Molecular basis of choroideremia (CHM): Mutations involving the rab escort protein‐1 (REP1) gene

Abstract

Choroideremia (CHM) is an X-linked recessive eye disease that results from mutations involving the Rab escort protein-1 (REP-1) gene. In 18 patients deletions of different sizes have been found. Two females suffering from CHM were reported to have translocations that disrupt the REP-1 gene. In 22 patients, small mutations have been identified* Interestingly, these are all nonsense, frameshift or splice-site mutations; with one possible exception, missense mutations have not been found. This comprises all the known mutations in the disease. Hum Mutat 9:110-117, 1997. © 1997 Wiley-Uss, Inc. key w o r d s : c h o r o i d e r e m i a (CHM), m u t a t i o n s , r a b e s c o r t p r o t e i n-1 (REP-1) gene by X-autosomal translocations (Kaplan et ab, 1989; Siu et al., 1990). In these cases, X-inacti-vation is nonrandom; the normal X is preferen­ tially inactivated, while both translocation frag­ ments remain active. The gene for CHM was localized to the X q l3-q22 region by linkage analysis (Lewis et a l., 1985; Nussbaum et alM 1985; Lesko et al., 1987; Sankila et al., 1989). This assignment was further refined by the characterization of cytogenetically visible deletions in patients with CHM, mental retarda-tion(M R), and deafness type 3 (DFN3) (Rosenberg et al.} 1987; Schwartz et al., 1988; Cremers et alM 1989a). Molecular analysis of deletions in patients with classic CHM (Cremers et al., 1987, 1989b, 1990a,b) formed the basis for the positional cloning of a part of the CHM gene from Xq21.2 (Cremers

De Novo Mutation in a Choroideremia Carrier

“…Her de novo mutation has been previously identified and described in other patients with the clinical diagnosis of CHM. 1,2,6 To our knowledge, this is the first case of a de novo mutation in the CHM gene described in either a carrier of or an affected individual with CHM.…”

“…1 In these cases, X chromosome inactivation is nonrandom; the normal X chromosome is preferentially inactivated, while both translocation fragments remain active. 1 The normal karyotype determined in our patient does not support translocation or chromosomal rearrangement as the cause of her phenotype. Her de novo mutation has been previously identified and described in other patients with the clinical diagnosis of CHM.…”

“…Its prevalence is estimated as 1 case in 100,000 population. 1 The severity of the ophthalmic manifestation of CHM may show considerable interfamilial as well as intrafamilial variability. 2,3 Affected males have progressive loss of initially peripheral and subsequently central visual function.…”

“…2,3 Affected males have progressive loss of initially peripheral and subsequently central visual function. 1,2 Female carriers generally do not have clinically significant visual impairment; most have some degree of pigmentary retinal degenerative change, which has been described as a "moth-eaten" fundus appearance. 3 Infrequently, carriers may manifest severe retinal pigmentary degenerative changes as well as choroidal atrophy and impairment of visual function.…”

“…5 Mutations in the gene for the protein REP-1 (Rab escort protein) have been identified in patients with choroideremia. 1 Rab proteins are geranylgeranyltransferases that control protein trafficking in secretory and endocytic pathways. REP is required for Rab geranylgeranylation and its subsequent association with the membrane of specific organelles.…”