In the past few years, a remarkable convergence of molecular genetics and biochemistry has led to an explosive new knowledge about the molecular basis of choroideremia (c H M).~ This chorioretinal degenerative disease was first recognized as a separate entity by Mauthner in 1872 and subsequently characterized as a progressive condition with X-linked inheritan~ e.~-~ Patients with choroideremia develop night blindness and progressive loss of peripheral vision usually starting in the second or third decade of life, slowly progressing to complete blindness in two or three decades. The fundoscopic changes found in choroideremia patients are distinct from those found in other chorioretinal degenerations. These changes are characterized by slowly progressive areas of scalloped loss of retinal pigment epithelium (RPE) and choroid in the midperiphery, eventually leading to diffuse loss of these The loss of the choriocapillaris and the preservation of the large choroidal vessels results in a fluorescein angiographic pattern that is characteristic of the di~ ease.~

The gene that is mutated in choroideremia was cloned by Cremers et al. 9 in 1990. CHM was among the first human disease genes identified by positional cloning techniques. This marked the beginning of a new era in choroideremia research. The identification of the c HM gene (now called Rab Escort Protein-1 or REP-I gene as discussed below) led to important and clinically relevant advances, including the possibility of establishing DNA diagnostic tests and providing a molecular handle to probe the pathophysiology of this disorder. lo A screening test for mutations in the CHM/REP-I gene using PCR-SSCP (polymerase chain reaction-single stranded conformation polymorphism) was developed" and the mutations that have been characterized to date in choroideremia patients were reviewed recently by Cremers and co-workers." All of the mutations, except one, are predicted to result in the loss-offunction of the c H M/REP-I gene, ie, the mutations lead to the synthesis of a truncated, nonfunctional, or rapidly degraded polypeptide. Approximately 25% of European CHM patients have large deletions or translocations that disrupt the CHM gene; 40% of the mutant alleles contain point mutations or small deletions/insertions that result in premature stop codons. In one case,