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Gene Review

EFEMP1  -  EGF containing fibulin-like extracellular...

Homo sapiens

Synonyms: DHRD, DRAD, EGF-containing fibulin-like extracellular matrix protein 1, Extracellular protein S1-5, FBLN3, ...
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Disease relevance of EFEMP1

  • Aberrant accumulation of EFEMP1 underlies drusen formation in Malattia Leventinese and age-related macular degeneration [1].
  • PURPOSE: To investigate the nature of symptomatic visual disturbance in patients with EFEMP1 retinal dystrophy in the absence of geographic atrophy or choroidal neovascularization [2].
  • RT-PCR suggests that the fibulin-3 gene is expressed in murine and human RPE, and in situ studies confirm that Fbln3 is expressed in the outer and inner nuclear layers, but strikingly not in the ganglion cell layer [3].
  • Our findings establish FBLN-3 and FBLN-5 as novel angiostatic agents capable of reducing tumor angiogenesis and, consequently, tumor growth in vivo and suggest that these angiostatic activities may one day be exploited to combat tumor angiogenesis and metastasis in cancer patients [4].
  • PURPOSE: To determine (1) clinical features that distinguish maculopathy due to the R345W substitution in fibulin-3 from other forms of inherited or early-onset drusen, (2) the phenotypic variability, and (3) the extent of retinal disease in those with a positive molecular diagnosis [5].

High impact information on EFEMP1

  • Here we use a combination of positional and candidate gene methods to identify a single non-conservative mutation (Arg345Trp) in the gene EFEMP1 (for EGF-containing fibrillin-like extracellular matrix protein 1) in all families studied [6].
  • Mutations were not observed in any of the 11 exons of EFEMP1 nor in exon 104 of hemicentin-1 [7].
  • S1-5 mRNA is overexpressed in Werner syndrome and senescent normal HDF, is induced by growth arrest of young normal cells, but is significantly decreased by high serum, conditions which promote cellular proliferation [8].
  • By differential screening, we isolated an overexpressed cDNA sequence (S1-5) that codes for a novel protein containing epidermal growth factor (EGF)-like domains which match the EGF-like consensus sequences within several known extracellular proteins that play a role in cell growth, development, and cell signalling [8].
  • We find FBLN-3 expression to be altered in some human tumors and that its constitutive expression in endothelial cells inhibited their proliferation, invasion, and angiogenic sprouting, as well as their response to vascular endothelial growth factor as measured by p38 mitogen-activated protein kinase activation [4].

Biological context of EFEMP1

  • Interestingly, a missense mutation in EFEMP1 is responsible for another hereditary macular degenerative disease, Malattia Leventinese (ML) [9].
  • The gene for one such protein, S1-5, was identified from a subtractively enriched cDNA library from a patient with Werner syndrome and was shown to be preferentially expressed in senescent and quiescent fibroblasts [10].
  • Exclusive segregation of Gln5345Arg with the disease haplotype in this large family, amino acid conservation of glutamine at this position among mammals, the non-conservative nature of the substitution and similarities to EFEMP1 support the conclusion that HEMICENTIN-1 is the ARMD1 gene [11].
  • Exons 1-12 of EFEMP1 were then investigated for mutation by direct sequencing [12].
  • These findings do not exclude the involvement of other alleles of the EFEMP1 gene in either phenotype [13].

Anatomical context of EFEMP1


Associations of EFEMP1 with chemical compounds


Other interactions of EFEMP1

  • Given that mutations in EFEMP1 have been recently described in patients with Doyne honeycomb retinal dystrophy, EFEMP2 becomes a good candidate for such disorders [10].
  • The nucleotide diversity of the ABCA4 coding region, a collective measure of the number and prevalence of polymorphic sites in a region of DNA, was found to be 1.28, a value that is 9 to 400 times greater than that of two other macular disease genes that were examined in a similar fashion (VMD2 and EFEMP1) [16].
  • Structure and chromosomal assignment of the human S1-5 gene (FBNL) that is highly homologous to fibrillin [17].
  • METHODS: Immunofluorescence microscopy was used to determine the distributions of vitronectin, fibronectin and a newly described fibrillin-like protein, the JB3 antigen, in the embryonic chicken heart [18].

