The Biology and Genetics of Choroideremia
At a Glance
Choroideremia is caused by a mutation in the CHM gene on the X chromosome, which stops the production of the REP-1 protein. Without this protein, eye cells cannot process waste and eventually die. Because it is X-linked, it primarily affects males, while females are carriers.
To understand Choroideremia (CHM), it helps to look at the “machinery” inside your eye cells. While the symptoms are visual, the cause is a deep biological breakdown in how cells move materials from one place to another.
The CHM Gene and the REP-1 “Escort”
Inside your body, the CHM gene is responsible for creating a protein called Rab Escort Protein-1 (REP-1) [1]. Think of REP-1 as a specialized “delivery escort” for other proteins called Rabs.
Rabs are like the traffic controllers of a cell; they tell “delivery trucks” (vesicles) full of nutrients and waste where to go [2]. For Rabs to work, they must undergo a process called prenylation—essentially, they need a “sticky tag” attached so they can grab onto the cell’s membranes [3][4].
In Choroideremia:
- The CHM mutation prevents the body from making enough functional REP-1 [1].
- Without the escort, the Rabs never get their “sticky tags” (prenylation deficiency) [2].
- The cell’s traffic control breaks down, leading to a build-up of waste and a lack of nutrients, which eventually causes the cell to die [5][6].
How it is Passed Down (Inheritance Rules)
Because the CHM gene is on the X chromosome, the rules for passing it on to your children are absolute for an affected male:
- Sons: You will pass your Y chromosome to all your sons, meaning 0% of your sons will inherit the condition or carry the gene.
- Daughters: You will pass your mutated X chromosome to all your daughters, meaning 100% of your daughters will be genetic carriers [7].
Why the RPE and Photoreceptors?
While this protein is missing throughout the body, the cells in the back of your eye are the most affected because they are incredibly “busy.” The Retinal Pigment Epithelium (RPE) is a support layer that must constantly “eat” and recycle waste from the light-sensing photoreceptor cells [8][9]. Because the RPE cells have such heavy “traffic,” they are the first to fail when the REP-1 escort system breaks down [10].
Contrast: CHM vs. Retinitis Pigmentosa (RP)
Choroideremia is frequently misdiagnosed as Retinitis Pigmentosa (RP) because both cause night blindness and tunnel vision [11]. However, to a doctor looking at the back of the eye, they look very different:
| Feature | Choroideremia (CHM) | Retinitis Pigmentosa (RP) |
|---|---|---|
| Primary Loss | Primarily involves the choroid (blood vessels) and RPE [7]. | Primarily involves the photoreceptors [11]. |
| Appearance | Large “scalloped” patches where the white sclera and large blood vessels are visible [11]. | Dark, spider-like “bone-spicule” pigment clumps [11]. |
| Inheritance | Strictly X-linked (affects males; females are carriers) [7]. | Can be dominant, recessive, or X-linked. |
Syndromic Choroideremia (The Xq21 Deletion)
In most cases, CHM only affects the eyes (non-syndromic). However, in rare instances, a patient may have what is called syndromic choroideremia [12].
This occurs due to a contiguous gene deletion at the Xq21 locus. Instead of just a small error in the CHM gene, a whole “chunk” of the X chromosome is missing, taking the CHM gene and neighboring genes with it [12][13]. This can lead to systemic symptoms such as:
- Sensorineural hearing loss (difficulty hearing) [12].
- Intellectual disability or developmental delays [13].
- Other rare metabolic or obesity-related issues [13].
If a genetic test shows a large deletion rather than a small mutation, doctors will often monitor the patient for these other symptoms.
Common questions in this guide
What causes Choroideremia?
How is Choroideremia passed down to children?
How is Choroideremia different from Retinitis Pigmentosa?
What does an Xq21 deletion mean on my genetic test?
Why are the cells in the eye most affected by the CHM mutation?
Questions to Ask Your Doctor
Curated prompts to bring to your next appointment.
- 1.Does my genetic testing show a specific point mutation or a larger 'contiguous gene deletion' at the Xq21 locus?
