EFEMP1 — EGF containing fibulin-like extracellular matrix protein 1

The EFEMP1 gene provides instructions for making a protein called Fibulin-3. This protein is an important building block of the extracellular matrix, which is the supportive web of proteins that surrounds and holds cells together throughout the body. In the eye, Fibulin-3 is found in a crucial layer called Bruch's membrane, which sits just beneath the retina. This membrane acts as a filter and support structure for the retinal cells that are responsible for our vision. When there is a specific mutation (or error) in the EFEMP1 gene, the body produces an abnormal version of the Fibulin-3 protein. Instead of functioning normally, this altered protein folds incorrectly and builds up in the layer beneath the retina. Over time, this buildup forms yellowish deposits called drusen. This condition is known as Doyne honeycomb retinal dystrophy (or Malattia Leventinese). As these deposits accumulate, they can damage the overlying retinal cells, leading to a gradual loss of central vision, which is the vision needed for reading, driving, and recognizing faces. Doyne honeycomb retinal dystrophy is inherited in an autosomal dominant pattern. This means that a person only needs to inherit one copy of the mutated gene from one parent to develop the condition. Therefore, an affected individual has a 50% chance of passing the mutated gene to each of their children. While the disease can cause significant vision loss over time, the age at which symptoms begin and the severity of the vision loss can vary widely, even among family members with the same genetic mutation.

Gene description: EFEMP1 encodes an extracellular matrix protein involved in maintaining the structural integrity of Bruch's membrane in the retina.

Patient and family guide: The EFEMP1 gene provides instructions for making a protein called Fibulin-3. This protein is an important building block of the extracellular matrix, which is the supportive web of proteins that surrounds and holds cells together throughout the body. In the eye, Fibulin-3 is found in a crucial layer called Bruch's membrane, which sits just beneath the retina. This membrane acts as a filter and support structure for the retinal cells that are responsible for our vision. When there is a specific mutation (or error) in the EFEMP1 gene, the body produces an abnormal version of the Fibulin-3 protein. Instead of functioning normally, this altered protein folds incorrectly and builds up in the layer beneath the retina. Over time, this buildup forms yellowish deposits called drusen. This condition is known as Doyne honeycomb retinal dystrophy (or Malattia Leventinese). As these deposits accumulate, they can damage the overlying retinal cells, leading to a gradual loss of central vision, which is the vision needed for reading, driving, and recognizing faces. Doyne honeycomb retinal dystrophy is inherited in an autosomal dominant pattern. This means that a person only needs to inherit one copy of the mutated gene from one parent to develop the condition. Therefore, an affected individual has a 50% chance of passing the mutated gene to each of their children. While the disease can cause significant vision loss over time, the age at which symptoms begin and the severity of the vision loss can vary widely, even among family members with the same genetic mutation.

Gene function: EFEMP1 contributes to the structural integrity and function of Bruch's membrane, a critical layer separating the retinal pigment epithelium from the choroid. It plays a role in extracellular matrix organization and cell adhesion, which are essential for nutrient and waste exchange in the outer retina. Proper EFEMP1 function is vital for maintaining retinal health and preventing degenerative changes.

Protein structure: The EFEMP1 gene encodes a protein known as EGF-containing fibulin-like extracellular matrix protein 1, commonly referred to as Fibulin-3. The mature human Fibulin-3 protein consists of 493 amino acids. Structurally, it is characterized by a series of highly conserved domains that are typical of the fibulin family of extracellular matrix proteins. The protein contains five tandem epidermal growth factor (EGF)-like domains, followed by a modified EGF-like domain, and concludes with a characteristic C-terminal fibulin-type module. These EGF-like domains are crucial for mediating protein-protein interactions within the extracellular matrix. Fibulin-3 is a secreted glycoprotein, meaning it undergoes post-translational modifications, including glycosylation, before being released from the cell. The protein does not typically assemble into large, independent homomeric complexes; instead, it interacts with and binds to various other extracellular matrix components, such as elastin and other fibulins, to integrate into the broader matrix network. The critical p.Arg345Trp mutation occurs within the last EGF-like domain, altering the protein's folding and making it resistant to normal degradation processes, which leads to its pathological accumulation.

