Duane syndrome is a rare genetic eye disorder that is caused by absent or the incorrect innervation by the motor neurons within the eye [1][2]. The incorrect innervation by the motor neurons can result in loss of vision, inability to move a person’s eye from side to side, being unable to look toward the nose, and can result in the inability to cross one’s eyes.
What eye structures are affected?A typical eye uses six key muscles called the superior rectus, inferior rectus, inferior oblique, superior oblique, medial rectus, and lateral rectus to move the eye around the socket [4]. Specifically, the eye uses the lateral rectus muscle to move the eye toward the ear. These 6 key muscles are innervated by the motor neurons called the oculomotor, trochlear, and abducens nerves to help the brain send signals to move the eyes [5]. The lateral rectus muscle is innervated by the motor neuron called the abducens nerve [1]. Unfortunately, during Duane syndrome, it is very common to have incorrect or absent abducens nerve wiring to the lateral rectus muscle [6]. The lack or incorrect nerve wiring by the abducens nerve can result in difficulty moving the eye outward toward the ear [2]. Furthermore, Duane syndrome can be caused by incorrect nerve wiring to the lateral rectus instead of the medial rectus muscle by the oculomotor nerve, which can result in difficulty moving the eyes in several directions [6].
Figure 1a. Shows the structure of healthy eye 1b. shows the eye muscles that move the eye in specific directions 1c. shows the innervation by the abducens nerve
What are the symptoms?Due to improper or absent nerve pathways, people with Duane syndrome can suffer from symptoms such as eyes that do not point in the same direction, unusual angle of the head to straighten the person's eyes, one eye having less vision called amblyopia, narrowing of the eyelids, or eyes that move down or up when glancing in a certain direction called hyperdeviation [2].
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Figure 2: This patient's left eye demonstrates a narrowing of the lid opening on adduction (ability to look towards the center of their face) [3].
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Figure 3: This patient's right eye demonstrates the limitation of their abduction (ability to look toward the center of their face) and increased hyperdeviation (high eye position) [3].
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How is Duane syndrome a genetic disorder?
Duane syndrome is a type of rare genetic disease based on mutations in the CHN1, MAFB, or SALL4 gene [2]. Typically, Duane syndrome can be inherited through the autosomal dominant pattern in 10% of cases [5]. When Duane syndrome is inherited, the condition usually affects both a person’s eyes. Most occurrences of Duane syndrome involve only one eye, called unilateral cases, and are not inherited through families [2].
There are four types of Duane syndrome. Duane syndrome-1 is placed on chromosome 8q13 [6] and is the most common form resulting in trouble crossing one’s eyes and increased narrowing of the eyelids [2]. Duane retraction syndrome-2 is caused by a missense mutation in the CHN1 gene on chromosome 2q31 [5]. Type 2 is the least common and usually results in the appearance of a person’s eyes looking toward their ears [2]. Duane syndrome-3 is related to a variant of MAFB gene on chromosome 20q12 [6]. The third type usually results in difficulty moving one’s eyes in any direction [2]. Additionally, Duane-radial ray syndrome results in Duane syndrome as well as malformations in the bones of the hands or arms. Duane-radial ray syndrome is associated with mutations in the SALL4 gene on chromosome 20q13.2 [7]. This project will focus on Duane syndrome-2 which is associated with mutations in the CHN1 gene.
There are four types of Duane syndrome. Duane syndrome-1 is placed on chromosome 8q13 [6] and is the most common form resulting in trouble crossing one’s eyes and increased narrowing of the eyelids [2]. Duane retraction syndrome-2 is caused by a missense mutation in the CHN1 gene on chromosome 2q31 [5]. Type 2 is the least common and usually results in the appearance of a person’s eyes looking toward their ears [2]. Duane syndrome-3 is related to a variant of MAFB gene on chromosome 20q12 [6]. The third type usually results in difficulty moving one’s eyes in any direction [2]. Additionally, Duane-radial ray syndrome results in Duane syndrome as well as malformations in the bones of the hands or arms. Duane-radial ray syndrome is associated with mutations in the SALL4 gene on chromosome 20q13.2 [7]. This project will focus on Duane syndrome-2 which is associated with mutations in the CHN1 gene.
Figure 4: Shows the various phenotypes that can be associated with the different types of Duane syndrome
What is the CHN1 gene and what is its function?
The CHN1 gene is expressed in neurons. The gene plays a role in neuronal growth and differentiation. Within CHN1, there are three main protein domains called SH2, C1, and RacGAP [8]. The SH2 protein domain inhibits signal propagation through molecules called phosphotyrosine polypeptides which inactivate tyrosine kinases. The C1 protein domain propagates signal transduction through molecules called tyrosine kinases. The RacGAP protein domain regulates signal transduction through molecules called GTPases which release energy in the cell from breaking down GTP molecules [6].
Figure 5: Shows the many known mutations within the CHN1 gene that are associated with the development of Duane syndrome-2. Those known mutations occur around the protein domains or within the C1 or RacGAP protein domains [5].
What is the gap in knowledge?
