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).
See also choroideremia, deafness, and mental retardation (303110), a ... 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). 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 caused by mutation in the CHM gene.
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 ... 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.
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 ... 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.
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 ... 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. In 6 patients with choroideremia from 12 Danish families, Schwartz et al. (1993) identified a nonsense mutation in the CHM gene (300390.0007). Van Bokhoven et al. (1994) reviewed the spectrum of mutations in the CHM gene in patients from 15 Danish and Swedish families. They noted that all CHM gene mutations detected to that time gave 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.
Affected males. The diagnosis of choroideremia (CHM) can be made if the following are present [Roberts et al 2002]: ...
DiagnosisClinical DiagnosisAffected males. The diagnosis of choroideremia (CHM) can be made if the following are present [Roberts et al 2002]: A history of defective dark adaptation. Poor vision in the dark is commonly the first symptom in affected males. Males may not note such symptoms until their early teens. Characteristic fundus appearance. Patchy areas of chorioretinal degeneration generally begin in the mid-periphery of the fundus. The areas of chorioretinal degeneration progress to marked loss of the retinal pigment epithelium and choriocapillaris (inner of the two vascular layers of the choroid that is composed largely of capillaries) with preservation of the deep choroidal vessels, as demonstrated by intravenous fluorescein angiography. The function and anatomy of the central macula is preserved until late in the disease process. Peripheral visual field loss. Peripheral visual field loss manifests as a ring scotoma and generally follows changes in the fundus appearance. Areas of visual field loss closely match areas of chorioretinal degeneration. The electroretinogram (ERG) of affected males may at first show a pattern of rod-cone degeneration, which eventually becomes non-recordable. Family history consistent with X-linked inheritance Carrier females Carrier females have fundus changes that are similar to those in affected males and follow a similar pattern of progression. Carrier females do not experience significant visual impairment and in general are asymptomatic. Carrier females may show changes with ERG, dark adaptation, and visual field testing. The ERG may be normal in obligate carriers or in carriers with characteristic fundus changes. Sieving et al [1986] demonstrated that although abnormal responses may be recorded in female carriers with a dim blue flash, a dark-adapted white flash, or a flickering stimulus, no one test consistently predicted carrier status. Fundus autofluorescence may demonstrate in female carriers patchy areas of loss of fluorescence throughout the fundus [Preising et al 2009].Carrier females age 21-65 years had no change in the Arden ratio of the electrooculogram [Yau et al 2007]. TestingChromosome analysis. A high-resolution karyotype may reveal deletion of Xq21 in males with a contiguous gene deletion or an X;autosome translocation in symptomatic females. Immunoblot analysis. Affected males show absence of the REP-1 protein by western analysis of protein from peripheral blood lymphocytes or cell lines using anti-REP-1 antibody [MacDonald et al 1998]. Molecular Genetic TestingGene. CHM is the only gene in which mutation is currently known to cause choroideremia. Clinical testingTargeted mutation analysis. A recurrent mutation (exon 13, donor splice site, insertion T) accounts for most mutations in the Finnish population [MacDonald et al 2004]. Sequence analysis. Sequence analysis of the 15 exons and adjacent splice sites detects mutations in approximately 60%-95% of affected males [van den Hurk et al 1997, Fujiki et al 1999, McTaggart et al 2002, van den Hurk et al 2003]. Duplication/deletion analysis. CHM deletions involving multiple and single exons, and even the entire gene, have been reported. See HGMD.Research testing. If sequence analysis and duplication/deletion analysis together fail to identify a mutation, reverse transcriptase PCR, northern blot analysis, or protein truncation testing can be employed on a research basis to detect aberrantly spliced products and/or check protein integrity [MacDonald et al 2004]. Table 1. Summary of Molecular Genetic Testing Used in ChoroideremiaView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityAffected MalesCarrier FemalesCHMSequence analysisSequence variants 2~60%-95% 360%-95%Clinical0% 4Whole- and partial-gene deletionsDuplication / deletion analysis 5 Whole- and partial-gene deletionsNot needed 64%-25% 3Targeted mutation analysisExon 13, donor splice site, insertion TMost mutations in the Finnish population1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Small intragenic deletions/insertions, missense, nonsense, and splice site mutations3. van den Hurk et al [1997], Fujiki et al [1999], McTaggart et al [2002], van den Hurk et al [2003]4. Sequence analysis of genomic DNA cannot detect exonic or whole-gene deletions on the X chromosome in carrier females.5. