr;56(4):246-251. doi: 10.1136/jmedgenet-2018-105793. Epub 2019 Feb 2. Citation on PubMed
  • Lanctot C, Moreau A, Chamberland M, Tremblay ML, Drouin J. Hindlimb patterning and mandible development require the Ptx1 gene. Development. 1999 May;126(9):1805-10. doi: 10.1242/dev.126.9.1805. Citation on PubMed
  • Spielmann M, Brancati F, Krawitz PM, Robinson PN, Ibrahim DM, Franke M, Hecht J, Lohan S, Dathe K, Nardone AM, Ferrari P, Landi A, Wittler L, Timmermann B, Chan D, Mennen U, Klopocki E, Mundlos S. Homeotic arm-to-leg transformation associated with genomic rearrangements at the PITX1 locus. Am J Hum Genet. 2012 Oct 5;91(4):629-35. doi: 10.1016/j.ajhg.2012.08.014. Epub 2012 Sep 27. Citation on PubMed or Free article on PubMed Central
  • Szeto DP, Rodriguez-Esteban C, Ryan AK, O'Connell SM, Liu F, Kioussi C, Gleiberman AS, Izpisua-Belmonte JC, Rosenfeld MG. Role of the Bicoid-related homeodomain factor Pitx1 in specifying hindlimb morphogenesis and pituitary development. Genes Dev. 1999 Feb 15;13(4):484-94. doi: 10.1101/gad.13.4.484. Citation on PubMed or Free article on PubMed Central

The information on this site should not be used as a substitute for professional medical care or advice. Contact a health care provider if you have questions about your health.