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SIX3 gene

SIX homeobox 3

Normal Function

The SIX3 gene provides instructions for making a protein that plays an important role in the development of the eyes and front part of the brain (forebrain). This protein is a transcription factor, which means that it attaches (binds) to specific regions of DNA and helps control the activity of certain genes. The SIX3 protein regulates genes involved in several signaling pathways that are important for embryonic development. Some of these genes are turned on (activated) by the SIX3 protein and others are turned off (repressed).

One gene that is activated by the SIX3 protein is the SHH gene, which provides instructions for making a protein called Sonic Hedgehog. Among its many functions, Sonic Hedgehog helps establish the right and left halves (hemispheres) of the forebrain. The SIX3 protein also regulates genes involved in the formation of the lens of the eye and the specialized tissue at the back of the eye that detects light and color (the retina).

Health Conditions Related to Genetic Changes

Nonsyndromic holoprosencephaly

At least 60 mutations in the SIX3 gene have been found to cause nonsyndromic holoprosencephaly. This condition occurs when the brain fails to divide into two hemispheres during early development. SIX3 gene mutations are the third most common cause of nonsyndromic holoprosencephaly. Although mutations in this gene can cause mild to severe forms of the condition, they tend to result in more severe signs and symptoms than mutations in other genes that cause nonsyndromic holoprosencephaly

SIX3 gene mutations change the structure of the SIX3 protein in different ways; however, all of them disrupt the protein's ability to bind with DNA. As a result, the genes involved in normal eye and forebrain development are not properly activated or repressed. Without the correct activity of these genes, the eyes will not form normally and the brain does not separate into two hemispheres. The signs and symptoms of nonsyndromic holoprosencephaly are caused by abnormal development of the brain and face.

More About This Health Condition


MedlinePlus Genetics provides information about Coloboma

More About This Health Condition

Other Names for This Gene

  • homeobox protein SIX3
  • HPE2
  • sine oculis homeobox homolog 3

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


  • Domene S, Roessler E, El-Jaick KB, Snir M, Brown JL, Velez JI, Bale S, Lacbawan F, Muenke M, Feldman B. Mutations in the human SIX3 gene in holoprosencephaly are loss of function. Hum Mol Genet. 2008 Dec 15;17(24):3919-28. doi: 10.1093/hmg/ddn294. Epub 2008 Sep 12. Citation on PubMed or Free article on PubMed Central
  • Geng X, Speirs C, Lagutin O, Inbal A, Liu W, Solnica-Krezel L, Jeong Y, Epstein DJ, Oliver G. Haploinsufficiency of Six3 fails to activate Sonic hedgehog expression in the ventral forebrain and causes holoprosencephaly. Dev Cell. 2008 Aug;15(2):236-47. doi: 10.1016/j.devcel.2008.07.003. Citation on PubMed or Free article on PubMed Central
  • Hehr U, Pineda-Alvarez DE, Uyanik G, Hu P, Zhou N, Hehr A, Schell-Apacik C, Altus C, Daumer-Haas C, Meiner A, Steuernagel P, Roessler E, Winkler J, Muenke M. Heterozygous mutations in SIX3 and SHH are associated with schizencephaly and further expand the clinical spectrum of holoprosencephaly. Hum Genet. 2010 Mar;127(5):555-61. doi: 10.1007/s00439-010-0797-4. Epub 2010 Feb 16. Citation on PubMed or Free article on PubMed Central
  • Jeong Y, Leskow FC, El-Jaick K, Roessler E, Muenke M, Yocum A, Dubourg C, Li X, Geng X, Oliver G, Epstein DJ. Regulation of a remote Shh forebrain enhancer by the Six3 homeoprotein. Nat Genet. 2008 Nov;40(11):1348-53. doi: 10.1038/ng.230. Epub 2008 Oct 5. Citation on PubMed or Free article on PubMed Central
  • Lacbawan F, Solomon BD, Roessler E, El-Jaick K, Domene S, Velez JI, Zhou N, Hadley D, Balog JZ, Long R, Fryer A, Smith W, Omar S, McLean SD, Clarkson K, Lichty A, Clegg NJ, Delgado MR, Levey E, Stashinko E, Potocki L, Vanallen MI, Clayton-Smith J, Donnai D, Bianchi DW, Juliusson PB, Njolstad PR, Brunner HG, Carey JC, Hehr U, Musebeck J, Wieacker PF, Postra A, Hennekam RC, van den Boogaard MJ, van Haeringen A, Paulussen A, Herbergs J, Schrander-Stumpel CT, Janecke AR, Chitayat D, Hahn J, McDonald-McGinn DM, Zackai EH, Dobyns WB, Muenke M. Clinical spectrum of SIX3-associated mutations in holoprosencephaly: correlation between genotype, phenotype and function. J Med Genet. 2009 Jun;46(6):389-98. doi: 10.1136/jmg.2008.063818. Epub 2009 Apr 2. Citation on PubMed or Free article on PubMed Central
  • Ribeiro LA, El-Jaick KB, Muenke M, Richieri-Costa A. SIX3 mutations with holoprosencephaly. Am J Med Genet A. 2006 Dec 1;140(23):2577-83. doi: 10.1002/ajmg.a.31377. Citation on PubMed
  • Roessler E, Muenke M. The molecular genetics of holoprosencephaly. Am J Med Genet C Semin Med Genet. 2010 Feb 15;154C(1):52-61. doi: 10.1002/ajmg.c.30236. Citation on PubMed or Free article on PubMed Central
  • Solomon BD, Lacbawan F, Jain M, Domene S, Roessler E, Moore C, Dobyns WB, Muenke M. A novel SIX3 mutation segregates with holoprosencephaly in a large family. Am J Med Genet A. 2009 May;149A(5):919-25. doi: 10.1002/ajmg.a.32813. Citation on PubMed or Free article on PubMed Central
  • Solomon BD, Mercier S, Velez JI, Pineda-Alvarez DE, Wyllie A, Zhou N, Dubourg C, David V, Odent S, Roessler E, Muenke M. Analysis of genotype-phenotype correlations in human holoprosencephaly. Am J Med Genet C Semin Med Genet. 2010 Feb 15;154C(1):133-41. doi: 10.1002/ajmg.c.30240. Citation on PubMed or Free article on PubMed Central
  • Tekendo-Ngongang C, Muenke M, Kruszka P. Holoprosencephaly Overview. 2000 Dec 27 [updated 2020 Mar 5]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from Citation on PubMed
  • Wallis DE, Roessler E, Hehr U, Nanni L, Wiltshire T, Richieri-Costa A, Gillessen-Kaesbach G, Zackai EH, Rommens J, Muenke M. Mutations in the homeodomain of the human SIX3 gene cause holoprosencephaly. Nat Genet. 1999 Jun;22(2):196-8. doi: 10.1038/9718. Citation on PubMed

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.