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.6. Sequence analysis can detect putative exonic and whole-gene deletions on the X chromosome in affected males based on lack of amplification by PCR.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing Strategy To confirm the diagnosis in a probandClinical examination, in general, suggests a putative diagnosis of choroideremia in an affected male. Sequence analysis is the first step to confirm the diagnosis. When the clinical diagnosis is consistent with choroideremia, but no mutation is found by sequence analysis, duplication/deletion analysis is the next step. Carrier testing for at-risk relatives requires prior identification of the disease-causing mutation in the family.Note: (1) Carriers are heterozygotes for this X-linked disorder and may develop clinical findings related to the disorder. (2) Identification of female carriers requires either (a) prior identification of the disease-causing mutation in the family or, (b) if an affected male is not available for testing, molecular genetic testing first by sequence analysis, and then, if no mutation is identified, by methods to detect gross structural abnormalities.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) DisordersCHM is typically an isolated finding; rarely, it may be part of a contiguous gene syndrome involving Xq21.Males with large interstitial deletions involving Xq21 and additional X-chromosome material may have CHM, severe cognitive deficits, and birth defects such as cleft lip and palate and agenesis of the corpus callosum [Schwartz & Rosenberg 1996]. Males with smaller deletions of Xq21 only may have CHM, mixed sensorineural and conductive hearing loss from stapes fixation with perilymphatic gusher caused by deletion of POU3F4 (locus name DFN3), and varying degrees of cognitive deficits caused by deletion of RSK4 [Yntema et al 1999]. The presence of premature ovarian failure (POF) and mixed conductive and sensorineural deafness in the female with a de novo X;4 translocation reported by Lorda-Sanchez et al [2000] is consistent with a contiguous gene deletion of Xq21.
Affected males. Choroideremia (CHM) is characterized by progressive chorioretinal degeneration in affected males. Typically, symptoms evolve from night blindness to peripheral visual field loss, with central vision preserved until late in life. Males in their 40s have very good visual acuity but only a small visual field. Later (age 50-70 years) the central vision is lost. ...
Natural HistoryAffected males. Choroideremia (CHM) is characterized by progressive chorioretinal degeneration in affected males. Typically, symptoms evolve from night blindness to peripheral visual field loss, with central vision preserved until late in life. Males in their 40s have very good visual acuity but only a small visual field. Later (age 50-70 years) the central vision is lost. A recent study in 115 males (mean age 39 years) with CHM confirmed the typically slow rate of visual acuity loss and the generally good prognosis for central visual acuity retention until the seventh decade [Roberts et al 2002]. In that study, 84% of males under age 60 years had visual acuity of 20/40 or better and 35% of individuals over age 60 years had a visual acuity of 20/200 or worse.Posterior subcapsular cataracts are found in 31% of males.Cystoid macular edema, common in individuals with retinitis pigmentosa (RP), is not seen in individuals with CHM.Carrier females. Carrier females are generally asymptomatic; however, signs of chorioretinal degeneration can be observed with careful fundus examination. These signs become more readily apparent after the second decade. Females are occasionally severely affected with findings that mimic those of affected males because of skewed X-chromosome inactivation or the presence of an X;autosome chromosome translocation involving Xq21 [Lorda-Sanchez et al 2000]. In the latter instance, CHM results from either disruption of the gene at the site of the translocation or from a submicroscopic deletion of multiple genes resulting in a continuous gene deletion syndrome.Symptomatic but mildly affected females are likely underreported in the literature.
Genotype-phenotype correlations have not yet been demonstrated for this disorder....
Genotype-Phenotype CorrelationsGenotype-phenotype correlations have not yet been demonstrated for this disorder.Individuals with full deletions of CHM appear to be no more adversely affected than those with point mutations; all point mutations characterized thus far are nonsense mutations that result in a truncated unstable protein, which is rapidly degraded. Thus, functionally, full-gene deletions and point mutations both result in absence of the REP-1 protein.
Laboratory analysis may not always support the clinical diagnosis of choroideremia (CHM). For instance, a study identified 13 individuals diagnosed with CHM in whom subsequent laboratory analysis showed either presence of the REP-1 protein or absence of mutations in the CHM exons/splice sites [Lee et al 2003]. Upon reassessment of available clinical data, alternate diagnoses were suggested for eight of the 13. Specifically, CHM needs to be distinguished from the following retinal dystrophies:...