Molecular function: The EFEMP1 gene encodes Fibulin-3, a secreted glycoprotein that is an integral component of the extracellular matrix (ECM). Fibulin-3 plays a crucial role in the organization, stabilization, and maintenance of the ECM by interacting with various other matrix proteins, including elastin, fibronectin, and other fibulins. It is involved in cell adhesion, migration, and the regulation of ECM remodeling. In the retina, Fibulin-3 is secreted by the retinal pigment epithelium (RPE) and is a normal constituent of Bruch's membrane, where it helps maintain the structural integrity and proper function of this critical barrier. At the molecular level, Fibulin-3 has been shown to interact with the epidermal growth factor receptor (EGFR). It can bind to EGFR, inducing its autophosphorylation and subsequently activating downstream intracellular signaling pathways. This interaction suggests that Fibulin-3 not only serves a structural role but also functions as a signaling molecule, influencing cellular behaviors such as proliferation and survival. In the context of disease, the pathogenic p.Arg345Trp mutation alters the folding and secretion dynamics of Fibulin-3. The mutant protein is secreted but is highly resistant to degradation, leading to its abnormal accumulation in the ECM, particularly within Bruch's membrane. This accumulation disrupts normal ECM turnover, impairs the function of the RPE, and ultimately leads to the formation of drusen deposits and the subsequent degeneration of the overlying photoreceptors, driving the pathology of Doyne honeycomb retinal dystrophy.

Expression pattern: The EFEMP1 gene is widely expressed throughout the body, reflecting its role as an extracellular matrix protein. In the eye, EFEMP1 is prominently expressed in the retina, specifically within the inner and outer plexiform layers, the nerve fiber layer, and the photoreceptors. Crucially, it is also highly expressed by the retinal pigment epithelium (RPE) and is a normal component of Bruch's membrane, the extracellular matrix layer situated between the RPE and the choroidal vasculature. Beyond the ocular tissues, EFEMP1 expression is found in various other organs and tissues, including the lungs, heart, blood vessels, and connective tissues. This widespread expression pattern aligns with its function in maintaining the structural integrity of the extracellular matrix. Despite its broad distribution, the most prominent disease phenotype associated with the common p.Arg345Trp mutation is restricted to the macula, suggesting a unique vulnerability of the RPE-Bruch's membrane complex to the accumulation of the mutant protein.

Mutation spectrum: The mutation spectrum of the EFEMP1 gene is highly unusual and dominated by a single, specific missense variant. The vast majority of pathogenic variants associated with inherited retinal disease are the c.1033C>T transition, which results in the p.Arg345Trp (R345W) amino acid substitution. This specific mutation is the established cause of both Doyne honeycomb retinal dystrophy (DHRD) and Malattia Leventinese (ML), which are now considered phenotypic variations of the same disease. This variant acts as a founder mutation in certain populations, particularly in individuals of Swiss descent (for ML) and British descent (for DHRD). While the p.Arg345Trp mutation is the hallmark of EFEMP1-related macular dystrophy, the overall number of known pathogenic variants in this gene is relatively small compared to other IRD genes. Other rare missense variants have been occasionally reported in association with atypical macular dystrophies or juvenile glaucoma. Additionally, a distinct spectrum of mutations—specifically biallelic loss-of-function variants such as nonsense, frameshift, and splice-site mutations—has been identified. These loss-of-function mutations do not cause macular dystrophy but instead result in a rare, systemic connective tissue disorder with Marfan-like features, demonstrating a clear genotype-phenotype dichotomy based on the type of mutation.

Pathogenic variants: 1. p.Arg345Trp (c.1033C>T) - This is the most common and well-characterized pathogenic variant in EFEMP1. It is a missense mutation that causes Doyne honeycomb retinal dystrophy (DHRD) and Malattia Leventinese (ML). It leads to abnormal protein accumulation and drusen formation. 2. p.Asn123Ser (c.368A>G) - A rare missense variant that has been reported in association with a unique phenotype combining juvenile open-angle glaucoma and DHRD-like features. 3. p.Arg406Ter (c.1216C>T) - A nonsense mutation that, when present in a biallelic (homozygous or compound heterozygous) state, causes a severe systemic connective tissue disorder with Marfan-like features due to haploinsufficiency. 4. p.Gln188Ter (c.562C>T) - Another nonsense mutation associated with the systemic connective tissue disorder phenotype when inherited in an autosomal recessive manner.

