Alternative titles; symbols
Other entities represented in this entry:
SNOMEDCT: 75241009; ICD10CM: H31.21; ICD9CM: 363.55; ORPHA: 180; DO: 9821;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Xq21.2 | Choroideremia | 303100 | X-linked | 3 | CHM | 300390 |
A number sign (#) is used with this entry because choroideremia (CHM) is caused by mutation in the CHM (REP1) gene (300390) on chromosome Xq21.
Choroideremia is an X-linked disease that leads to the degeneration of the choriocapillaris, the retinal pigment epithelium, and the photoreceptor of the eye (Cremers et al., 1990). The characteristic lesion of choroideremia is chorioretinal scalloped atrophy in the midperipheral fundus, with preservation of the macula (Li et al., 2014).
See also choroideremia, deafness, and mental retardation (303110), a contiguous gene deletion syndrome involving the CHM and POU3F4 (300039) genes on Xq21. X-linked deafness-2 with stapes fixation (DFNX2; 304400) is also caused by mutation in the CHM gene.
Affected males suffer progressive loss of vision (reduction of central vision, constriction of visual fields, night blindness) beginning at an early age, and the choroid and retina undergo complete atrophy. Heterozygous females show no visual defect but often show striking funduscopic changes such as irregular pigmentation and atrophy around the optic disc (Cremers et al., 1989; Lesko et al., 1987; Ohba and Isashiki, 2000). Fully affected females have been reported (Fraser and Friedmann, 1967; Shapira and Sitney, 1943). These raise the usual questions of X-chromosomal aberration, unfortunate lyonization in a heterozygote, homozygosity, etc.
Stankovic (1958) reported a family with 'choroidal sclerosis,' which was of interest because female carriers showed partial expression. Sorsby (cited in Franceschetti et al., 1963) was of the opinion that the cases reported by Sorsby and Savory (1956) as X-linked choroidal sclerosis were instances of choroideremia. Krill and Archer (1971) were of the same view. An extensive study in Holland was conducted by Kurstjens (1965). Harris and Miller (1968) observed visual impairment in a heterozygote in the family reported earlier by McCulloch and McCulloch (1948). From study of affected members of 1 kindred, Shapiro and Gorlin (1974) concluded that choroidal sclerosis is a stage in the evolution of choroideremia.
In Finland, about 58 cases had been identified by 1980 (Forsius et al., 1980). Almost all of them come from the northern part of the country. Karna (1986) traced 111 choroideremia patients and 188 carriers in 4 kindreds from northern Finland and 1 from the Savo district. A large proportion of both groups, 80 patients and 126 carriers, were examined ophthalmologically. The largest of the kindreds, from the Salla area of Finland, had 80 cases and 146 carriers in 8 generations among the more than 3,000 descendants of an ancestral female. The clinical picture proved unexpectedly variable with some males already virtually blind under age 30 years and others over age 50 who were symptom-free. By history, only 7 of 105 carriers had symptoms, but 21 of 52 carriers examined had changes in the visual fields and defective dark adaptation. Decline in the latter function over a 3-year period was observed in 1 heterozygote and the changes, including funduscopic alterations, were most marked in older carriers. It was often difficult to be sure of the diagnosis before the person was 10 years of age, but the diagnosis was made in 2 boys aged 3 months and 10 months.
Cheung et al. (2004) showed that the multifocal electroretinogram might be a sensitive tool to measure functional abnormalities in choroideremia carriers. They also noted that mosaic inactivation of the normal allele might cause expression of the mutation with severe visual loss in some choroideremia carriers.
Grover et al. (2002) compared the extent of intraocular light scatter (straylight) in carriers of CHM and the various forms of X-linked retinitis pigmentosa (XLRP) to clarify the relationship between photoreceptor cell degeneration and intraocular light scatter in hereditary retinal degenerations. The carriers of XLRP who had evidence of photoreceptor cell dysfunction (as determined by visual field loss and reduced electroretinogram amplitudes) had increased levels of intraocular straylight, whereas the carriers of CHM, who showed fundus abnormalities alone, in the absence of demonstrable photoreceptor cell dysfunction, had normal or minimally elevated levels of light scatter. The authors concluded that the increased levels of intraocular light scatter observed in some patients with hereditary retinal degenerations may result from subclinical changes in the posterior subcapsular cataract portion of the crystalline lens as a consequence of photoreceptor cell degeneration.
