Alternative titles; symbols
HGNC Approved Gene Symbol: EFEMP1
SNOMEDCT: 193411004;
Cytogenetic location: 2p16.1 Genomic coordinates (GRCh38): 2:55,865,967-55,923,782 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2p16.1 | Cutis laxa, autosomal recessive, type ID | 620780 | Autosomal recessive | 3 |
| Doyne honeycomb degeneration of retina | 126600 | Autosomal dominant | 3 | |
| Glaucoma 1, open angle, H | 611276 | Autosomal dominant | 3 |
Members of the fibulin family of proteins, like EFEMP1, are extracellular matrix proteins characterized by tandem arrays of EGF (131530)-like domains and a C-terminal fibulin (see FBLN1; 135820)-type module (Kobayashi et al., 2007).
Ikegawa et al. (1996) identified a gene highly homologous to fibrillin. The cDNA for this gene, designated 'fibrillin-like' (FBNL), was isolated from a fibroblast cDNA library. The FBNL cDNA probe detected 2 transcripts of 2.2 and 3.0 kb in mRNA from multiple tissues. The FBNL gene was expressed in many tissues but it was not expressed in brain and lymphocytes. Ikegawa et al. (1996) reported that the amino acid sequence of FBNL is 36.3% identical to that of FBN1 (134797) and 35.4% identical to that of FBN2 (612570) and that FBNL contains repeated EGF-like domains, a cardinal motif of FBN genes.
By subtractive hybridization to identify genes upregulated in senescent human diploid fibroblasts cultured from Werner syndrome (277700) patients, followed by PCR analysis, Lecka-Czernik et al. (1995) cloned EFEMP1, which they called S1-5. They found evidence of alternative splicing at the 5-prime end and identified alternative initiating AUG codons and alternative polyadenylation signals. Full-length 493-amino acid EFEMP1 has an N-terminal signal sequence, followed by an EGF-like domain, a linker region, and 5 central EGF-like domains. The EGF-like domains contain conserved cysteines that promote folding into a beta-sheet structure and conserved aspartic acid and tyrosine residues involved in binding calcium. EGF-like domain-4 also has a putative N-glycosylation site. Four other potential isoforms contain 387 to 485 amino acids and differ in their N termini only, including introduction of an alternative N-terminal signal sequence, loss of the signal sequence, and loss of all or part of EGF-like domain-1. Northern blot analysis detected a major transcript of 2.2 kb and a minor transcript of 3.0 kb in human fibroblasts and in several transformed cell lines, but not in normal human myoblasts or myotubes. Analysis of adult mouse tissues detected a single 2.2-kb transcript that showed highest expression in lung, with lower expression in ovary, kidney, and skeletal muscle, weak expression in liver and stomach, and no expression in spleen, heart, brain, and intestine.
Using radioimmunoassays, Kobayashi et al. (2007) found variable Fbln3 expression in all 14 mouse tissues examined, with highest expression in lung and esophagus, and lowest expression in heart and brain. Immunohistochemical analysis localized Fbln3 in perichondrium of developing bone in day-15 mouse embryos and in blood vessel wall and basement membrane of large, but not distal, airways in day-14 mouse embryos. Kobayashi et al. (2007) stated that the major isoform of mouse Fbln3 has 2 potential N- and 5 potential O-glycosylation sites. SDS-PAGE detected Fbln3 at apparent molecular masses of 80 and 63 kD, which represented different degrees of O-glycosylation. Electron microscopy after rotary shadowing revealed that recombinant mouse Fbln3, like Fbln4 (EFEMP2; 604633) and Fbln5 (604580) appeared as a 20-nm rod with a globular domain at one end, which represented the N-terminal EGF modules.
By in situ hybridization analysis of Efemp1 mRNA transcripts in the mouse eye at postnatal day 22, Mackay et al. (2015) observed the strongest expression in the ciliary body (nonpigmented epithelium) and cornea (basal epithelium). Lower transcript levels were detected in the inner nuclear layer of the retina and optic nerve head region, with barely traceable levels in the lens. The authors stated that this ocular expression profile was consistent with EFEMP1 transcript levels detected by microarray analysis of mouse and human eye tissues.
