Alternative titles; symbols
HGNC Approved Gene Symbol: CHM
SNOMEDCT: 75241009; ICD10CM: H31.21; ICD9CM: 363.55;
Cytogenetic location: Xq21.2 Genomic coordinates (GRCh38) : X:85,861,180-86,047,558 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xq21.2 | Choroideremia | 303100 | X-linked | 3 |
CHM encodes REP1, a subunit of a 2-subunit RAB geranylgeranyl transferase (EC 2.5.1.60) that attaches 20-carbon isoprenoid groups to cysteine residues in Rab proteins, a family of GTP-binding proteins that regulate vesicular traffic (Seabra et al., 1993).
Nussbaum et al. (1987) used phenol-enhanced reassociation of 48,XXXX DNA in competition with excess DNA from a family with choroideremia (CHM; 303100), also known as tapetochoroidal dystrophy (TCD), to generate a library of cloned DNA enriched for sequences that might be deleted. Two of the first 83 sequences characterized from the library were found to be deleted in probands from 2 affected families. Isolation of these sequences proved that the second family carried a submicroscopic deletion and provided a starting point for identifying overlapping genomic sequences that span the deletion and may contain exons from the choroideremia locus.
Using chromosome walking and jumping techniques in a study of 4 deletions associated with choroideremia and a de novo X/13 translocation in a female with choroideremia, Cremers et al. (1989) narrowed the assignment of the TCD gene, or part of it, to a DNA segment of only 15 to 20 kb. Cremers et al. (1990) identified new DNA markers around the locus for choroideremia. They used these markers to define the minimal region of overlap from 4 deletions found in male patients with TCD and to isolate a 45-kb genomic DNA segment corresponding to this region of overlap. cDNA clones from a human retinal library were isolated using an evolutionarily conserved sequence from this DNA segment as a probe. cDNA subclones detected a transcript in choroid, retinal pigment epithelium, and other cells. The consensus cDNA of approximately 4.5 kb contained an open reading frame encoding a polypeptide of 316 amino acids. Fodor et al. (1991) pointed to homology between the predicted sequence of this protein and a protein involved in GTP metabolism, p25A-GDI. Waldherr et al. (1993) presented evidence based on sequence that MRS6 of S. cerevisiae is the yeast homolog of the CHM gene.
Van Bokhoven et al. (1994) isolated and characterized the complete open reading frame of the CHM gene and found that it encodes a protein of 653 amino acids.
Van Bokhoven et al. (1994) determined that the CHM gene contains 15 exons. They found that there may be an additional exon corresponding to the 5-prime noncoding region of the gene.
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 (303100). 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.
X-Inactivation Studies
To test directly the question of whether the choroideremia gene is subject to inactivation, Carrel and Willard (1993) examined inactive X-chromosome expression of the CHM gene in a lymphoblastoid cell line derived from a female with a translocation that disrupted the gene. The normal X chromosome in this t(X;13) cell line was nonrandomly inactivated as shown by late-replication studies and by methylation analysis at the DXS255 and FMR1 (309550) loci. Using PCR of reverse transcribed RNA (RT-PCR) from this cell line, Carrel and Willard (1993) identified CHM transcripts that crossed the translocation breakpoint, indicating that CHM is expressed from the normal, inactivated X chromosome. Quantitative comparison of RT-PCR products from the inactive X in the t(X;13) cell line with that from cell lines from a normal male and a 49,XXXXX female indicated that there was significant CHM transcription from the inactive X, at levels that were at least 50% of those seen in the active X. Confirming these results, CHM expression was also seen in RT-PCR in 3 active and 5 inactive human X-containing somatic cell hybrids. CHM is the first gene that is distal to the X-inactivation center on Xq, i.e., on the 'ancestral X chromosome,' to be shown to escape inactivation.