Mura et al. (2007) reported the clinical, functional, and in vivo microanatomic characteristics of a family with choroideremia with a deletion of the entire CHM gene. At 4 years of age, the proband had a hypopigmented fundus, retinal pigment epithelial (RPE) mottling, and reduced dark-adapted electroretinograms (ERGs). Severe RPE and choriocapillaris atrophy developed by age 6 years, paralleled by a lesser ERG decline. Optical coherence tomography (OCT) findings showed normal neural retina overlying mild changes in the RPE as well as thinned neural retina with impaired lamination over RPE and choriocapillaris atrophy. The carrier mother had diffuse elevation of 650-nm dark-adapted thresholds. Mura et al. (2007) concluded that deletion of the CHM gene causes severe choroideremia. Results of serial ERGs and fundus examinations documented progression first of rod and then cone disease. Fundus appearance deteriorated rapidly, in excess of the severity of the ERG decline. OCT findings explained this observation, at least in part.
Li et al. (2014) studied 6 Chinese probands who were initially diagnosed with retinitis pigmentosa (RP; see 268000) but who were later found to have choroideremia (see MOLECULAR GENETICS). All probands experienced night blindness from early childhood, with gradually reduced visual acuity later in life and retinal degeneration with pigmentary disturbance on fundus examination. Review of fundus images demonstrated changes consistent with choroideremia, although the characteristic chorioretinal scalloped atrophy in the midperiphery with macular sparing was not seen. ERGs in 3 probands showed no appreciable responses of cones or rods in both eyes. Examination of an obligate carrier mother revealed normal visual acuity without night blindness but also revealed a number of yellow crystalline-like spots in the macular area and irregular mottled pigmentation in the midperiphery, with normal rod responses and mildly reduced cone responses on ERG. Li et al. (2014) noted that although none of the probands exhibited the characteristic chorioretinal scalloped atrophy with preservation of the macula of choroideremia, their fundus changes were also atypical compared to those seen in classic RP.
Jolly et al. (2015) used the Farnsworth-Munsell 100 hue test, visual acuity testing, and autofluorescence imaging in a prospective cohort study of functional defects in color vision in 30 patients with CHM and 10 age-matched male controls. To exclude changes caused by degeneration of the fovea, a subgroup of 14 CHM patients with visual acuity greater than 6/6 (or 20/20) was analyzed. Mean color vision total error scores were 120 in the greater than 6/6 group, 206 in the lower than 6/6 group, and 47 in the control group. Covariate analysis showed a significant difference in color vision total error score between the groups. The color vision defect deteriorated as the degeneration encroached on the fovea. The reduction in color vision was generalized across the spectrum, varying between patients.
The term choroideremia, which is comparable to irideremia and means absence of choroid, is, strictly speaking, inappropriate since there is no congenital absence of the choroid. The condition is an abiotrophy beginning shortly after birth and progressing gradually. Waardenburg favored the alternative designation 'tapetochoroidal dystrophy' (TCD) (Pameyer et al., 1960).
MacDonald et al. (1998) concluded that the clinical diagnosis of CHM can be confirmed simply by immunoblot analysis with anti-REP1 antibody, showing the absence of REP1 protein in peripheral blood samples. Because all known mutations in the CHM gene create stop codons that truncate the protein product and result in absence of REP1, the authors predicted that most patients with CHM may be diagnosed by this procedure.
Poloschek et al. (2008) studied 2 brothers and a 15-year-old unrelated boy with choroideremia. All had deletions on chromosome Xq21, ranging in size from approximately 6.3 to 9.7 Mb in the sibs and from 8.5 to 14.1 Mb in the unrelated boy; both deletions encompassed the REP1 gene. Other features in these patients included mental retardation, motor delays, and hearing loss, findings that the authors suggested might be components of the Martin-Probst deafness-mental retardation syndrome (MPDMRS; 300519), which also maps to this region of the X chromosome. Fundus autofluorescence (FAF) in the affected sibs was almost intact in the macula but severely reduced in the midperiphery to periphery; FAF could not be performed in the 15-year-old boy due to fixation problems. FAF in both carrier mothers and the sibs' carrier sister displayed speckles, representing small areas of reduced or increased autofluorescence, but was otherwise normal; Poloschek et al. (2008) stated that this flecked pattern seemed to be specific to choroideremia carriers and had not been described in any other retinal dystrophy, and suggested that it represented a powerful tool for identifying CHM carriers and distinguishing them from carriers of other X-linked ocular disorders such as retinitis pigmentosa (see RP2, 312600), in which there is a radial FAF pattern.
