Alternative titles; symbols
HGNC Approved Gene Symbol: MFAP5
Cytogenetic location: 12p13.31 Genomic coordinates (GRCh38): 12:8,645,943-8,662,826 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12p13.31 | Aortic aneurysm, familial thoracic 9 | 616166 | Autosomal dominant | 3 |
MFAP5 is a component of fibrillin-containing microfibrils where it partners with MFAP2 (MAGP; 156790) and other microfibril-associated proteins to define microfibril function (summary by Combs et al., 2013).
Gibson et al. (1996) found that MAGP2 (MFAP5), also referred to as MP25, is approximately 80% homologous in bovine and human and contains 170 and 173 amino acids, respectively. MAGP (MFAP2; 156790) was referred to as MAGP1 by Gibson et al. (1996). The close similarity between MAGP1 and MAGP2 was confined to a central region of 60 amino acids where there is precise alignment of 7 cysteine residues. Elsewhere, the MAGP2 molecule is rich in serine and threonine residues and contains an RGD motif. MAGP2 lacks the proline-, glutamine-, and tyrosine-rich sequences and a hydrophobic carboxyl terminus, characteristic of MAGP1. These structural differences suggest that MAGP2 has some functions that are distinct from those of MAGP1.
Hatzinikolas and Gibson (1998) determined that the MFAP5 gene contains 10 exons and spans about 11 kb. The translation initiation codon is in exon 2, and a single major transcription initiation site is located 213 bp upstream. The promoter region is AT rich, but it lacks a TATA box and other common regulatory elements. However, the sequence surrounding the transcription start site is similar to an initiator element found in highly regulated, TATA-less genes.
Gibson et al. (1996) mapped the MFAP5 gene to chromosome 12p13.1-p12.3 by fluorescence in situ hybridization.
Gibson et al. (1999) found that purified bovine Magp2 functioned as a substrate for adherence of fetal bovine aortic smooth muscle cells, ear cartilage chondrocytes, and arterial endothelial cells and human skin fibroblasts and osteoblasts. Human peripheral blood monocytes and several human cancer cell lines did not adhere to Magp2. Except for endothelial cells, each adherent cell type was able to spread on the Magp2 substrate. Binding was inhibited by calcium chelation, exposure to antiintegrin alpha-V (ITGAV; 193210)-beta-3 (ITGB3; 173470) antibody, or exposure to a peptide containing the integrin-binding RGD sequence of Magp2. Magp1, which lacks the RGD motif, required 10-fold greater molar quantities to promote equivalent cellular adherence. Gibson et al. (1999) concluded that MAGP2 promotes attachment of cells to microfibrils via alpha-V-beta-3 integrin.
Segade et al. (2002) found that fluorescence-tagged human MAGP2 was secreted from transfected RFL-6 rat lung fibroblasts, but that, unlike MAGP1, it did not associate with the extracellular matrix (ECM). Both MAGP1 and MAGP2 contain a putative C-terminal ECM-binding domain, but MAGP1A contains 7 cysteines within this domain, whereas MAGP2 contains only 6. Segade et al. (2002) found that substitution of val101 with cys in MAGP2 permitted association of MAGP2 with ECM.
Using solid-phase binding assays, Hanssen et al. (2004) found that purified fetal bovine Magp1 and Magp2 showed distinct patterns of binding to recombinant human fibrillin-1 (FBN1; 134797) and FBN2 (612570). Both bound the same central region of FBN1, but they also bound distinct N-terminal sites of FBN1. Immunogold labeling of developing bovine nuchal ligament revealed regular covalent and periodic association of Magp2 with fibrillin-containing microfibrils and that Magp2 was attached at 2 distinct points. In contrast, Magp1 had only a single attachment site. Hanssen et al. (2004) hypothesized that MAGP2 may be involved in the stabilization of fibrillin monomers within microfibrils by forming interdomain and/or intermonomer connections.
