CHM — choroideremia regulator of Rab3 GTPase activity
The CHM gene provides instructions for making a protein called Rab escort protein 1 (REP-1). This protein acts like a delivery service within cells, helping to attach special fat molecules to other proteins called Rabs. This attachment is necessary for Rab proteins to direct the movement of materials inside the cell. While REP-1 is found in cells all over the body, it is particularly important in the eye for the health and survival of the light-sensing cells (photoreceptors) and their supporting layer (the retinal pigment epithelium). When the CHM gene is mutated, the body cannot produce functional REP-1 protein. Without it, the transport system inside the retinal cells breaks down, causing these cells to gradually die. This leads to a condition called choroideremia, an inherited eye disease that causes progressive vision loss. The disease typically starts with night blindness in childhood, followed by a narrowing of the field of vision (tunnel vision), and eventually leads to severe central vision loss or blindness in adulthood. Choroideremia is inherited in an X-linked recessive pattern. Because males have only one X chromosome, a single mutated copy of the CHM gene is enough to cause the disease. Females have two X chromosomes, so if they inherit one mutated copy, the normal copy usually compensates, making them "carriers." Carriers typically do not have severe vision loss, though they may develop mild signs of the disease later in life. A mother who is a carrier has a 50% chance of passing the mutated gene to each of her children.
Gene description: CHM encodes Rab escort protein 1 (REP-1), involved in lipid modification of Rab proteins, crucial for intracellular protein trafficking.
Patient and family guide: The CHM gene provides instructions for making a protein called Rab escort protein 1 (REP-1). This protein acts like a delivery service within cells, helping to attach special fat molecules to other proteins called Rabs. This attachment is necessary for Rab proteins to direct the movement of materials inside the cell. While REP-1 is found in cells all over the body, it is particularly important in the eye for the health and survival of the light-sensing cells (photoreceptors) and their supporting layer (the retinal pigment epithelium). When the CHM gene is mutated, the body cannot produce functional REP-1 protein. Without it, the transport system inside the retinal cells breaks down, causing these cells to gradually die. This leads to a condition called choroideremia, an inherited eye disease that causes progressive vision loss. The disease typically starts with night blindness in childhood, followed by a narrowing of the field of vision (tunnel vision), and eventually leads to severe central vision loss or blindness in adulthood. Choroideremia is inherited in an X-linked recessive pattern. Because males have only one X chromosome, a single mutated copy of the CHM gene is enough to cause the disease. Females have two X chromosomes, so if they inherit one mutated copy, the normal copy usually compensates, making them "carriers." Carriers typically do not have severe vision loss, though they may develop mild signs of the disease later in life. A mother who is a carrier has a 50% chance of passing the mutated gene to each of her children.
Gene function: CHM's product, REP-1, is essential for the prenylation of Rab proteins, which regulate vesicular transport. In the retina, this process is critical for the maintenance of photoreceptor and retinal pigment epithelium (RPE) cells. Defective REP-1 leads to impaired protein trafficking, causing progressive degeneration of the choroid, RPE, and photoreceptors, resulting in choroideremia.
Protein structure: The CHM gene encodes Rab escort protein 1 (REP-1), a protein consisting of 653 amino acids with a molecular weight of approximately 74 kDa. REP-1 is a multi-domain protein that shares significant structural homology with Rab GDP dissociation inhibitors (RabGDIs). It contains a highly conserved sequence known as the sequence conserved in Rab escort proteins and GDIs (SCR). Structurally, REP-1 consists of two main domains: a large complex domain that binds to the Rab GTPase, and a smaller domain that interacts with the Rab geranylgeranyl transferase (RabGGTase) enzyme. REP-1 functions as a monomer but forms a tight ternary complex with the unprenylated Rab protein and the RabGGTase heterodimer during the prenylation reaction. After the lipid anchor is attached, REP-1 remains bound to the prenylated Rab, escorting it to its target intracellular membrane before dissociating.