Differential DiagnosisLaboratory analysis may not always support the clinical diagnosis of choroideremia (CHM). For instance, a study identified 13 individuals diagnosed with CHM in whom subsequent laboratory analysis showed either presence of the REP-1 protein or absence of mutations in the CHM exons/splice sites [Lee et al 2003]. Upon reassessment of available clinical data, alternate diagnoses were suggested for eight of the 13. Specifically, CHM needs to be distinguished from the following retinal dystrophies:X-linked retinitis pigmentosa (RP). Retinitis pigmentosa (RP) is a group of inherited disorders in which abnormalities of the photoreceptors (rods and cones) or the retinal pigment epithelium (RPE) of the retina lead to progressive visual loss. The symptoms of RP, i.e., "night blindness" and constriction of peripheral visual field are similar to those of CHM. Diagnosis of RP also relies on electroretinography (ERG) and visual field testing. RP can be inherited in an autosomal dominant, autosomal recessive, or X-linked manner. X-linked RP (XLRP) can be either recessive, affecting males only, or dominant, affecting both males and females; females are always more mildly affected. Mutations in RPGR (also called RP3) and RP2 are the most common causes of XLRP. Linkage studies suggest that they account for 70%-90% and 10%-20%, respectively, of X-linked RP. In the later stages of CHM, when the loss of choroid and retina are significant, the fundus appearance may be confused with end-stage RP; however, the degree of migration of pigment into the retina that typifies RP is not seen in individuals with CHM. The X-linked pattern of inheritance may lead one to suggest a diagnosis of X-linked RP. Obligate carriers of CHM have patchy areas of mid-peripheral chorioretinal degeneration, whereas female carriers of X-linked RP may have areas of bone spicule formation in the retinal periphery. Usher syndrome type 1 is characterized by congenital, bilateral, profound hearing loss, vestibular areflexia, and adolescent-onset retinitis pigmentosa. Unless fitted with a cochlear implant, individuals do not typically develop speech. Retinitis pigmentosa develops in adolescence, resulting in progressively constricted visual fields and impaired visual acuity. The diagnosis is established on clinical grounds using electrophysiologic and subjective tests of hearing and retinal function. Mutations in genes at six different loci cause Usher syndrome type I. Genes at five of these loci, MYO7A (locus USH1B), USH1C (USH1C), CDH23 (USH1D), PCDH15 (USH1F), and USH1G have been identified. Usher syndrome type 1 may be confused with the contiguous gene deletion syndrome, CHM and deafness with perilymphatic gusher. The scalloped areas of significant chorioretinal degeneration with preservation of the choroidal vessels, typical of CHM, are not seen in Usher syndrome type 1. Gyrate atrophy of the choroid and retina. The progressive nature of scalloped areas of chorioretinal atrophy seen in gyrate atrophy of the choroid and retina may be confused with CHM. Gyrate atrophy of the choroid and retina is an autosomal recessive condition caused by mutations in the gene encoding ornithine aminotransferase. Individuals with gyrate atrophy of the choroid and retina have elevated plasma concentration of ornithine, which is not seen in individuals with CHM. Kearns-Sayre syndrome (KSS) is a multisystem mitochondrial DNA deletion syndrome defined by the triad of onset before age 20 years, pigmentary retinopathy, and progressive external ophthalmoplegia (PEO). In addition, affected individuals have at least one of the following: cardiac conduction block, cerebrospinal fluid protein concentration greater than 100 mg/dL, or cerebellar ataxia. Onset is usually in childhood. Diagnosis of mtDNA deletion syndromes relies upon presence of characteristic clinical findings and, in KSS, changes on muscle biopsy (i.e., ragged-red fibers [RRF] with the modified Gomori trichrome stain, hyperactive fibers with the succinate dehydrogenase [SDH] stain, and failure of both RRF and some non-RRF to stain with the histochemical reaction for cytochrome c oxidase [COX]) and decreased activity of respiratory chain complexes containing mtDNA-encoded subunits in muscle extracts. A "choroideremia-like" fundus appearance was observed in an 18-year-old who had a total loss of retina, retinal pigment epithelium, and choroid, but who had normal-caliber major retinal vessels, a few remaining choroidal vessels, and no optic atrophy. While this clinical presentation may be found in end-stage CHM after age 60 years, the central macula of an 18-year-old with CHM is typically preserved. The affected individual's mother and sister did not show carrier signs of CHM. The later onset of external ophthalmoplegia, hearing loss, ataxia, and insulin-dependent diabetes mellitus in this individual led to the diagnosis of Kearns-Sayre syndrome; a 2309-base pair deletion was identified in mtDNA.