Nussbaum et al. (1985) found that the polymorphic DNA probe DXYS1, located at Xq13-q21, shows no recombination with choroideremia (lod = 5.78). This result indicates that, with 90% probability, choroideremia maps within 9 cM of DXYS1. Lesko et al. (1985) had a lod score of 12 for 0.0 recombination with DXYS1. Gal et al. (1986) suggested the following order: Xcen--DXYS1--DXS3--TCD--DXS11--Xqter. DXS3 maps to Xq21.3-q22 and DXS11 to Xq24-q26 (HGM8). Lesko et al. (1987) found recombination frequencies of 0 to 4% between TCD and 5 markers located in Xq13-q22. Uhlhaas et al. (1987) also provided data on linkage to multiple DNA markers. MacDonald et al. (1987) found a maximum lod score of 3.98 at theta = 0.14 for linkage with DXS3 and a total maximum lod score from all studies of 5.23 at theta = 0.05 for DXYS1. These findings represented looser linkage than had previously been reported. In a study of 14 families, Wright et al. (1990) found linkage to 3 markers on Xq21, giving a 4 point lod score of 8.25. No evidence of submicroscopic deletion was observed using 2 DNA markers thought to lie within 1 Mb of the TCD gene. Siu et al. (1988, 1990) found a de novo balanced translocation, t(X;13)(q21.2;p12), in a patient with choroideremia. They found evidence that the DXYS1 locus is distal to the choroideremia gene; the derivative chromosome 13 carried a RFLP allele of this locus. Cremers et al. (1989) reported a case of a female with TCD and a de novo X-autosome translocation. Merry et al. (1990) also studied the X;13 translocation described by Siu et al. (1988).
Genealogic Studies
Sankila et al. (1986, 1987) urged a historical-genealogic approach to linkage analysis. In studies of isolated populations, they found that all of 36 patients and 48 carriers with choroideremia in Finland had the same haplotype: TCD/DXYS1, 11 kb/DXYS12, 1.6 kb. The DXYS1 locus and the DXYS12 locus are located at Xq13-q21 and Xq13-q22, respectively. Given that at least 105 female meioses transmitting TCD occurred in these kindreds since 1650, extremely close linkage between the 3 loci is suggested. Sankila et al. (1987) also reported haplotype data on Finnish TCD using multiple DNA probes and presented evidence on the order of the several marker loci and TCD. Multipoint linkage analysis by Sankila et al. (1989) placed TCD distal to PGK (311800) and DXS72, very close to DXYS1 and DXYS5 (maximum lod = 24 at theta = 0) and proximal to DXYS4.
Using DNA markers in 3 Danish families, Schwartz et al. (1986) provided further evidence for assignment for the choroideremia locus to Xq13-q21.
Deletion Studies
Hodgson et al. (1987) described a family in which an X-chromosome deletion was segregating with choroideremia. The affected male was also mentally retarded. The loss of 2 RFLPs in the affected male indicated the localization of the choroideremia locus to Xq13-q21 and placed the loci for anhidrotic ectodermal dysplasia (305100) and the X-linked immunodeficiencies (e.g., 300755) outside this region. Schwartz et al. (1987) mapped the TCD locus by demonstrating deletion of 3 XY-probes in 2 males with choroideremia and X-chromosomal deletion. Nussbaum et al. (1987) studied 2 families in which males with choroideremia also had mental retardation and deafness (303110). In 1 family an interstitial deletion in Xq21 was visible by cytogenetic analysis, and 2 DNA markers, DXYS1 and DXS72, were deleted. In the second family, an interstitial deletion was suspected on phenotypic grounds but could not be confirmed by high-resolution cytogenetic analysis.