The finding of van den Hurk et al. (1997) and that of Skuse et al. (1997), who found evidence of an imprinted X-linked locus affecting cognitive function (CGF1; 300082), expanded the list of imprinted X-linked genes from 1 (XIST; 314670) to 3. Naumova et al. (1998) analyzed the transmission of maternal alleles at loci spanning the length of the X chromosome in 47 normal, genetic disease-free families. They found a significant deviation from the expected mendelian 1:1 ratio of grandparental:grandmaternal alleles at loci in Xp21.1-p11.4. The distortion in the inheritance ratio was found only among male offspring and was manifested as a strong bias in favor of inheritance of the alleles of the maternal grandfather. No evidence for significant heterogeneity among the families was found, which implies that the major determinant involved in the generation of the nonmendelian ratio is epigenetic. The analysis of recombinant chromosomes inherited by male offspring indicated that an 11.6-cM interval on the short arm of the X chromosome, bounded by DXS538 and DXS7, contains an imprinted gene that affects the survival of male embryos.
Carrel and Willard (1999) described an unusual pattern of expression of the REP1 gene in females. In mammalian females, most genes on 1 X chromosome are transcriptionally silenced as the result of X chromosome inactivation. Whereas it is well established that some X-linked genes 'escape' X inactivation and are expressed from both active (Xa) and inactive (Xi) X chromosomes, most models for the chromosomal control of X-linked gene expression assume that the X-inactivation status of the given gene is constant among different females within a population. Carrel and Willard (1999) found, however, by using transcribed polymorphisms to distinguish Xa and Xi expression, a novel pattern of expression for the REP1 gene: monoallelic expression, indicating inactivation, was detected in some cell lines, whereas biallelic expression, indicating escape from inactivation, was detected in others. Furthermore, levels of Xi expression varied among cell lines that expressed REP1. The cellular basis of Xi expression was examined by expression assays in single cells. These data indicate that REP1 is expressed from the Xi in all cells, but that the level of expression relative to Xa levels is reduced. These findings suggested that Xi gene expression is under a previously unsuspected level of genetic or epigenetic control, likely involving local or regional changes in chromatin organization that determine whether a gene escapes or is subject to X inactivation.
To identify genes that escape X inactivation and to generate a first-generation X-inactivation profile of the X chromosome, Carrel et al. (1999) evaluated the expression of 224 X-linked genes and expressed sequence tags by RT-PCR analysis of a panel of multiple independent mouse/human somatic cell hybrids containing a normal inactivated X chromosome but no active X chromosome. The resulting survey yielded an initial X-inactivation profile estimated to represent 10% of all X-linked transcripts. Of the 224 transcripts tested, 34 (3 of which were pseudoautosomal) were expressed in as many as 9 inactive-X hybrids and thus appeared to escape inactivation. The genes that escaped inactivation were distributed nonrandomly along the X chromosome; 31 of 34 such transcripts mapped to Xp, implying that the 2 arms of the X are epigenetically and/or evolutionarily distinct and suggesting that genetic imbalance of Xp may be more severe clinically than imbalance of Xq. One hundred seventy-seven of the 224 transcripts appeared to be subject to inactivation. Notably, the status of only 13 genes (6%) was indeterminate, because they were expressed in about half of the hybrids tested. Such heterogeneous patterns may reflect a naturally occurring heterogeneity in human cells, as demonstrated for the REP1 and TIMP1 (305370) genes; occasional reactivation of human X-linked genes in somatic cell hybrids; and/or an innately unstable epigenetic state.
Rak et al. (2004) reported the crystal structures of REP1 in complex with monoprenylated or C-terminally truncated RAB7 (602298). The structures revealed that RAB7 interacts with the RAB-binding platform of REP1 via an extended interface involving the switch 1 and 2 regions. The C terminus of the REP1 molecule functions as a mobile lid covering a conserved hydrophobic patch on the surface of REP1 that in the complex coordinates the C termini of RAB proteins.