To establish the extent of disease in an individual diagnosed with choroideremia (CHM), the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with choroideremia (CHM), the following evaluations are recommended:Ophthalmologic examination including visual acuity and Goldmann visual field testing for a baseline Family history Electroretinogram Funduscopic examination Treatment of ManifestationsNutrition and ocular health have become increasingly topical: For those individuals who do not have access to fresh fruit and leafy green vegetables, a supplement with antioxidant vitamins may be important. No information is available on the effectiveness of vitamin A supplementation in the treatment of CHM. A source of omega-3 very-long-chain fatty acids, including docosahexaenoic acid, may be beneficial, as clinical studies suggest that a regular intake of fish is important. Cataract surgery may be required for individuals with a posterior subcapsular cataract. UV-blocking sunglasses may have a protective role when an affected individual is outdoors. Low vision services are designed to benefit those whose ability to function is compromised by vision impairment. Low vision specialists, often optometrists, help optimize the use of remaining vision. Services provided vary based on age and needs. Counseling from organizations or professionals who work with the blind and visually impaired may be needed to help the affected individual cope with issues such as depression, loss of independence, fitness for driving, and anxiety over job loss. SurveillancePeriodic ophthalmologic examination to monitor progression of CHM is recommended as affected individuals need advice regarding their levels of visual function. Goldmann visual field examinations provide practical information for both the clinician and the affected individual.Agents/Circumstances to AvoidUV exposure from sunlight reflected from water and snow should be avoided.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationGene therapy for individuals with CHM may be a future possibility. Introduction of adenovirus containing the CHM coding region can restore in vitro protein levels and REP-1 activity in CHM-deficient lymphocytes and fibroblasts [Anand et al 2003]. CHM is a likely target for gene therapy with defined clinical parameters that may guide when to intervene and how to monitor the outcome [Jacobson et al 2006]. Note: A gene therapy trial for CHM is currently planned but not yet registered with www.clinicaltrials.gov. No public information is available [Author, personal communication].Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.OtherA small short-term study of lutein oral supplementation (20 mg/day) showed that macular lutein was increased in individuals with CHM who received the supplement [Duncan et al 2002]; however, whether or not such supplementation provides a long-term protective effect is unknown. A small study of 30 persons, including individuals with CHM, concluded that individuals with CHM already have normal levels of macular carotenoids (e.g., lutein and zeaxanthin). Therefore, diet supplementation is unlikely to alter the clinical course of the disease [Zhao et al 2003].
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Choroideremia: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDCHMXq21.2Rab proteins geranylgeranyltransferase component A 1CHM @ LOVD CHM @ USHbases Retina International Mutations of the Rab Escort Protein 1 Finnish Disease DatabaseCHMData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Choroideremia (View All in OMIM) View in own window 300390CHM GENE; CHM 303100CHOROIDEREMIA; CHMNormal allelic variants. The gene comprises 15 exons. Described normal allelic variants include: Single nucleotide polymorphism in exon 5 (p.Ala117Ala) and 13 (p.Val506Ala, p.Thr532Ser) Polymorphic microsatellite marker in intron 9 Dinucleotide repeat polymorphism in intron 14 Pathologic allelic variants. Virtually all known mutations in CHM result in the truncation and therefore functional loss of the CHM gene product, REP-1. One exception is the report of an L1 retrotransposon insertion in exon 6 that results in the direct splicing of exon 5 to exon 7 with maintenance of the reading frame. The missing amino acids are part of a conserved region that forms a hydrophobic groove that is proposed to bind geranyl-geranyl groups [van den Hurk et al 2003]. Normal gene product. Rab escort protein-1 (REP-1) is a component of Rab geranylgeranyltransferase, an enzyme complex that mediates correct intracellular vesicular transport. The REP1 protein functions in the prenylation (covalent addition of 20-carbon geranylgeranyl units) to Rab GTPases. Lymphocytes from individuals with CHM show marked inability to prenylate Rab proteins, in particular Rab27A. Rab proteins have a role in organelle formation and trafficking of vesicles in exocytic and endocytic pathways [Seabra et al 2002]. In an individual with choroideremia, REP-2, a protein that is functionally similar to REP-1, may compensate for the loss of REP-1 function in all but the retinal cells.Larijani et al [2003] showed that the REP-1-Rab27A complex was prenylated more efficiently in vitro than the REP-2-Rab27A complex. GDP-bound Rabs are the preferred substrate for REPs, whereas Rab27A was shown to have a slower rate of intrinsic hydrolysis than other Rabs. Based on these observations, Larijani et al [2003] suggest that the prenylation defect underlying CHM is twofold:1.Rab27A relies solely on prenylation by the already less efficient REP-2. 2.The innately slower GTP hydrolysis of Rab27A results in a higher proportion of the inactive form of this molecule, which is unable to bind REPs. Alternatively, Rak et al [2004] demonstrated that Rab7 successfully out-competed Rab27A in vitro for prenylation and proposed that when REP-1 function is lost, all prenylation function is provided by REP-2; however, Rab molecules with a higher affinity for REP-2 compete with Rab27A for prenylation. The molecular pathogenesis of CHM remains speculative.Abnormal gene product. Truncated and putatively lost