Ikegawa et al. (1996) determined that the EFEMP1 gene spans approximately 18 kb of genomic DNA and contains 12 exons.
By in situ hybridization, Ikegawa et al. (1996) determined that the FBNL gene maps to chromosome 2p16.
Using Northern blot analysis, Lecka-Czernik et al. (1995) found higher S1-5 expression in older human diploid fibroblasts and lower S1-5 expression in younger fibroblasts. Human fibroblasts reduced expression of S1-5 following growth stimulation. However, expression of S1-5 cDNA clones encoding proteins with either 5 or 6 EGF-like domains stimulated DNA synthesis in human fibroblasts in an autocrine and paracrine manner.
Kobayashi et al. (2007) found that mouse Fbln3 and Fbln4 and both mouse and human FBLN5 were secreted into the culture media of transfected HEK293 cells. Solid-phase binding assays showed that these proteins bound differentially to extracellular proteins. Mouse Fbln3 bound weakly to tropoelastin (ELN; 130160) and to collagen XV (see 120325)-derived endostatin, but not to fibronectin (FN1; 135600) or other basement membrane proteins examined. The authors stated that Fbln3 had also been shown to interact with tissue inhibitor of metalloproteinase-3 (TIMP3; 188826).
Doyne Honeycomb Retinal Dystrophy/Malattia Leventinese
Doyne honeycomb retinal dystrophy (DHRD; 126600), or malattia leventinese (MLVT), is an autosomal dominant disease characterized by yellow-white deposits known as drusen that accumulate beneath the retinal pigment epithelium (RPE). The locus for DHRD maps to chromosome 2p21-p16. The clinical significance of DHRD resides in large part in its close phenotypic similarity to age-related macular degeneration (ARMD; see 153800), a disorder with a strong genetic component that accounts for approximately 50% of registered blindness in the Western world. As in MLVT and DHRD, the early hallmark of ARMD is the presence of drusen. By a combination of positional and candidate gene methods, Stone et al. (1999) identified a single nonconservative mutation (R345W; 601548.0001) in the EFEMP1 gene in all 5 families with MLVT studied. The mutation, which was subsequently identified in 37 families with DHRD/MLVT, was not found in 477 control individuals or in 494 patients with ARMD. The authors also investigated samples from 2 nuclear families with genealogic evidence for a relationship with the original DHRD family reported by Doyne (1899), and found that affected individuals from both families harbored the R345W variation. Noting the absence of de novo R345W mutations in these 39 families, and the complete sharing of alleles of 4 intragenic EFEMP1 polymorphisms among the families, the authors suggested that the R345W mutation occurred only once, in a common ancestor of every affected patient in the study.
Using an HpaII restriction digest test, Tarttelin et al. (2001) identified the R345W variant in 7 (70%) of 10 DHRD families and in 1 of 17 sporadic patients.
Marmorstein et al. (2002) showed that wildtype EFEMP1 is a secreted protein, whereas mutant EFEMP1 is misfolded, secreted inefficiently, and retained within cells. In normal eyes, EFEMP1 is not present at the site of drusen formation. However, in malattia leventinese eyes, EFEMP1 accumulates within the RPE cells and between the RPE and drusen, but does not appear to be a major component of drusen. Furthermore, in ARMD eyes, EFEMP1 is found to accumulate beneath the RPE immediately overlying drusen, but not in the region where there is no apparent retinal pathology. Marmorstein et al. (2002) interpreted these data as evidence that folding and aberrant accumulation of EFEMP1 may cause drusen formation and cellular degeneration and play an important role in the etiology of both MLVT and ARMD.
In a consanguineous Indian family with early-onset macular degeneration, Fu et al. (2007) identified the R345W mutation in the EFEMP1 gene. The mother and father were heterozygous for the mutation, whereas their more severely affected sons were homozygous. The disease haplotype in this family was distinctly different from previously reported haplotypes, suggesting that the mutation arose independently.
