Isolation of a candidate gene for choroideremia.

Abstract

Choroideremia is an X chromosome-linked retinal dystrophy of unknown pathogenesis. We have isolated cDNAs from a human retinal library with a genomic probe located at the X chromosomal breakpoint in a female with choroideremia and an X;13 translocation. This cDNA spans the breakpoint in the X;13 translocation female and is deleted in

Yeast Artificial Chromosome Cloning of the Xq13.3-q21.31 Region and Fine Mapping of a Deletion Associated with Choroideremia and Nonspecific Mental Retardation

“…The ated in the chromosomal region defined by identification of submicroscopic deletions as-intervals 8, 9 and 10. At the proximal side, so ciated w ith eith erC H M [2 8 ]o rD F N 3 [6 ,9] this region is demarcated by the deletions has enabled the subsequent cloning of the found in DFN3 patients II/7, 1/10, and TD relevant genes [10][11][12][13]. Characterization of [9].…”

“…Sizeable deletions have also been found in patients with nonsyndromic CHM or DFN3 [4-6, 8,9], Employing positional cloning strategies, the genes underlying CHM and DFN3 have been isolated. Analysis of patients with Xq21 deletions and syndromic and nonsyndromic forms of MR has enabled us to map the gene for X-linked MR to a region between CHM and DFN3 [4,7,[10][11][12][13].…”

Deficient Geranylgeranylation of Ram/Rab27 in Choroideremia

“…Studies of carriers and early diseased eyes suggest that the RPE and/or the choriocapillaris are the primary site of degeneration, with secondary involvement of photoreceptors (1). The gene responsible for CHM was localized to chromosomal band Xq21 and isolated by positional cloning techniques (2,3). An insight into the function of the CHM protein came with the finding that it encodes a subunit of Rab geranylgeranyl transferase, an enzyme that modifies Rab proteins with the covalent attachment of a lipid moiety (4,5).…”

Amino- and carboxy-terminal domains of the yeast Rab escort protein are both required for binding of Ypt small G proteins.

“…In humans, deletions in the chromosomal locus coding for REP1 (the CHM locus) result in a syndrome called choroideremia (Cremers et al, 1990;Merry et al, 1992;Seabra et al, 1992), an X-linked progressive tapetochoroidal dystrophy resulting in blindness in early adulthood (McCulloch, 1988). An autosomal homologue (CHML) of the choroideremia gene is located on human chromosome lq, and its gene product REP2 has been shown to have functions overlapping those of REP1 (Cremers et al, 1992;Seabra et al, 1992;van Bokhoven et al, 1994a,c) but with different activity toward the Rab3 subfamily Cremers et al, 1994) and toward the Rab27 protein (Seabra et al, 1995).…”