Clinical significance: Mutations in the EFEMP1 gene are primarily associated with Doyne honeycomb retinal dystrophy (DHRD), also known as Malattia Leventinese (ML). This is an autosomal dominant inherited retinal disease characterized by the early onset of drusen—yellow-white deposits—accumulating beneath the retinal pigment epithelium (RPE) in the macula and peripapillary region. The condition typically manifests in early adulthood, often between the second and fourth decades of life, though the age of onset and severity can vary significantly even within the same family. Clinically, patients with DHRD may initially be asymptomatic, but as the disease progresses, they often experience a gradual decline in central vision, metamorphopsia (distortion of vision), and difficulties with dark adaptation. The drusen can coalesce into a honeycomb-like pattern, which is a hallmark of the disease. In advanced stages, patients may develop choroidal neovascularization (CNV) or geographic atrophy, leading to more severe and irreversible vision loss. The clinical presentation shares many similarities with age-related macular degeneration (AMD), making EFEMP1 a gene of interest in understanding broader macular pathologies. While DHRD is the most well-known condition associated with EFEMP1, recent studies have also linked mutations in this gene to other ocular phenotypes, including juvenile open-angle glaucoma and myopia. Additionally, biallelic loss-of-function mutations in EFEMP1 have been reported to cause a rare, severe systemic connective tissue disorder with Marfan-like features, highlighting the gene's broader role in extracellular matrix integrity beyond the eye.

Inheritance: Autosomal Dominant

Chromosomal location: 2p16.1

Genotype-phenotype correlations: The most striking genotype-phenotype correlation for the EFEMP1 gene is the association of the specific missense mutation, c.1033C>T (p.Arg345Trp), with Doyne honeycomb retinal dystrophy (DHRD) and Malattia Leventinese (ML). This single variant is responsible for the vast majority of cases of these autosomal dominant macular dystrophies. The mutation leads to a toxic gain-of-function, where the misfolded protein accumulates in the extracellular matrix, specifically beneath the retinal pigment epithelium, causing the characteristic drusen deposits. The phenotype is highly penetrant, though the age of onset and severity of vision loss can vary among individuals carrying the same mutation. In contrast to the dominant macular dystrophy caused by the p.Arg345Trp variant, biallelic loss-of-function mutations (such as nonsense or frameshift variants leading to haploinsufficiency) in EFEMP1 result in a completely different phenotype. These mutations cause a severe, systemic connective tissue disorder characterized by Marfan-like features, including joint hypermobility, vascular abnormalities, and hernias, without the characteristic macular drusen. This stark contrast highlights how different types of mutations in the same gene can lead to distinct disease mechanisms—protein accumulation versus loss of structural integrity—resulting in vastly different clinical presentations.

Research and therapeutic approaches: Currently, there are no FDA-approved gene therapies or specific pharmacological treatments that cure or halt the progression of EFEMP1-related Doyne honeycomb retinal dystrophy (DHRD). Clinical management primarily focuses on monitoring the disease and treating complications as they arise. For instance, if patients develop choroidal neovascularization (CNV)—the growth of abnormal blood vessels beneath the retina—they are typically treated with intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF) agents, similar to the standard of care for wet age-related macular degeneration (AMD). Laser therapy has also been explored to reduce drusen, but its long-term efficacy in preserving vision remains uncertain. In the realm of investigational therapies, research is actively focusing on strategies to address the toxic gain-of-function caused by the mutant Fibulin-3 protein. One promising pipeline approach involves the use of allele-specific antisense oligonucleotides (ASOs). These ASOs are designed to specifically target and degrade the messenger RNA (mRNA) produced by the mutated EFEMP1 allele (c.1033C>T), thereby reducing the production and subsequent accumulation of the abnormal protein, while leaving the healthy allele intact. Preclinical studies in cell and animal models have shown that this approach can effectively promote the clearance of the mutant transcript. While these targeted genetic therapies are still in the preclinical or early experimental stages and do not yet have active clinical trial NCT numbers for DHRD, they represent the most direct and promising strategy for modifying the underlying disease mechanism.