Molecular function: The CHM gene encodes Rab escort protein 1 (REP-1), which plays a critical role in intracellular vesicular trafficking. REP-1 binds to newly synthesized, unprenylated Rab GTPases and presents them to the catalytic subunits of the Rab geranylgeranyl transferase (RabGGTase) enzyme complex. This complex attaches geranylgeranyl lipid anchors to the C-terminus of the Rab proteins, a process known as prenylation. Prenylation is essential for Rab proteins to attach to intracellular membranes and function properly in directing vesicle transport, fusion, and exocytosis. In the absence of functional REP-1, a subset of Rab proteins remains unprenylated and inactive. In the retina, this disrupts crucial cellular processes, including the transport of proteins within photoreceptor cells and the phagocytosis of shed photoreceptor outer segments by the retinal pigment epithelium (RPE), ultimately leading to cell death and retinal degeneration.
Expression pattern: The CHM gene is ubiquitously expressed throughout the body, meaning it is active in virtually all tissues and cell types. Despite this widespread expression, the clinical manifestations of CHM mutations are almost exclusively limited to the eye, specifically the retina, retinal pigment epithelium (RPE), and choroid. This tissue-specific phenotype is thought to be due to the presence of a closely related protein, Rab escort protein 2 (REP-2), encoded by the CHML gene. REP-2 can compensate for the loss of REP-1 in most tissues by prenylating the majority of Rab GTPases. However, in the retina, certain Rab proteins (such as Rab27a) are heavily dependent on REP-1 for prenylation, and REP-2 cannot fully compensate for its absence, leading to the specific degeneration seen in choroideremia.
Mutation spectrum: The mutation spectrum of the CHM gene is characterized predominantly by loss-of-function mutations. Over 90% of the disease-causing variants are null mutations, which include nonsense mutations, frameshift mutations (insertions or deletions), and splice-site mutations that lead to premature truncation of the REP-1 protein. Nonsense mutations alone account for approximately 30% of all cases. Large structural variants, such as whole-gene or multi-exon deletions, are also relatively common, accounting for 25-50% of mutations. Missense mutations are extremely rare in choroideremia, as most single amino acid changes do not completely abolish REP-1 function. There are no major founder mutations or distinct hotspot regions, with pathogenic variants distributed throughout the 15 exons of the gene.
Pathogenic variants: 1. p.Arg293* (c.877C>T) - A common nonsense mutation leading to premature protein truncation and classic choroideremia. 2. p.Arg253* (c.757C>T) - Another frequent nonsense mutation resulting in a loss of function of the REP-1 protein. 3. c.715_716del (p.Leu239fs) - A frameshift mutation causing a premature stop codon and a non-functional protein. 4. c.1166-1G>A - A canonical splice site mutation that disrupts normal mRNA splicing, leading to an aberrant protein product. 5. Whole gene deletion - Large deletions encompassing the entire CHM gene are a common cause of the disease, resulting in complete absence of the REP-1 protein.
Clinical significance: Mutations in the CHM gene cause choroideremia, an X-linked recessive chorioretinal dystrophy. The disease primarily affects males, who typically present with nyctalopia (night blindness) in early childhood due to rod photoreceptor loss. As the disease progresses, patients develop peripheral visual field loss (scotomas) corresponding to areas of chorioretinal atrophy. In the late stages, the atrophy encroaches on the fovea, leading to central vision loss and legal blindness, usually by the fourth or fifth decade of life. The clinical severity and rate of progression can vary even among individuals with the same mutation. Female carriers are generally asymptomatic but may display mild signs of the disease later in life, such as RPE mottling and patchy chorioretinal atrophy, due to X-chromosome inactivation (lyonization). In rare cases, contiguous gene deletion syndromes involving the Xq21.2 region can cause choroideremia accompanied by systemic features like cognitive impairment, sensorineural deafness, and cleft lip or palate.
Inheritance: X-linked Recessive
Chromosomal location: Xq21.2
Genotype-phenotype correlations: In choroideremia, there is generally a lack of strong genotype-phenotype correlation. The vast majority of CHM mutations result in a complete loss of function of the REP-1 protein (null alleles). Because the end result is the absence of functional protein regardless of the specific mutation type (e.g., nonsense, frameshift, or deletion), the clinical presentation is relatively uniform in its overall trajectory. However, significant phenotypic variability exists in the age of onset, rate of progression, and severity of vision loss, even among family members carrying the exact same mutation. This suggests that other genetic modifiers, environmental factors, or epigenetic influences play a significant role in determining the clinical course of the disease.