Although the CHN1 gene is involved in neuron growth and mutations in the CHN1 gene are associated with the development of Duane syndrome-2, the mechanism of how CHN1 impacts the abducens nerve growth is not known. Furthermore, the overall role of CHN1 in eye development is unclear as well, so I hope to focus this project on the possible role of CHN1 in eye development that could lead to Duane syndrome-2.
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References
[1] Duane Syndrome. (n.d.). National Center for Advancing Translational Sciences GARD: https://rarediseases.info.nih.gov/diseases/6288/duane-syndrome
[2] Duane Syndrome. (2022). Cleveland Clinic: https://my.clevelandclinic.org/health/diseases/24315-duane-syndrome
[3] Department of Ophthalmology and Vision Science-University of Arizona. (2022). Duane Retraction Syndrome 1. Hereditary Ocular Disease: https://disorders.eyes.arizona.edu/disorders/duane-retraction-syndrome-1
[4]Ferng, Alice. (2022). Extraocular muscles. Ken Hub: https://www.kenhub.com/en/library/anatomy/muscles-of-the-orbit
[5] Miyake et al. (2008). Human CHN1 Mutations Hyperactivate alpha2-Chimaerin and cause Duane's Retraction Syndrome. Science (New York, N.Y.), https://doi.org/10.1126/science.1156121
[6] Angelini, et al. (2021, April). CHN1 and Duane Retraction Syndrome: Expanding the Phenotype to Cranial Nerves Development Disease. European Journal of Medical Genetics, Volume 64, Issue 4, 2021, 104188, ISSN 1769-7212, https://doi.org/10.1016/j.ejmg.2021.104188.
[7]National Institute of Health. (2009). Duane-radial ray syndrome. Medline Plus: https://medlineplus.gov/genetics/condition/duane-radial-ray-syndrome/
[8] Alliance. (2022, October 28). CHN1. Alliance of Genome Resources: https://www.alliancegenome.org/gene/HGNC:1943
Image Sources (besides those that are linked)
[Header]First Ever Vision Restoration after Optic Nerve Injury in Mice. (2016). Switch Board Blog: http://switchboardblog.blogspot.com/2017/04/first-ever-vision-restoration-after.html
[Two Gallery Photos] Department of Ophthalmology and Vision Science-University of Arizona. (2022). Duane Retraction Syndrome 1. Hereditary Ocular Disease: https://disorders.eyes.arizona.edu/disorders/duane-retraction-syndrome-1
[Figure1a]https://www.thehealthboard.com/what-are-the-different-layers-of-eye-tissue.htm
[Figure1b]https://www.pinterest.pt/pin/470344754831489025/
Figure1c] https://www.gograph.com/clipart/trochlear-and-abducens-nerves-gg61055980.html
[2] Duane Syndrome. (2022). Cleveland Clinic: https://my.clevelandclinic.org/health/diseases/24315-duane-syndrome
[3] Department of Ophthalmology and Vision Science-University of Arizona. (2022). Duane Retraction Syndrome 1. Hereditary Ocular Disease: https://disorders.eyes.arizona.edu/disorders/duane-retraction-syndrome-1
[4]Ferng, Alice. (2022). Extraocular muscles. Ken Hub: https://www.kenhub.com/en/library/anatomy/muscles-of-the-orbit
[5] Miyake et al. (2008). Human CHN1 Mutations Hyperactivate alpha2-Chimaerin and cause Duane's Retraction Syndrome. Science (New York, N.Y.), https://doi.org/10.1126/science.1156121
[6] Angelini, et al. (2021, April). CHN1 and Duane Retraction Syndrome: Expanding the Phenotype to Cranial Nerves Development Disease. European Journal of Medical Genetics, Volume 64, Issue 4, 2021, 104188, ISSN 1769-7212, https://doi.org/10.1016/j.ejmg.2021.104188.
[7]National Institute of Health. (2009). Duane-radial ray syndrome. Medline Plus: https://medlineplus.gov/genetics/condition/duane-radial-ray-syndrome/
[8] Alliance. (2022, October 28). CHN1. Alliance of Genome Resources: https://www.alliancegenome.org/gene/HGNC:1943
Image Sources (besides those that are linked)
[Header]First Ever Vision Restoration after Optic Nerve Injury in Mice. (2016). Switch Board Blog: http://switchboardblog.blogspot.com/2017/04/first-ever-vision-restoration-after.html
[Two Gallery Photos] Department of Ophthalmology and Vision Science-University of Arizona. (2022). Duane Retraction Syndrome 1. Hereditary Ocular Disease: https://disorders.eyes.arizona.edu/disorders/duane-retraction-syndrome-1
[Figure1a]https://www.thehealthboard.com/what-are-the-different-layers-of-eye-tissue.htm
[Figure1b]https://www.pinterest.pt/pin/470344754831489025/
Figure1c] https://www.gograph.com/clipart/trochlear-and-abducens-nerves-gg61055980.html
This webpage was produced as an assignment for Genetics 564, an undergraduate capstone at UW-Madison.
Abigail Olsen
[email protected]
Last updated 5/12/2023
Abigail Olsen
[email protected]
Last updated 5/12/2023