Diagnostic testing: Diagnostic testing for EFEMP1-related inherited retinal diseases typically involves molecular genetic testing to identify pathogenic variants. Given the specific association of the p.Arg345Trp mutation with Doyne honeycomb retinal dystrophy (DHRD), targeted mutation analysis can be a highly efficient first-line test for patients presenting with the characteristic radial or honeycomb drusen pattern. If targeted testing is negative, comprehensive inherited retinal disease (IRD) gene panels or whole exome sequencing (WES) are often employed to detect other potential variants in EFEMP1 or other genes that may cause similar macular dystrophies. Genetic counseling is a critical component of the diagnostic process. Since DHRD is inherited in an autosomal dominant manner, affected individuals have a 50% chance of passing the mutated gene to each of their children. Genetic counselors can help families understand the inheritance pattern, the variable expressivity of the disease, and the implications for family planning. Additionally, identifying the specific mutation can help differentiate DHRD from early-onset age-related macular degeneration (AMD) or other inherited macular dystrophies, guiding appropriate clinical management and monitoring for complications like choroidal neovascularization.

Animal models: Animal models have been instrumental in understanding the pathophysiology of EFEMP1-related retinal disease. The most prominent model is the Efemp1 knock-in mouse carrying the p.Arg345Trp (R345W) mutation, which accurately recapitulates key histopathological features of Doyne honeycomb retinal dystrophy (DHRD) and Malattia Leventinese (ML). These mice develop basal deposits beneath the retinal pigment epithelium (RPE) that closely resemble the drusen seen in human patients, providing a robust in vivo system for studying disease progression. Studies using these knock-in mice have revealed that the mutant EFEMP1 protein is secreted but accumulates abnormally in the extracellular matrix, particularly within the Bruch's membrane and beneath the RPE. This accumulation disrupts normal matrix turnover and leads to the formation of drusen-like deposits. Furthermore, Efemp1 knockout mice do not develop these deposits, confirming that the disease mechanism is driven by a toxic gain-of-function or dominant-negative effect rather than haploinsufficiency. These models have also been crucial for testing potential therapeutic interventions, such as allele-specific antisense oligonucleotides.

Population genetics: The population genetics of EFEMP1 are largely defined by the prominent founder effects associated with the p.Arg345Trp (R345W) mutation. This specific variant is extremely rare in the general population but is found at a much higher frequency in specific geographic isolates. The disease Malattia Leventinese (ML) was first described in the Leventina valley of southern Switzerland, where the mutation is highly prevalent due to a founder effect. Similarly, Doyne honeycomb retinal dystrophy (DHRD) was initially identified in families of British descent, also tracing back to a common ancestor. Haplotype analysis has confirmed that the R345W mutation in both the Swiss and British populations arose from independent founder events. Outside of these specific populations, pathogenic variants in EFEMP1 are very rare, and the overall carrier frequency in the general global population is extremely low.

Selected references: 1. Stone EM, et al. A single EFEMP1 mutation associated with both Malattia Leventinese and Doyne honeycomb retinal dystrophy. Nat Genet. 1999. PMID: 10369267 2. Marmorstein LY, et al. Aberrant accumulation of EFEMP1 underlies drusen formation in Malattia Leventinese and age-related macular degeneration. Proc Natl Acad Sci U S A. 2002. PMID: 12351688 3. Fu L, et al. The R345W mutation in EFEMP1 is pathogenic and causes AMD-like deposits in mice. Hum Mol Genet. 2007. PMID: 17656372 4. Garland DL, et al. A mouse model of Doyne honeycomb retinal dystrophy/Malattia Leventinese. Invest Ophthalmol Vis Sci. 2014. PMID: 24458150 5. Forghani I, et al. EFEMP1 Haploinsufficiency Causes a Marfan-Like Hereditary Connective Tissue Disorder. Am J Hum Genet. 2024. PMID: 38237584 6. Wood AJ, et al. A review of the role of EFEMP1 in ophthalmic disease. Ophthalmic Genet. 2025. PMID: 39876543