Using subtractive hybridization, Lesko et al. (1987) isolated and characterized the sequences deleted from an individual with choroideremia and a visible deletion at Xq21. In 1 patient with no visible deletion, submicroscopic deletion was indicated by the absence of 2 single-copy sequences. Using these sequences as probes for in situ hybridization, Lesko et al. (1987) localized the choroideremia gene to Xq21. In 2 of 8 unrelated male patients with choroideremia, Cremers et al. (1987) found deletion of DXS165, which maps to Xq12-q21.3. Two other closely linked and probably flanking TCD markers, DXYS1 and DXS72, were not deleted, which may indicate that the physical distance between DXS165 and TCD is small. Schwartz et al. (1988) used DNA from 2 unrelated males who had choroideremia and an interstitial deletion on the proximal long arm of the X chromosome. In one the deletion was Xq21.1-q21.33; in the other the deletion was Xq21.2-q21.31. By Southern blot analysis, the authors mapped 10 different polymorphic DNA loci to the deletion and to the TCD locus. One probe was shown to cover one of the breakpoints of the smaller deletion.
Choroideremia is an X-linked disorder. In his Atlas of the Fundus Oculi, Wilmer (1934) showed the fundus of a 35-year-old man with 'choroidal sclerosis' whose maternal grandfather was also affected. Furthermore, 2 brothers and the maternal grandfather of the proband's maternal grandfather were also affected, i.e., the proband had inherited the disorder from his great-great-grandfather through the intermediacy of a carrier mother and great-grandmother.
Siu et al. (1988, 1990) found a de novo balanced translocation, t(X;13) (q21.2;p12), in a patient with choroideremia (303100). Cremers et al. (1989) reported another case of a female with TCD and a de novo X-autosome translocation. Merry et al. (1990) also studied the X;13 translocation described by Siu et al. (1988). Van Bokhoven et al. (1994) demonstrated that the breakpoint on the X chromosome in a CHM female with an X;7 translocation lay between exons 3 and 4 of the CHM gene.
Van den Hurk et al. (1992) analyzed the CHM gene in 30 choroideremia patients and identified 5 different nonsense and frameshift mutations in 5 probands (300390.0002-300390.0006, respectively). Each of these mutations introduced a termination codon into the open reading frame of the CHM candidate gene, thereby predicting a distinct truncated protein product.
In affected individuals from 16 branches of a large, 13-generation Salla pedigree from northeastern Finnish Lapland that accounted for one-fifth of the world's choroideremia patients, Sankila et al. (1992) identified a splice site mutation in the CHM gene (300390.0001), predicted to result in a truncated gene product. The mutation was unique in that it was not responsible for choroideremia in any of 4 additional Finnish pedigrees. Haplotyping performed by Sankila et al. (1987) had previously suggested that the large northern Finnish choroideremia pedigrees carried the same mutation.
Schwartz et al. (1993) analyzed 5 exons of the CHM gene in 12 Danish families with choroideremia and identified 6 different mutations in 6 unrelated probands, including 4 deletions of various sizes, 1 splice site mutation, and 1 nonsense mutation (see, e.g., 300390.0006 and 300390.0007).
In a 3-generation French family with choroideremia, consisting of 3 affected males, 5 carrier females, and 1 unaffected male, Pascal et al. (1993) analyzed 5 exons of the CHM gene and identified a 4-bp deletion (delTGTT; 300390.0006) that had been found in 2 unrelated patients from different geographic regions, Germany (van den Hurk et al., 1992) and Denmark (Schwartz et al., 1993). Pascal et al. (1993) suggested that the tetranucleotide TGTT might represent a minor hotspot for deletion due to slippage during replication.
Van Bokhoven et al. (1994) analyzed 9 exons of the 15-exon CHM gene in the 6 Danish families in which Schwartz et al. (1993) had not detected a mutation and in 3 Swedish families, and identified mutations in all but 2 of the patients (see, e.g., 300390.0008 and 300390.0009). The authors noted that all known CHM gene mutations in patients with choroideremia give rise to the introduction of a premature stop codon.
In a male patient with choroideremia, van den Hurk et al. (2003) identified an insertion of a full-length L1 retroposon in the coding region of the CHM gene (300390.0010).