In a Chinese family in which a sister and brother and their mother had DHRD/MLVT, Zhang et al. (2018) sequenced the EFEMP1 gene and identified heterozygosity for the recurrent R345W mutation.
In a 32-year-old Swiss woman with MLVT, Vaclavik et al. (2020) identified heterozygosity for a de novo occurrence of the recurrent R345W mutation. The authors concluded that R345W represents a hot spot mutation rather than a founder mutation.
By screening 7 genes associated with flecked retina in a 57-year-old Danish woman with DHRD, Sheyanth et al. (2021) identified heterozygosity for the recurrent R345W mutation in the EFEMP1 gene. Haplotype analysis suggested that the mutation arose independently, although parental DNA was not tested.
Open Angle Glaucoma 1H
In a father and 4 sons from a 3-generation African American family with primary open angle glaucoma (GLC1H; 611276) with onset after age 35, Mackay et al. (2015) identified heterozygosity for a missense mutation in the EFEMP1 gene (R140W; 601548.0002) that segregated with disease. Functional analysis suggested that the mutant protein accumulated within the cell rather than being secreted.
In 2 large multigenerational Filipino families and an unrelated Filipino proband with primary open angle glaucoma, Collantes et al. (2022) identified heterozygosity for 3 different mutations in the EFEMP1 gene (see, e.g., 601548.0003 and 601548.0004) that segregated with disease. Almost all affected individuals had onset before age 40, with only 1 patient presenting at age 43. Funduscopy was possible in 19 patients, and none showed evidence of subretinal deposits (drusen). Functional analysis showed significantly increased intracellular retention of all 3 mutant proteins compared to wildtype EFEMP1.
Autosomal Recessive Cutis Laxa ID
In a Lebanese sister and brother with marfanoid features and multiple inguinal, crural, and abdominal herniae as well as large diverticula throughout the gastrointestinal tract and bladder (ARCL1D; 620780), Bizzari et al. (2020) identified homozygosity for a missense mutation in the EFEMP1 gene (C55R; 601548.0005) that segregated with disease in the family and was not found in public variant databases.
In a New Zealand man with a connective tissue disorder that severely affected internal viscera, who was negative for mutation in known connective tissue disorder-associated genes, Driver et al. (2020) identified compound heterozygosity for a 5-bp deletion (601548.0006) and a nonsense mutation (Y205X; 601548.0007) in the EFEMP1 gene. The variants were not found in control or public variant databases; DNA was unavailable from the unaffected parents. Expression of EFEMP1 was almost undetectable in patient skin fibroblasts.
In a 9-year-old Turkish boy with redundant skin, multiple abdominal herniae, and generalized joint hypermobility, Verlee et al. (2021) identified homozygosity for a nonsense mutation in the EFEMP1 gene (R401X; 601548.0008). The mutation segregated with disease in the family and was not found in the gnomAD database.
Associations Pending Confirmation
Jorgenson et al. (2015) showed that EFEMP1 maps to a significant signal in a genomewide association study of susceptibility loci for inguinal hernia. The study included 5,295 cases and 67,510 controls with top associations confirmed in an independent cohort of 9,701 cases and 82,743 controls. The authors showed that EFEMP1 is expressed in mouse connective tissue and, by network analysis, that it is likely to be involved in connective tissue maintenance and homeostasis.
McLaughlin et al. (2007) obtained Efemp1 -/- mice at the mendelian ratio, and all animals appeared normal at birth. Efemp1 -/- mice showed reduced fertility and displayed premature aging, with reduced life span, decreased body mass, lordokyphosis, reduced hair growth, and generalized fat, muscle, and organ atrophy. However, they did not show an age-related defect in wound healing. Depending on their background strain, some Efemp1 -/- mice also developed large hernias, including inguinal hernias, pelvic prolapse, and protrusions of the xiphoid process. Histologic analysis revealed a marked reduction of elastic fibers in fascia throughout the body in Efemp1 -/- mice, but no apparent macular degeneration.
