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

• Our results were supported by significant accumulation and expression overlap of both TIMP-3 and EFEMP1 between the retinal pigment epithelia and Bruch membrane in the eyes of ML and AMD patients [9].
• In contrast to EFEMP1, however, EFEMP2 is not significantly overexpressed in senescent or quiescent fibroblasts, suggesting a diversity of function within this new EGF-like domain subfamily [10].
• Like EFEMP1, this novel gene is expressed in a wide range of adult and fetal tissues [10].
• FBLN-3 is homologous to FBLN-5 and expressed in endothelial cells, yet its role in tumorigenesis and angiogenesis is unknown [4].
• The presence of fibrillin-like beaded microfibrils in the ECM of P. carnea is furthermore demonstrated by electron microscopy after rotary shadowing [14].

Associations of EFEMP1 with chemical compounds

• The effect of 17beta-estradiol on fibulin-3 production was studied in COS-7 and ARPE-19 cells [3].
• Expression profiling on patient's primary fibroblasts revealed down-regulation of the diabetes associated plasma membrane glycoprotein (PC-1) gene, and up-regulation of fibulin-3, a gene connected to senescence [15].

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

• Here we report on the cloning and sequence analysis of human fibulin-3 (487 residues), also known as protein S1-5, and fibulin-4 (443 residues) [19].
• Paradoxically, microinjection into young HDF of two different lengths of S1-5 mRNA, containing different putative AUG translational start sites, consistently stimulated rather than inhibited DNA synthesis by an apparent autocrine/paracrine mechanism [8].
• Fibulin-3 expression in mouse and human retina was studied by in situ hybridization and RT-PCR [3].
• Fibulin-3 expression in ARPE-19 cells could be modified by varying the amount of estrogen in the cell culture medium [3].
• Human fibulin-1D: molecular cloning, expression and similarity with S1-5 protein, a new member of the fibulin gene family [20].

References