Choroideremia (CHM) is a progressive degeneration of the retinal pigment epithelium, choroid, and retina that is inherited in an X-chromosomal recessive fashion.

Usually, night blindness is the first clinical sign, and it already may be present in early childhood and is followed by visual loss. Typically, the central vision is not affected until late in the disease. Many patients are blind by age 45, but the course of the disease is very variable.

These symptoms are paralleled by loss of the choroidal vessels and depigmentation of the fundus, which are most prominent in the midperiphery, whereas the macular region is conspicuously spared. In the end stage of the disorder, the fundus is of scleral whiteness, choroidal vessels are absent except for possible remnants in the macular region, and retinal vessels are sometimes attenuated.

With an estimated incidence of 1 in 100,000, CHM is regarded as a rare disorder. However, in contrast to many other retinopathies, there is only one gene involved in CHM, which renders mutations in the CHM gene a relatively frequent cause of blindness.

Linkage studies and clinical findings in males with X-chromosomal deletions have assigned the CHM gene (MIM 303100) to Xq21, and subsequent molecular studies have led to its isolation by means of positional cloning strategies. The CHM gene encodes an mRNA of approximately 6.0 kb and a protein of 653 amino acids. Microdeletions, translocations, and a variety of small mutations in patients with classic CHM have established that dysfunction of this gene is the fundamental cause of CHM.

In the western European population, roughly 25 percent of patients with CHM have deletions encompassing part of the CHM gene. Frameshift, stop codon, and splice-site mutations have been observed in approximately 50 percent of patients. Invariably, CHM gene mutations result in the absence or truncation of the protein.

Sequence comparisons revealed that the product of the CHM gene is identical to a subunit of the heterotrimeric Rab geranylgeranyl transferase (GGT). Thus the CHM protein, also called REP-1 (Rab escort protein-1), plays an indispensable role in the prenylation of Rab GTPases.

A closely related but intronless gene, choroideremia-like (CHML/REP-2) (MIM 118825), has been isolated. The CHML/REP-2 gene maps to human chromosome 1q42-qter. Like CHM/REP-1, CHML/REP-2 is ubiquitously expressed, and in Rab GGTase assays, REP-1 and REP-2 have largely overlapping substrate specificities.

Recently, a novel member of the Rab GTPase family, Rab27, has been isolated from lymphoblastoid cells that is prenylated much more efficiently by REP-1 than by REP-2. Rab27 is highly, but not uniquely, expressed in the rat eye, particularly in the retinal pigment epithelium (RPE) and choroid. Since these tissues are generally believed to be involved in the degenerative process, underprenylation of Rab27 may explain why in humans, clinical features of CHM are confined to the eye.

In the mouse, targeted inactivation of the chm/rep-1 gene causes early embryonic lethality if the defective gene is transmitted maternally. Chimeric males and their heterozygous offspring are viable but show patchy loss of the photoreceptor cell layer. Thus generation of an animal model for CHM may be possible if the embryonic lethality can be overcome.