Fu et al. (2007) generated Efemp1-R345W knockin mice and observed the development of deposits of material between Bruch's membrane and the retinal pigment epithelium (RPE) that resembled basal deposits in patients with ARMD. The deposits contained Efemp1 and Timp3 (188826), an Efemp1-interacting protein. Evidence of complement activation was detected in the RPE and Bruch's membrane of the R345W-mutant mice. Fu et al. (2007) concluded that the R345W mutation in EFEMP1 is pathogenic, and suggested that alterations in the extracellular matrix may stimulate complement activation and represent a connection between these 2 etiologic factors in macular degeneration.
Marmorstein et al. (2007) generated knockin mice carrying the R345W mutation and found that small isolated sub-RPE deposits developed as early as 4 months of age in both R345W heterozygous and homozygous mice. Over time, these deposits increased in size and number, eventually becoming continuous sheets. In older mice, membranous debris was observed within the deposits and within Bruch's membrane, and was accompanied by general RPE and choroidal abnormalities including degeneration, vacuolation, loss or disruption of the RPE basal infoldings, choroidal atrophy, and focal thickening of and invasion of cellular processes into Bruch's membrane. Fibulin-3 was found to accumulate in the sub-RPE deposits.
In affected members of 5 families diagnosed with malattia leventinese (MLVT), also known as Doyne honeycomb retinal dystrophy (DHRD; 126600), including 2 families from the U.S., 2 from Switzerland, and 1 from Australia, Stone et al. (1999) identified heterozygosity for a C-T transition in the EFEMP1 gene, resulting in an arg345-to-trp (R345W) substitution. They then assessed the potential involvement of this variation in MLVT, DHRD, and age-related macular dystrophy (ARMD; see 153800) by SSCP screening of all 162 affected patients in 37 families, as well as 477 control individuals and 494 unrelated patients with ARMD. They found that DNA from 161 of 162 patients initially thought to be affected with MLVT or DHRD harbored an SSCP shift in exon 10 resulting from the R345W mutation. This shift was found in none of the DNA from ARMD or control individuals. Of the 161 MLVT/DHRD patients harboring the R345W mutation, 160 were heterozygotes; 1 individual was homozygous for this change and had a retinal phenotype equivalent to that of heterozygotes of similar age. Stone et al. (1999) reexamined the retinal photographs of the 2 'affected' members of the single family that was discordant for the R345W change and found that the individual with the mutation had the characteristic MLVT phenotype (and the shared Swiss haplotype), whereas the individual lacking the mutation had a phenotype more typical of common ARMD (and failed to share alleles with the Swiss haplotype). This is, then, an exceptionally close genotype/phenotype correlation.
Stone et al. (1999) also investigated samples from 2 nuclear families with genealogic evidence for a relationship with the original DHRD family reported by Doyne (1899), and found that affected individuals from both families harbored the R345W variation. Noting the absence of de novo R345W mutations in the 39 families they studied, and the complete sharing of alleles of 4 intragenic EFEMP1 polymorphisms among these families, Stone et al. (1999) suggested that the R345W mutation occurred only once, in a common ancestor of every affected patient in the study.
Tarttelin et al. (2001) identified this mutation in 7 of 10 families with Doyne honeycomb retinal dystrophy and 1 of 17 sporadic patients.
In a consanguineous Indian family with early-onset macular degeneration, Fu et al. (2007) identified the R345W mutation in the EFEMP1 gene. The mother and father were heterozygous for the mutation, whereas their more severely affected sons were homozygous. The disease haplotype in this family was distinctly different from previously reported haplotypes, suggesting that the mutation arose independently.
In a Chinese family in which a sister and brother and their mother had DHRD/MLVT, Zhang et al. (2018) sequenced the EFEMP1 gene and identified heterozygosity for the recurrent R345W mutation.
In a 32-year-old Swiss woman with MLVT, Vaclavik et al. (2020) identified heterozygosity for a de novo occurrence of the recurrent R345W mutation (c.1033C-T, NM_001039349.2).
In a 57-year-old Danish woman with DHRD, Sheyanth et al. (2021) sequenced 7 genes associated with flecked retina and identified heterozygosity for the R345W mutation in EFEMP1. No pathogenic variants were found in the remaining genes. Analysis of microsatellite markers and intragenic SNPs indicated a different haplotype compared to the original study by Stone et al. (1999), suggesting that the mutation arose independently.
