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SIX3 gene
Reviewed by Medicinsk Expert•Last updated: 2026-10-22•Gene

SIX3 gene

The SIX3 gene provides instructions for a protein that is critical for the development of the eyes and the forebrain.

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.

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 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 this condition. 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.

Frequently Asked Questions

During pregnancy, severe cases might be detected via ultrasound showing a single brain ventricle or facial abnormalities like cyclopia or cleft lip/palate. After birth, signs can range from severe facial malformations and intellectual disability to more subtle neurological issues, depending on the severity of brain division failure.
Yes, genetic testing for SIX3 mutations can be performed, often via a blood test. It is recommended for individuals diagnosed with holoprosencephaly, especially if the cause is unknown, or for families with a history of the condition to assess recurrence risk. Prenatal testing may also be an option in some cases.
SIX3 gene mutations tend to cause more severe forms of nonsyndromic holoprosencephaly compared to mutations in other genes. This can lead to significant developmental delays, intellectual disability, seizures, and feeding difficulties. The specific impact varies widely depending on the extent of brain malformation.
Ongoing care is typically multidisciplinary, involving neurologists, developmental pediatricians, physical and occupational therapists, and speech therapists. Management focuses on symptom control, such as anti-seizure medications, feeding support, and therapies to maximize developmental potential. Regular monitoring for complications is also crucial.
Source: MedlinePlus, National Library of Medicine

MedlinePlus brings together authoritative health information from the National Library of Medicine (NLM), the National Institutes of Health (NIH), and other government agencies and health-related organizations.

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