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Genetics Home Reference: your guide to understanding genetic conditions     A service of the U.S. National Library of Medicine®


Reviewed September 2010

What is the official name of the SIX3 gene?

The official name of this gene is “SIX homeobox 3.”

SIX3 is the gene's official symbol. The SIX3 gene is also known by other names, listed below.

What is the normal function of the SIX3 gene?

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).

Does the SIX3 gene share characteristics with other genes?

The SIX3 gene belongs to a family of genes called homeobox (homeoboxes).

A gene family is a group of genes that share important characteristics. Classifying individual genes into families helps researchers describe how genes are related to each other. For more information, see What are gene families? ( in the Handbook.

How are changes in the SIX3 gene related to health conditions?

nonsyndromic holoprosencephaly - caused by mutations in the SIX3 gene

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.

Where is the SIX3 gene located?

Cytogenetic Location: 2p21

Molecular Location on chromosome 2: base pairs 44,941,729 to 44,966,751

(Homo sapiens Annotation Release 107, GRCh38.p2) (NCBI (

The SIX3 gene is located on the short (p) arm of chromosome 2 at position 21.

The SIX3 gene is located on the short (p) arm of chromosome 2 at position 21.

More precisely, the SIX3 gene is located from base pair 44,941,729 to base pair 44,966,751 on chromosome 2.

See How do geneticists indicate the location of a gene? ( in the Handbook.

Where can I find additional information about SIX3?

You and your healthcare professional may find the following resources about SIX3 helpful.

You may also be interested in these resources, which are designed for genetics professionals and researchers.

What other names do people use for the SIX3 gene or gene products?

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

See How are genetic conditions and genes named? ( in the Handbook.

What glossary definitions help with understanding SIX3?

DNA ; embryonic ; gene ; holoprosencephaly ; homeobox ; protein ; retina ; tissue ; transcription ; transcription factor

You may find definitions for these and many other terms in the Genetics Home Reference Glossary.


  • Domené S, Roessler E, El-Jaick KB, Snir M, Brown JL, Vélez 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. (
  • Gene Review: Holoprosencephaly Overview (
  • 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. (
  • 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. (
  • 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. (
  • Lacbawan F, Solomon BD, Roessler E, El-Jaick K, Domené S, Vélez 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, Njølstad PR, Brunner HG, Carey JC, Hehr U, Müsebeck 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. (
  • NCBI Gene (
  • 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. (
  • 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. Review. (
  • Solomon BD, Lacbawan F, Jain M, Domené 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. (
  • Solomon BD, Mercier S, Vélez 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. Review. (
  • 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. (


The resources on this site should not be used as a substitute for professional medical care or advice. Users seeking information about a personal genetic disease, syndrome, or condition should consult with a qualified healthcare professional. See How can I find a genetics professional in my area? ( in the Handbook.

Reviewed: September 2010
Published: February 8, 2016