Cremers et al. (1990) found that the open reading frame of the CHM gene was partially deleted or disrupted in 8 male patients with tapetochoroidal dystrophy (choroideremia, 303100), and in a female patient with a balanced translocation involving the Xq21 band. These findings strongly arguing for a causal role of this gene in CHM. They found that deletions in CHM cases varied in size from 45 kb to several megabases.
Van den Hurk et al. (1992) detected and characterized different point mutations in the CHM gene in 5 of 30 patients with choroideremia (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.
Schwartz et al. (1993) analyzed 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, Pascal et al. (1993) analyzed 5 exons of the CHM gene and identified the same 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 may 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 choroideremia patients give rise to the introduction of a premature stop codon.
Van den Hurk et al. (1997) reviewed mutations in the CHM gene, which they called REP1 (Rab escort protein-1), in choroideremia. In 18 patients, REP1 gene deletions of different sizes were found. Two females with CHM were reported to have translocations that disrupted the REP1 gene. In 22 patients, small mutations were identified. The authors noted that these were all nonsense, frameshift, or splice site mutations; with one possible exception, missense mutations were not found.
In a mutation analysis of 57 families diagnosed with CHM, McTaggart et al. (2002) found CHM mutations in 54. Most of the mutations (more than 42%) were transitions and transversions. Complete deletions of the CHM gene and deletion/insertion mutations each accounted for almost 4% of the total, while over 9% had large intragenic and other partial deletions. Almost 28% of the mutations were deletions of fewer than 5 basepairs and almost 13% were splice site mutations. Although mutations were found throughout the gene with no common mutation for the disorder, identical mutations were identified in unrelated individuals. The majority of these recurrent mutations were C-to-T transitions, changing an arginine residue (CGA) to a stop codon (TGA). Four of the 5 CGA codons in the CHM gene were found to be sites of recurring mutations.
In a mutation analysis of 35 patients with CHM, van den Hurk et al. (2003) identified at least 21 different causative CHM gene defects. These included 2 partial CHM gene deletions and an insertion of a full-length L1 retrotransposon (see 151626) into the coding region of the gene (300390.0010), a type of mutation that had not previously been reported as a cause of CHM. They also detected 9 different nonsense mutations, 5 of which were recurrent, a small deletion, a small insertion, and at least 5 distinct splice site mutations, 1 of which had previously been described. Moreover, they identified a previously undescribed intronic mutation remote from the exon-intron junctions that created a strong acceptor splice site and led to the inclusion of a cryptic exon into the CHM mRNA. In an affected male who did not have a mutation in any of the CHM exons or their splice sites, they found deletion of a complete exon from the CHM mRNA.
Esposito et al. (2011) screened 20 Italian probands with choroideremia and identified mutations in the CHM gene in all but 1 of the men. All of the variants were nonsense or frameshift mutations or deletions except for 1 missense mutation (H507R; 300390.0011). Esposito et al. (2011) demonstrated that the H507R substitution excludes REP1 from the isoprenylation cycle due to impaired interaction with RGGTase (see 179080), which is essential for REP1 activity.
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 (RP; see 268000). No pathogenic mutations in 62 known RP-associated genes were detected, and the CHM mutations were confirmed by Sanger sequencing. Three of the probands were sporadic cases, whereas the remaining 3 had a family history consistent with the X-linked trait. Li et al. (2014) noted that although none of the probands exhibited the characteristic chorioretinal scalloped atrophy with macular preservation of choroideremia, their fundus changes were also atypical compared to those seen in classic RP. All 6 mutations resulted in truncation or loss of function.
A gene targeting approach was used by van den Hurk et al. (1997) to disrupt the mouse chm/rep-1 gene. Chimeric males transmitted the mutated gene to their carrier daughters but, surprisingly, these heterozygous females had neither affected male nor carrier female offspring. The targeted rep-1 allele was detectable, however, in male as well as female blastocyst stage embryos isolated from a heterozygous mother. Thus, disruption of the rep-1 gene gives rise to lethality in male embryos; in females embryos, it is lethal only if the mutation is of maternal origin. This observation could be explained by preferential inactivation of the paternal X chromosome in murine extraembryonic membranes, suggesting that expression of rep-1 is essential in these tissues. In both heterozygous females and chimeras, the rep-1 mutation caused photoreceptor cell degeneration. Consequently, conditional rescue of the embryonic lethal phenotype of the rep-1 mutation may provide a faithful mouse model for choroideremia.