Variant Function
Hulleman et al. (2011) noted that arg345 is adjacent to cys344, which is required to form the second disulfide bond of EGF domain-6 in EFEMP1. By examining secretion of mutant EFEMP1 proteins in transfected HEK293T cells, they found that the R345W mutation or substitution of R345 with a different aromatic residue interfered with disulfide bond formation and secretion of EFEMP1. EFEMP1 with the R345W mutation accumulated intracellularly.
Using immunocytochemistry to analyze transfected COS-7 cells, Collantes et al. (2022) observed increased intracellular retention of the R345W mutant compared to wildtype EFEMP1, which was confirmed by Western blot analysis.
Tsai et al. (2021) found that genetic correction of the EFEMP1 R345W mutation in induced pluripotent stem cells (iPSCs) from individuals with DHRD alleviated reduced EFEMP1 secretion but did not affect iPSC differentiation into retinal pigment epithelium cells (iRPEs). Proteomic profiling revealed a significant number of differentially expressed genes between iRPE cells derived from iPSCs of DHRD-affected individuals and wildtype iRPE cells; however, correction of the R345W mutation greatly reduced the number of differentially expressed genes. ELISA showed that, in contrast to previous reports, EFEMP1 R345W iRPEs did not display inflammatory cytokine release or unfolded protein response. Instead, they exhibited downregulation of CES1 (114835), an enzyme expressed predominantly in the RPE layer of human eye that converts cholesteryl ester to free cholesterol. The reduced CES1 expression hampered secretion of cholesterol, leading to lipid accumulation in iRPEs. Further analysis showed that the EFEMP1 R345W mutant had a hyperinhibitory effect on EGFR (131550) signaling, resulting in downregulation of the transcription factor SP1 (189906), which controlled CES1 transcription by binding to its promoter.
In father and 4 sons from a 3-generation African American family with primary open angle glaucoma (GLC1H; 611276), who all had onset of disease at age 35 years or older, Mackay et al. (2015) identified heterozygosity for a c.418C-T transition (c.418C-T, NM_001039348.2) in exon 5 of the EFEMP1 gene, resulting in an arg140-to-trp (R140W) substitution at a highly conserved residue within the first calcium-binding EGF-like domain. The mutation segregated with disease in the first 2 generations of the family; the mutation was present in several members of the third generation who were of unknown disease status due to their young age. Analysis of transfected HEK293T cell lysates showed a 2-fold increase in mutant EFEMP1 compared to wildtype levels, suggesting that the R140W mutant accumulated abnormally and/or was secreted less efficiently than the wildtype protein.
Variant Function
Using immunocytochemistry to analyze transfected COS-7 cells with the R140W mutation, Collantes et al. (2022) observed significant intracellular aggregation of the R140W mutant compared to wildtype. Colocalization with an endoplasmic reticulum (ER) marker suggested that the aggregates formed in the vicinity of the ER. Western blot analysis confirmed a significant increase in intracellular retention of the mutant protein compared to wildtype EFEMP1.
In a large 4-generation Filipino family (family A) in which 16 members had primary open angle glaucoma (GLC1H; 611276) with onset before age 30 years, Collantes et al. (2022) identified heterozygosity for a c.238A-T transversion (c.238A-T, NM_001039348.3) in the EFEMP1 gene, resulting in an asn80-to-tyr (N80Y) substitution at a conserved residue within the first EGF-like domain. The mutation was present in the 16 affected family members and not in 18 unaffected family members over the age of 18 years; it was also present in 1 young family member, aged 13, who was clinically unaffected at the time of study, but it was not found in the gnomAD or TOPMed databases. Immunocytochemical analysis of transfected COS-7 cells showed significant intracellular aggregation of the N80Y mutant compared to wildtype, and colocalization with an endoplasmic reticulum (ER) marker suggested that the aggregates formed in the vicinity of the ER. Western blot analysis confirmed a significant increase in intracellular retention of the mutant protein compared to wildtype EFEMP1.