Perez-Cano et al. (2009) analyzed the X-inactivation pattern in 12 carrier females, 1 of whom was severely affected, from 2 Mexican choroideremia families with mutations in the CHM gene. The X-chromosome inactivation pattern was random in 11 of the 12 females, including the affected female, who exhibited a fundus phenotype comparable to diseased males. The remaining carrier female, who had a conspicuous pattern of pigment epithelium mottling primarily in the peripheral retina, was found to have a skewed inactivation pattern; however, further analysis revealed that the preferentially inactivated X chromosome was the mutation-carrying X chromosome. Perez-Cano et al. (2009) stated that their results did not support a correlation between X-inactivation status and abnormal retinal phenotype in heterozygous carrier females.
Esposito et al. (2011) screened 20 Italian probands with choroideremia and identified mutations in the CHM gene in all but 1 of the men, in whom the authors concluded that the phenotype might overlap with that of other X-linked retinopathies. All of the variants were nonsense or frameshift mutations or deletions except for 1 missense mutation (H507R; 300390.0011), which segregated with disease in the proband's family, was not found in 200 control alleles, and caused functional impairment of REP1 due to exclusion from the isoprenylation cycle. Esposito et al. (2011) stated that this was the first evidence that a prenylation deficiency is necessary to cause CHM.
By whole-exome sequencing, Li et al. (2014) identified 6 hemizygous CHM mutations, 1 of which was the recurrent TGTT deletion (300390.0006), in 6 (4%) of 157 Chinese probands who had been diagnosed with retinitis pigmentosa. No pathogenic mutations in 62 known RP-associated genes were detected, and the CHM mutations were confirmed by Sanger sequencing; review of fundus images revealed changes consistent with choroideremia. Three of the probands were sporadic cases, whereas the remaining 3 had a family history consistent with the X-linked trait. All 6 mutations resulted in truncation or loss of function.
In the rat, Seabra et al. (1992) purified component A of RAB geranylgeranyl transferase, a single 95-kD polypeptide. The holoenzyme, which consists of components A and B (179080), attaches (3)H-geranylgeranyl to cysteines in 2 GTP-binding proteins, RAB3A (179490) and RAB1A (179508). The reaction is abolished when both cysteines in the COOH-terminal cys-cys sequence of RAB1A are mutated to serines. Six peptides from rat component A showed striking similarity to the products of the gene defective in choroideremia. The choroideremia protein resembles RAB3A GDI, which binds RAB3A. Seabra et al. (1992) suggested that component A binds conserved sequences in RAB and that component B transfers geranylgeranyl. A defect in this reaction may cause choroideremia. Seabra et al. (1993) established this to be the case by demonstrating that lymphoblasts from choroideremia subjects have a marked deficiency in the activity of component A, but not component B, of RAB GG transferase. The deficiency was more pronounced when the substrate was RAB3A, a synaptic vesicle protein, than it was when the substrate was RAB1A, a protein of the endoplasmic reticulum. Their studies suggested the existence of multiple component A proteins, one of which is missing in choroideremia. The multiplicity and functional redundancy of component A genes creates a situation in which defects in one of them might cause a degenerative disease of the organ in which that particular form of component A is most essential.
To clarify the pathogenesis of CHM, Syed et al. (2001) performed histopathologic examination, including immunocytochemistry with an antibody against the CHM gene product, REP1, and retinal cell-specific markers, on the eyes of an 88-year-old symptomatic female carrier of CHM and 6 normal, age-matched donors. The CHM carrier retina showed patchy degeneration, but the photoreceptor and retinal pigment epithelium loss appeared to be independent. The choriocapillaris was normal except where the retina had degenerated severely. REP1 was localized in the cytoplasm of rods but not cones. The authors stated that photoreceptor degeneration in CHM is generally considered secondary to the loss of choriocapillaris or retinal pigment epithelium. This study suggested that the rod photoreceptors might be the primary site of disease in CHM.
By conditional knockout of the Chm gene, Tolmachova et al. (2006) created a mouse model of choroideremia: heterozygous-null females exhibited characteristic hallmarks of CHM, with progressive degeneration of photoreceptors, patchy depigmentation of the retinal pigment epithelium, and Rab prenylation defects. Using tamoxifen-inducible and tissue-specific Cre expression in combination with conditionally deleted Chm alleles, Tolmachova et al. (2006) showed that CHM pathogenesis involves independently triggered degeneration of photoreceptors and the retinal pigment epithelium, associated with different subsets of defective Rabs.
Close linkage of choroideremia with the Xg locus was excluded by Bell and McCulloch (1971), who found 3 recombinants out of 6.
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