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.
Starr et al. (2004) created random point mutations throughout the zebrafish genome and identified a recessive mutation in the Chm gene that introduced a premature stop codon and resulted in impaired sensory organ development and function. Mutant embryos showed behavioral defects, developed edema around the heart and abdomen, and began to die after 6 days. Histologic examination revealed degeneration of retina and inner ear and loss of inner ear total hair-cell number.
Sankila et al. (1992) described a point mutation that is responsible for choroideremia (303100) in the large Salla pedigree from northeastern Finnish Lapland that accounts for one-fifth of the world's choroideremia patients. They showed that the mutation is unique in that it is not responsible for choroideremia in any of the other Finnish pedigrees. The mutation was detected by single-strand conformation polymorphism (SSCP) analysis with subsequent sequencing of the relevant DNA segment. Sequencing showed insertion of a T within the splice donor site of the intron downstream of exon C, changing the normal sequence of AGgtaag to AGgttaag. A new restriction site for MseI was created by the mutation, thus permitting screening. Although the CHM gene is mainly expressed in the retina, choroid, and retinal pigment epithelium, low levels of transcripts are also found in lymphoblasts by means of polymerase chain reaction (PCR). This illegitimate transcription provides a convenient means of screening and analyzing the transcript. Lymphoblast-derived mRNA from a patient with what the authors referred to as the CHM*SAL mutation showed 2 aberrantly spliced mRNAs and no normal transcript.
According to the CHM sequence published by van Bokhoven et al. (1994), this mutation is referred to as 1639+2insT in intron 13.
Using PCR-SSCP analysis and direct DNA sequencing, van den Hurk et al. (1992) detected and characterized different point mutations in the CHM gene in 5 patients with choroideremia (CHM; 303100). Patient 2084 had a TCC-to-TGA change in codon 116 in exon B3 leading to the change of a serine codon to a stop codon (S116X). Codons 116 and 117 in exon B3 are TCC (ser) and AGG (arg). The mutation in this case involved the replacement of CC by G, so that codons 116 and 117 became TGA (stop) and GGG. Van den Hurk et al. (1997) referred to this mutation as a change of CC to G at nucleotides 1388 and 1389 in exon 11, resulting in a ser453-to-ter (S453X).
Using PCR-SSCP analysis and direct DNA sequencing, van den Hurk et al. (1992) detected and characterized different point mutations in the CHM gene in 5 patients with choroideremia (CHM; 303100). Patient 17.1 had a C-to-A transversion in exon B4 converting serine (TCA) to a stop codon (TAA) at position 158 (S158X). Van den Hurk et al. (1997) referred to this mutation as a 1514C-A transversion in exon 12, resulting in a ser495-to-ter (S495X) substitution.
Using PCR-SSCP analysis and direct DNA sequencing, van den Hurk et al. (1992) detected and characterized different point mutations in the CHM gene in 5 patients with choroideremia (CHM; 303100). Patient 2.1 had a G-to-T transversion changing codon 154 from glutamic acid (GAG) to stop (TAG) (E154X). Van den Hurk et al. (1997) referred to this mutation as a 1501G-T transversion in exon 12, resulting in a ser495-to-ter (S495X) substitution.
Using PCR-SSCP analysis and direct DNA sequencing, van den Hurk et al. (1992) detected and characterized different mutations in the CHM gene in 5 patients with choroideremia (CHM; 303100). Patient 1.2 had a 1-bp deletion, a G, in exon B4, converting glycine (GGA) to glutamic acid (GAA) at position 146 and causing a frameshift with premature termination at codon 159. Van den Hurk et al. (1997) referred to this mutation as 1476delA in exon 12, resulting in a frameshift.