In a large 6-generation Filipino family (family B) with primary open angle glaucoma (GLC1H; 611276), in which 16 affected individuals had onset of disease before age 21 years and 1 patient presented at age 43, Collantes et al. (2022) identified heterozygosity for a c.1480T-C transition (c.1480T-C, NM_001039348.3) in the EFEMP1 gene, replacing the stop codon with a gln residue and adding 29 amino acid residues to the polypeptide (Ter494GlnExtTer29). The mutation was present in all 17 affected family members and not in 6 unaffected family members over the age of 18 years; it was also present in 4 young family members, aged 7 to 12 years, who were clinically unaffected at the time of study, but it was not found in the gnomAD or TOPMed databases. Immunocytochemical analysis of transfected COS-7 cells showed significant intracellular aggregation of the mutant protein compared to wildtype, and colocalization with an endoplasmic reticulum (ER) marker suggested that the aggregates formed in the vicinity of the ER. Western blot analysis confirmed a significant increase in intracellular retention of the mutant protein compared to wildtype EFEMP1.
In a Lebanese sister and brother with marfanoid features and multiple inguinal, crural, and abdominal herniae as well as large diverticula throughout the gastrointestinal tract and bladder (ARCL1D; 620780), originally described by Megarbane et al. (2012), Bizzari et al. (2020) identified homozygosity for a c.163T-C transition (c.163T-C, NM_001039348) in the EFEMP1 gene, resulting in a cys55-to-arg (C55R) substitution at a highly conserved residue within the first N-terminal EGF-like domain. Their unaffected first-cousin parents and an unaffected brother were heterozygous for the mutation, which was not found in the Saudi Human Genome Program, dbSNP, 1000 Genomes Project, or gnomAD databases.
Woodard et al. (2022) studied the C55R variant in transfected HEK293A cells and observed that under reducing conditions, the C55R mutant is secreted at similar levels to wildtype. Under nonreducing conditions, they found that in addition to a monomeric form of fibulin-3, the C55R variant also forms a secreted disulfide-linked homodimer. C55R extracellular dimerization was also clearly observed in the conditioned media of dermal fibroblasts overexpressing EFEMP1. Cotransfection experiments indicated a lack of interaction between wildtype and C55R fibulin-3, consistent with the unaffected clinical status of heterozygotes. Using CRISPR/Cas9 gene editing, the authors knocked out EFEMP1 in a retinal pigment epithelium (RPE) cell line, and observed a significant reduction in MMP2 (120360) activity and in collagen type VI (COL6A1; 120220) filament formation. Both were partially rescued by wildtype EFEMP1, but overexpression of similar amounts of the C55R mutant did not rescue these defects. The authors concluded that C55R is a loss-of-function mutation.
In a New Zealand man with multiple and recurrent abdominal and thoracic herniae, myopia, hypermobile joints, scoliosis, and thin translucent skin that became progressively more lax with age (ARCL1D; 620780), Driver et al. (2020) identified compound heterozygosity for a 5-bp deletion (c.320_324delTGGCA, NM_001039348.3), causing a frameshift predicted to result in a premature termination codon (Met107fs), and a c.615T-A transversion, resulting in a tyr205-to-ter (Y205X; 601548.0007) substitution. The variants were not found in 302 controls or in the gnomAD database; DNA was unavailable from the proband's unaffected parents.
For discussion of the c.615T-A transversion (c.615T-A, NM_001039348.3) in the EFEMP1 gene, resulting in a tyr205-to-ter (Y205X) substitution, that was found in compound heterozygous state in a New Zealand man with ARCL1D (620780) by Driver et al. (2020), see 601548.0006.
In a 9-year-old Turkish boy with redundant skin, multiple abdominal herniae, and generalized joint hypermobility (ARCL1D; 620780), Verlee et al. (2021) identified homozygosity for a c.1201C-T transition (c.1201C-T, NM_001039348.3) in the EFEMP1 gene, resulting in an arg401-to-ter (R401X) substitution. The mutation segregated with disease in the family and was not found in the gnomAD database.
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