DOCK6

The DOCK6 gene encodes the dedicator of cytokinesis 6 protein, which regulates cell shape, movement, and growth by activating CDC42 and RAC1—key proteins involved in controlling the actin cytoskeleton. 

Uniquely localized to the endoplasmic reticulum, DOCK6 plays a critical role in the development of blood vessels, nerves, and limbs, with mutations in this gene being linked to congenital disorders such as Adams-Oliver Syndrome 2.

What is the DOCK6 Gene and Protein?

The DOCK6 gene provides instructions for making dedicator of cytokinesis 6 (DOCK6), a protein that helps regulate cell shape, movement, and growth. It does this by activating CDC42 and RAC1, two proteins that control the actin cytoskeleton, the internal framework that gives cells structure and allows them to move. 

Unlike most proteins in the DOCK family, DOCK6 is found inside the endoplasmic reticulum (ER), suggesting it plays a role in intracellular signaling and membrane function.

DOCK6 is highly active in developing tissues, especially in the lungs, heart, ovaries, kidneys, and limb buds. It is important in forming blood vessels, nerves, and bones. The protein contains two key regions (DHR1 and DHR2) that allow it to turn on CDC42 and RAC1, which are essential for cell division, brain development, and limb formation.

Genetic Mutations in DOCK6

Mutations in DOCK6 can prevent it from working correctly, disrupting cell structure and development. Many of these mutations truncate the protein, making it too short to function. Others change key building blocks, reducing its ability to activate CDC42 and RAC1.

Cells try to compensate for DOCK6 loss by adjusting other proteins involved in cell structure and movement, such as ISG15 and IQGAP1. This adaptation may explain why some people with DOCK6 mutations have milder symptoms than expected.

How DOCK6 Mutations Affect the Body

DOCK6 mutations disrupt RAC1 and CDC42 signaling. These proteins help control how cells move, change shape, and divide. 

Disrupted RAC1 and CDC42 signaling leads to:

• Poor blood vessel development, increasing the risk of strokes and organ damage
• Weak connective tissue, affecting skin, bones, and nerves
• Growth restriction during pregnancy due to abnormal placental blood flow

Conditions Associated with DOCK6 Mutations

Adams-Oliver Syndrome 2 (AOS2) is a rare condition caused by recessive DOCK6 mutations. 

Adams-Oliver Syndrome 2

AOS 2 is characterized by:

• Missing patches of scalp skin at birth (aplasia cutis congenita, ACC)
• Malformations of fingers and toes (terminal transverse limb defects, TTLD)
• Brain and nervous system problems, such as small head size (microcephaly), developmental delay, epilepsy, and abnormal brain structure
• Blood vessel abnormalities, including eye problems, strokes, and poor circulation
• Heart defects, such as tetralogy of Fallot and valve abnormalities

DOCK6 Mutations: Clinical Significance and Testing

Genetic Testing: next-generation sequencing (NGS) and Sanger sequencing can confirm DOCK6 mutations, helping with early diagnosis and family planning.

Variability in Symptoms: some people with DOCK6 mutations have milder symptoms, possibly due to other genes compensating for the loss.

DOCK6 is a key regulator of cell development and blood vessel formation. Understanding its function may help improve the diagnosis and treatment of Adams-Oliver Syndrome and related conditions.

Who Should Consider DOCK6 Testing?

DOCK6 genetic testing should be considered for individuals with suspected Adams-Oliver Syndrome Type 2 (AOS2) or unexplained congenital abnormalities affecting the skin, limbs, brain, or cardiovascular system. Testing may be particularly useful in the following cases:

• Infants with ACC: missing patches of scalp skin at birth.
• Newborns with limb malformations: this includes underdeveloped or missing fingers and toes.
• Patients with neurological abnormalities: such as microcephaly, developmental delays, epilepsy, or abnormal brain structure.
• Individuals with vascular or circulatory problems: including retinal defects, intracranial hemorrhages, or other blood vessel abnormalities.
• Cases of congenital heart defects: particularly tetralogy of Fallot or valve dysplasia, when other genetic causes have been ruled out.
• Families with a history of autosomal recessive inheritance of similar congenital defects: particularly in consanguineous families.

Test Procedure and Interpretation

The following section outlines typical genetic testing procedures and interpretation.

Testing Procedure and Preparation

Genetic testing involves blood, saliva, or cheek swab samples, although specialized laboratories may recommend different sample types. 

A cheek swab or saliva sample is easily obtained from the comfort of home, while blood samples typically require a blood draw.

Normal Reference Ranges

Normal reference ranges for DOCK6 genetic testing are considered to be without mutations that can alter the activity of the DOCK6 proteins.

Clinical Implications of Positive DOCK6 Mutations

The clinical implications of a positive DOCK6 mutation test result will vary by individual, although DOCK6 mutations in symptomatic patients may signal a need for further assessment and possibly treatment, especially in the setting of various symptoms and/or congenital abnormalities or cardiovascular or neurological problems.

Patients or practitioners with questions about the clinical implications of DOCK6 mutations should seek further assessment with a genetic counselor or expert. 

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