Using PCR-SSCP analysis and direct DNA sequencing, van den Hurk et al. (1992) detected and characterized different mutations in the CHM gene in 5 patients with choroideremia (CHM; 303100). Patient 2086 had a 4-bp deletion (delTGTT) in exon 'C,' causing a frameshift predicted to result in premature termination at codon 198. Van den Hurk et al. (1997) referred to this mutation as 1614_1617delTGTT in exon 13.
In a Danish patient with choroideremia, Schwartz et al. (1993) identified the same 4-bp deletion in exon 'C' of the CHM gene. Noting that this deletion was identical to that found by van den Hurk et al. (1992) in a German family with choroideremia, Schwartz et al. (1993) suggested that it may represent a mutational hotspot that is susceptible to slippage during replication since the TGTT sequence is duplicated in the normal sequence position.
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 the same 4-bp deletion.
In a 21-year-old Chinese man with retinal degeneration that was initially diagnosed as retinitis pigmentosa (see 268000), Li et al. (2014) identified the recurrent 4-bp deletion, which they designated c.1584_1587delTGTT, in exon 13 of the CHM gene. Review of fundus images showed changes consistent with choroideremia. The patient had an affected maternal uncle. Examination of the proband's obligate carrier mother, who had normal visual acuity without night blindness, revealed a number of yellow crystalline-like spots in the macular area and irregular mottled pigmentation in the midperiphery. Electroretinography showed normal rod responses and mildly reduced cone responses.
In a Danish patient with choroideremia (CHM; 303100), Schwartz et al. (1993) identified heterozygosity for a C-A transversion in the CHM gene, resulting in a cys162-to-ter (C162X) substitution.
In a mutation screening of patients from 15 Danish and Swedish families with choroideremia (CHM; 303100), van Bokhoven et al. (1994) found mainly deletions or insertions. There were, however, 4 single nucleotide substitutions of which 2 were missense mutations and 2 were splice errors. One of the missense mutations (in patient LN) was a C-to-T transition at nucleotide 907 resulting in a change of arg294 to a termination codon.
In patient TN with choroideremia (CHM; 303100), van Bokhoven et al. (1994) found a C-to-A transversion at nucleotide 1527 of the CHM gene resulting in a substitution of a termination codon for cys500.
In a male with choroideremia (CHM; 303100), van den Hurk et al. (2003) identified the insertion of a full-length L1 retrotransposon in the coding region of the CHM gene as the mutational basis of the disorder. Exon 6 was increased in size by approximately 6 kb. The L1 element was inserted in reverse orientation. It was flanked by a perfect 14-bp duplication of the target site. In studies of the effect of the L1 insertion on splicing, RNA was examined by RT-PCR using primers derived from exon 5 and exon 8. Sequencing of the resulting fragment demonstrated the direct splicing of exon 5 to exon 7. The absence of exon 6 from the CHM mRNA maintained a reading frame, predicting a protein product lacking amino acids 235-273.
In a 21-year-old Italian man with choroideremia (CHM; 303100), Esposito et al. (2011) identified a 1520A-G transition in exon 13 of the CHM gene, resulting in a his507-to-arg (H507R) substitution. The mutation segregated fully with disease in the family and was not found in 200 control alleles. Western blot of transiently transfected HEK293 cells showed that wildtype protein was expressed at higher levels than the mutant. Immunoprecipitation studies demonstrated that the mutant was associated with a total loss of REP1 essential activity because it was unable to interact with RGGTase (see RABGGTB, 179080). The patient had visual acuity of 20/30 bilaterally and concentric loss of visual fields with perimacular scotomata; funduscopy revealed widespread chorioretinal atrophy sparing the macula and optic nerve, and scotopic b-waves were extinguished on electroretinography.
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