Analytical, diagnostic and therapeutic context of EFEMP1


  1. Aberrant accumulation of EFEMP1 underlies drusen formation in Malattia Leventinese and age-related macular degeneration. Marmorstein, L.Y., Munier, F.L., Arsenijevic, Y., Schorderet, D.F., McLaughlin, P.J., Chung, D., Traboulsi, E., Marmorstein, A.D. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  2. Symptomatic abnormalities of dark adaptation in patients with EFEMP1 retinal dystrophy (Malattia Leventinese/Doyne honeycomb retinal dystrophy). Haimovici, R., Wroblewski, J., Piguet, B., Fitzke, F.W., Holder, G.E., Arden, G.B., Bird, A.C. Eye (London, England) (2002) [Pubmed]
  3. Transcriptional regulation and expression of the dominant drusen gene FBLN3 (EFEMP1) in mammalian retina. Blackburn, J., Tarttelin, E.E., Gregory-Evans, C.Y., Moosajee, M., Gregory-Evans, K. Invest. Ophthalmol. Vis. Sci. (2003) [Pubmed]
  4. Fibulins 3 and 5 antagonize tumor angiogenesis in vivo. Albig, A.R., Neil, J.R., Schiemann, W.P. Cancer Res. (2006) [Pubmed]
  5. Maculopathy due to the R345W substitution in fibulin-3: distinct clinical features, disease variability, and extent of retinal dysfunction. Michaelides, M., Jenkins, S.A., Brantley, M.A., Andrews, R.M., Waseem, N., Luong, V., Gregory-Evans, K., Bhattacharya, S.S., Fitzke, F.W., Webster, A.R. Invest. Ophthalmol. Vis. Sci. (2006) [Pubmed]
  6. A single EFEMP1 mutation associated with both Malattia Leventinese and Doyne honeycomb retinal dystrophy. Stone, E.M., Lotery, A.J., Munier, F.L., Héon, E., Piguet, B., Guymer, R.H., Vandenburgh, K., Cousin, P., Nishimura, D., Swiderski, R.E., Silvestri, G., Mackey, D.A., Hageman, G.S., Bird, A.C., Sheffield, V.C., Schorderet, D.F. Nat. Genet. (1999) [Pubmed]
  7. Dissection of genomewide-scan data in extended families reveals a major locus and oligogenic susceptibility for age-related macular degeneration. Iyengar, S.K., Song, D., Klein, B.E., Klein, R., Schick, J.H., Humphrey, J., Millard, C., Liptak, R., Russo, K., Jun, G., Lee, K.E., Fijal, B., Elston, R.C. Am. J. Hum. Genet. (2004) [Pubmed]
  8. An overexpressed gene transcript in senescent and quiescent human fibroblasts encoding a novel protein in the epidermal growth factor-like repeat family stimulates DNA synthesis. Lecka-Czernik, B., Lumpkin, C.K., Goldstein, S. Mol. Cell. Biol. (1995) [Pubmed]
  9. Tissue inhibitor of metalloproteinases-3 (TIMP-3) is a binding partner of epithelial growth factor-containing fibulin-like extracellular matrix protein 1 (EFEMP1). Implications for macular degenerations. Klenotic, P.A., Munier, F.L., Marmorstein, L.Y., Anand-Apte, B. J. Biol. Chem. (2004) [Pubmed]
  10. Isolation of a paralog of the Doyne honeycomb retinal dystrophy gene from the multiple retinopathy critical region on 11q13. Katsanis, N., Venable, S., Smith, J.R., Lupski, J.R. Hum. Genet. (2000) [Pubmed]
  11. Analysis of the ARMD1 locus: evidence that a mutation in HEMICENTIN-1 is associated with age-related macular degeneration in a large family. Schultz, D.W., Klein, M.L., Humpert, A.J., Luzier, C.W., Persun, V., Schain, M., Mahan, A., Runckel, C., Cassera, M., Vittal, V., Doyle, T.M., Martin, T.M., Weleber, R.G., Francis, P.J., Acott, T.S. Hum. Mol. Genet. (2003) [Pubmed]
  12. Molecular genetic heterogeneity in autosomal dominant drusen. Tarttelin, E.E., Gregory-Evans, C.Y., Bird, A.C., Weleber, R.G., Klein, M.L., Blackburn, J., Gregory-Evans, K. J. Med. Genet. (2001) [Pubmed]
  13. Analysis of the Arg345Trp disease-associated allele of the EFEMP1 gene in individuals with early onset drusen or familial age-related macular degeneration. Guymer, R.H., McNeil, R., Cain, M., Tomlin, B., Allen, P.J., Dip, C.L., Baird, P.N. Clin. Experiment. Ophthalmol. (2002) [Pubmed]
  14. An extracellular matrix protein of jellyfish homologous to mammalian fibrillins forms different fibrils depending on the life stage of the animal. Reber-Müller, S., Spissinger, T., Schuchert, P., Spring, J., Schmid, V. Dev. Biol. (1995) [Pubmed]
  15. Expressional and functional studies of Wolframin, the gene function deficient in Wolfram syndrome, in mice and patient cells. Philbrook, C., Fritz, E., Weiher, H. Exp. Gerontol. (2005) [Pubmed]
  16. An analysis of allelic variation in the ABCA4 gene. Webster, A.R., Héon, E., Lotery, A.J., Vandenburgh, K., Casavant, T.L., Oh, K.T., Beck, G., Fishman, G.A., Lam, B.L., Levin, A., Heckenlively, J.R., Jacobson, S.G., Weleber, R.G., Sheffield, V.C., Stone, E.M. Invest. Ophthalmol. Vis. Sci. (2001) [Pubmed]
  17. Structure and chromosomal assignment of the human S1-5 gene (FBNL) that is highly homologous to fibrillin. Ikegawa, S., Toda, T., Okui, K., Nakamura, Y. Genomics (1996) [Pubmed]
  18. Distribution of connective tissue proteins during development and neovascularization of the epicardium. Bouchey, D., Drake, C.J., Wunsch, A.M., Little, C.D. Cardiovasc. Res. (1996) [Pubmed]
  19. Sequence, recombinant expression and tissue localization of two novel extracellular matrix proteins, fibulin-3 and fibulin-4. Giltay, R., Timpl, R., Kostka, G. Matrix Biol. (1999) [Pubmed]
  20. Human fibulin-1D: molecular cloning, expression and similarity with S1-5 protein, a new member of the fibulin gene family. Tran, H., Mattei, M., Godyna, S., Argraves, W.S. Matrix Biol. (1997) [Pubmed]
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