Molecular Genetics of Choroideremia


Choroideremia (CHM) is an X‐linked disorder that causes progressive loss of vision. Affected males initially present with nyctalopia (night blindness) and experience progressive loss of peripheral vision until they are legally blind by middle age. Degeneration continues until there is a complete loss of vision. CHM is caused by mutations in the CHM gene, which encodes Rab escort protein (REP) 1. Molecular genetic techniques have identified more than 100 mutations affecting in the CHM gene and all but one results in the absence of REP1 protein. The degenerative process of CHM initially affects rod photoreceptors and the retinal pigment epithelium (RPE), then progresses to involve the choroid and cone photoreceptors. The exact pathophysiological mechanism of this degradation has not yet been elucidated. There is no established treatment for CHM available at this time but gene therapy trials are currently underway.

Key Concepts:

  • Choroideremia is a progressive degenerative disorder affecting the photoreceptor, retinal pigment epithelium and choroid layers of the retina.

  • Mutations in the CHM gene result in the absence of REP1 protein, causing low levels of prenylation of RAB proteins.

  • Confirmatory testing for CHM can be done by direct sequencing of the CHM exons or through immunoblot analysis for CHM protein expression.

  • Zebrafish and mouse CHM knock‐out models have significant limitations due to the lack of viability. A conditional knock‐out mouse model has been developed and used in pre‐clinical testing of CHM therapies.

  • Successful techniques in gene therapy for Leber congenital amaurosis‐2, another single gene disorder of blindness, are currently being applied to choroideremia.

Keywords: choroideremia; phenotype; genetics; CHM; REP1; RAB; gene therapy; AAV2; translational bypass therapy

Figure 1.

Images from the left eye of a 52‐year‐old male with choroideremia. Fundus photography (a) shows an absence of chorioretinal tissue, exposing bare sclera in the periphery. The neuroretinal tissue of the macula still remains intact. Fundus autofluorescence (b) shows hypofluorescent signal throughout the retina indicating severely deficient RPE, even in the areas with normally appearing pigment in the colour photograph. An OCT slice (c) shows the anatomical difference between intact tissue and atrophic areas. The outer nuclear layer and outer segments, RPE and choroid are absent on both sides of the OCT scan. Arrows indicate rosettes formed by abnormal outer segments as a result of dysfunctional RPE.

Figure 2.

A schematic of a Rab protein and its association with REP1 and GGTase2. GGTase2 and REP1 bind to the Rab protein. The GGTase/REP1 complex binds two geranyl fatty acid chains to newly synthesised Rab protein. REP1 escorts the prenylated Rab protein to its membrane target where it dissociates and the Rab protein carries out its function. Adapted from MacDonald et al. .

Figure 3.

A comparison of reported mutations in the CHM gene DNA sequence. Data from

Figure 4.

A comparison of the reported mutations in REP1 protein coding. Data from



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Further Reading

MacDonald IM and Seabra MC (2011) Choroideremia. In: Traboulsi EI (ed.) Genetic Diseases of the Eye, 2nd edn., pp. 484–490. New York: Oxford University Press, Inc.

Stone EM (2003) Finding and interpreting genetic variations that are important to ophthalmologists. Transactions of the American Ophthalmological Society 101: 437–484.

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How to Cite close
Freund, Paul R, and MacDonald, Ian M(Dec 2012) Molecular Genetics of Choroideremia. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0024310]