- 2.How does the appearance of my retina specifically differ from Retinitis Pigmentosa?
- 3.Are the blood vessels of my choroid visible on my fundus exam, and what does that indicate about my disease stage?
- 4.Should I have my hearing tested to rule out any 'syndromic' involvement associated with my genetic result?
- 5.Is the REP-1 protein deficiency affecting only my eyes, or is it active in other parts of my body?
Questions For You
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References
References (13)
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Lytic photoreceptor cell death caused by Rab escort protein deficiency in Drosophila.
Sasaki S, Satoh R, Satoh T, Satoh AK
FEBS letters 2025; (599(18)):2598-2611 doi:10.1002/1873-3468.70056.
PMID: 40325959 - 3
Molecular genetics characterization and homology modeling of the CHM gene mutation: A study on its association with choroideremia.
Imani S, Ijaz I, Shasaltaneh MD, et al.
Mutation research. Reviews in mutation research 2018; (775()):39-50 doi:10.1016/j.mrrev.2018.02.001.
PMID: 29555028 - 4
Expression of Rab Prenylation Pathway Genes and Relation to Disease Progression in Choroideremia.
Fry LE, Patrício MI, Jolly JK, et al.
Translational vision science & technology 2021; (10(8)):12 doi:10.1167/tvst.10.8.12.
PMID: 34254989 - 5
REP1 deficiency causes systemic dysfunction of lipid metabolism and oxidative stress in choroideremia.
Cunha DL, Richardson R, Tracey-White D, et al.
JCI insight 2021; (6(9)).
PMID: 33755601 - 6
Is subretinal AAV gene replacement still the only viable treatment option for choroideremia?
Han RC, Fry LE, Kantor A, et al.
Expert opinion on orphan drugs 2021; (9(1)):13-24 doi:10.1080/21678707.2021.1882300.
PMID: 34040899 - 7
X-linked Choroideremia.
Tsang SH, Sharma T
Advances in experimental medicine and biology 2018; (1085()):37-42 doi:10.1007/978-3-319-95046-4_9.
PMID: 30578482 - 8
Oxidative and Endoplasmic Reticulum Stress Represent Novel Therapeutic Targets for Choroideremia.
Sarkar H, Lahne M, Nair N, Moosajee M
Antioxidants (Basel, Switzerland) 2023; (12(9)) doi:10.3390/antiox12091694.
PMID: 37759997 - 9
Loss of REP-1 in retinal pigment epithelial cells leads to impaired phagosome processing and altered lysosomal pathway function.
Coelho R, Antas P, Fonseca AF, et al.
Molecular biology of the cell 2025; (36(9)):ar116 doi:10.1091/mbc.E24-11-0497.
PMID: 40768322 - 10
Reduced Retinal Pigment Epithelial Autophagy Due to Loss of Rab12 Prenylation in a Human iPSC-RPE Model of Choroideremia.
Raeker MÖ, Perera ND, Karoukis AJ, et al.
Cells 2024; (13(12)) doi:10.3390/cells13121068.
PMID: 38920696 - 11
Choroideremia Gene Therapy.
Lam BL, Davis JL, Gregori NZ
International ophthalmology clinics 2021; (61(4)):185-193 doi:10.1097/IIO.0000000000000385.
PMID: 34584056 - 12
A novel large multi-gene deletion in syndromic choroideremia.
Jung EH, Duemler A, Iannaccone A, Alekseev O
Ophthalmic genetics 2024; (45(5)):546-550 doi:10.1080/13816810.2024.2401850.
PMID: 39257251 - 13
A maternally inherited 8.05 Mb Xq21 deletion associated with Choroideremia, deafness, and mental retardation syndrome in a male patient.
Liang S, Jiang N, Li S, et al.
Molecular cytogenetics 2017; (10()):23 doi:10.1186/s13039-017-0324-6.
PMID: 28630650
This page explains the biology and genetics of Choroideremia for educational purposes. Always consult your ophthalmologist or genetic counselor to interpret your specific genetic test results, inheritance risks, or symptoms.
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