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.
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.
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.
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:
Adams-Oliver Syndrome 2 (AOS2) is a rare condition caused by recessive DOCK6 mutations.
AOS 2 is characterized by:
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.
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:
The following section outlines typical genetic testing procedures and interpretation.
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 for DOCK6 genetic testing are considered to be without mutations that can alter the activity of the DOCK6 proteins.
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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Cerikan B, Schiebel E. Mechanism of cell-intrinsic adaptation to Adams-Oliver Syndrome gene DOCK6 disruption highlights ubiquitin-like modifier ISG15 as a regulator of RHO GTPases. Small GTPases. 2019 May;10(3):210-217. doi: 10.1080/21541248.2017.1297882. Epub 2017 Mar 13. PMID: 28287327; PMCID: PMC6548285.
DOCK6 dedicator of cytokinesis 6 [Homo sapiens (human)] - Gene - NCBI. (2025). Nih.gov. https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=DetailsSearch&Term=57572
DOCK6 Gene - Dedicator Of Cytokinesis 6 [Review of DOCK6 Gene - Dedicator Of Cytokinesis 6]. Gene Cards: The Human Gene Database. https://www.genecards.org/cgi-bin/carddisp.pl?gene=DOCK6
DOCK6 gene: MedlinePlus Genetics. (2015). Medlineplus.gov. https://medlineplus.gov/genetics/gene/dock6/
Entry - *614194 - DEDICATOR OF CYTOKINESIS 6; DOCK6 - OMIM. (2023). Omim.org. https://www.omim.org/entry/614194
Lehman A, Stittrich AB, Glusman G, Zong Z, Li H, Eydoux P, Senger C, Lyons C, Roach JC, Patel M. Diffuse angiopathy in Adams-Oliver syndrome associated with truncating DOCK6 mutations. Am J Med Genet A. 2014 Oct;164A(10):2656-62. doi: 10.1002/ajmg.a.36685. Epub 2014 Aug 4. PMID: 25091416; PMCID: PMC4167472.
Shaheen R, Faqeih E, Sunker A, Morsy H, Al-Sheddi T, Shamseldin HE, Adly N, Hashem M, Alkuraya FS. Recessive mutations in DOCK6, encoding the guanidine nucleotide exchange factor DOCK6, lead to abnormal actin cytoskeleton organization and Adams-Oliver syndrome. Am J Hum Genet. 2011 Aug 12;89(2):328-33. doi: 10.1016/j.ajhg.2011.07.009. Epub 2011 Aug 4. PMID: 21820096; PMCID: PMC3155174.