Research and therapeutic approaches: Currently, there is no approved cure or treatment to halt the progression of choroideremia. Management is primarily supportive, involving low vision aids, UV protection, and monitoring for complications such as cataracts or choroidal neovascularization. However, several therapeutic approaches are under active investigation, with gene therapy being the most advanced. Gene therapy for choroideremia involves using an adeno-associated virus (AAV) vector to deliver a healthy copy of the CHM gene directly to the retinal cells via subretinal injection. Several clinical trials have been conducted, including the Phase 3 STAR study (NCT03496012) evaluating timrepigene emparvovec. While early phase trials showed promise in maintaining or improving visual acuity, the Phase 3 trial unfortunately did not meet its primary endpoints. Research in optimizing vector design and delivery methods continues. Another promising approach is nonsense suppression therapy, which targets the approximately 30% of patients with nonsense mutations. Drugs like ataluren (Translarna) are designed to make the cellular machinery "read through" premature stop codons, allowing the production of full-length, functional REP-1 protein. This approach has shown efficacy in preclinical models of choroideremia and represents a potential non-surgical, systemic treatment option, though it has not yet been proven in human clinical trials for this specific disease.
Diagnostic testing: Diagnosis of choroideremia is typically confirmed through genetic testing, usually via targeted retinal gene panels, which have a detection rate of approximately 95%. If panel testing is negative but clinical suspicion remains high, whole genome sequencing can be used to identify deep intronic mutations or structural variants. In cases where no mutation is found, Western blot analysis of leukocytes can be performed to detect the absence of the REP-1 protein. Genetic counseling is essential for affected individuals and their families. Because choroideremia is an X-linked recessive condition, affected males will pass the mutated gene to all their daughters (who become carriers) but none of their sons. Carrier females have a 50% chance of passing the mutated gene to each child. Prenatal testing and preimplantation genetic diagnosis are options for families with a known CHM mutation.
Animal models: Animal models have been crucial for understanding CHM pathogenesis and testing therapies. The mouse model of choroideremia (Chm null) is a key model, though creating it was challenging because complete loss of the Chm gene is embryonic lethal in mice. Researchers developed conditional knockout mice where the Chm gene is specifically deleted in photoreceptors or the retinal pigment epithelium (RPE). These models demonstrate independent degeneration of photoreceptors and RPE, mimicking the human disease. Zebrafish models have also been utilized, as they possess a single chm gene. Loss of rep1 in zebrafish leads to early embryonic lethality, but studies on these models have revealed noncell-autonomous photoreceptor degeneration and disrupted choroidal melanogenesis. These models have been instrumental in preclinical testing of gene therapies and nonsense suppression therapies like ataluren.
Population genetics: Choroideremia is a rare disorder with an estimated prevalence of 1 in 50,000 to 1 in 100,000 individuals. Because it is an X-linked recessive condition, it almost exclusively affects males, while females are carriers. The carrier frequency in the general population is estimated to be around 1 in 25,000 to 1 in 50,000 females. The disease occurs in all ethnic groups, and while most mutations are unique to individual families, some founder effects have been observed in specific isolated populations, such as in certain regions of Finland.
Selected references: 1. MacDonald IM, et al. Choroideremia. GeneReviews. 2021. PMID: 20301511 2. Sarkar H, et al. Choroideremia: molecular mechanisms and therapies. Trends Mol Med. 2022. PMID: 35339365 3. Simunovic MP, et al. The Spectrum of CHM Gene Mutations in Choroideremia and Their Relationship to Clinical Phenotype. Invest Ophthalmol Vis Sci. 2016. PMID: 27842160 4. Mitsios A, et al. Choroideremia: from genetic and clinical phenotyping to gene therapy and future treatments. Ther Adv Ophthalmol. 2018. PMID: 30627685 5. Lam BL, et al. Choroideremia Gene Therapy. Cold Spring Harb Perspect Med. 2021. PMID: 33782042 6. Strunnikova NV, et al. Loss-of-Function Mutations in Rab Escort Protein 1 (REP-1) Affect Intracellular Transport in Fibroblasts and Monocytes of Choroideremia Patients. PLoS One. 2009. PMID: 20011539 7. Tolmachova T, et al. Independent degeneration of photoreceptors and retinal pigment epithelium in conditional knockout mouse models of choroideremia. J Clin Invest. 2006. PMID: 16453024