Combs et al. (2013) found that mouse Magp2 protein bound active human TGFB1 (190180), mouse Tgfb2 (190220), and mouse Bmp2 (112261) in solid-phase binding assays.
In 2 unrelated families with thoracic aortic aneurysm-9 (AAT9; 616166), Barbier et al. (2014) identified heterozygosity for a nonsense (R158X; 601103.0001) and a missense (W21L; 601103.0002) mutation in the MFAP5 gene.
Combs et al. (2013) found that mice with targeted inactivation of the Mfap5 gene appeared normal by several measures, were fertile, and had a normal life span, but were neutropenic. The authors noted that, in contrast, Mfap2 -/- mice were monocytopenic. Combs et al. (2013) demonstrated that double knockout of both genes resulted in age-related aortic dilation, indicating that the MAGP genes are important in maintaining large vessel integrity.
In affected individuals from a 3-generation family segregating autosomal dominant thoracic aortic aneurysm-9 (AAT9; 616166), Barbier et al. (2014) identified heterozygosity for a c.472C-T transition in exon 10 of the MFAP5 gene, resulting in an arg158-to-ter (R158X) substitution. The mutation was not found in unaffected family members. Analysis of patient fibroblasts demonstrated pure haploinsufficiency, and transfection studies confirmed that the R158X mutation abrogates protein production.
In a 58-year-old woman with thoracic aortic aneurysm and type A aortic dissection (AAT9; 616166), Barbier et al. (2014) identified heterozygosity for a c.62G-T transversion in exon 3 of the MFAP5 gene, resulting in a trp21-to-leu (W21L) substitution at a highly conserved residue in the N-terminal domain, near a putative peptide-signal cleavage site. The mutation was also found in her affected sister and daughter. Transfection studies showed that the signal from the W21L mutant was significantly lower than that of wildtype in cellular lysates.
Barbier, M., Gross, M.-S., Aubart, M., Hanna, N., Kessler, K., Guo, D.-C., Tosolini, L., Ho-Tin-Noe, B., Regalado, E., Varret, M., Abifadel, M., Milleron, O., and 10 others. MFAP5 loss-of-function mutations underscore the involvement of matrix alteration in the pathogenesis of familial thoracic aortic aneurysms and dissections. Am. J. Hum. Genet. 95: 736-743, 2014. [PubMed: 25434006] [Full Text: https://doi.org/10.1016/j.ajhg.2014.10.018]
Combs, M. D., Knutsen, R. H., Broekelmann, T. J., Toennies, H. M., Brett, T. J., Miller, C. A., Kober, D. L., Craft, C. S., Atkinson, J. J., Shipley, J. M., Trask, B. C., Mecham, R. P. Microfibril-associated glycoprotein 2 (MAGP2) loss of function has pleiotropic effects in vivo. J. Biol. Chem. 288: 28869-28880, 2013. [PubMed: 23963447] [Full Text: https://doi.org/10.1074/jbc.M113.497727]
Gibson, M. A., Hatzinikolas, G., Kumaratilake, J. S., Sandberg, L. B., Nicholl, J. K., Sutherland, G. R., Cleary, E. G. Further characterization of proteins associated with elastic fiber microfibrils including the molecular cloning of MAGP-2 (MP25). J. Biol. Chem. 271: 1096-1103, 1996. Note: Erratum: J. Biol. Chem. 271: 5288 only, 1996. [PubMed: 8557636] [Full Text: https://doi.org/10.1074/jbc.271.2.1096]
Gibson, M. A., Leavesley, D. I., Ashman, L. K. Microfibril-associated glycoprotein-2 specifically interacts with a range of bovine and human cell types via alpha-V-beta-3 integrin. J. Biol. Chem. 274: 13060-13065, 1999. [PubMed: 10224057] [Full Text: https://doi.org/10.1074/jbc.274.19.13060]
Hanssen, E., Hew, F. H., Moore, E., Gibson, M. A. MAGP-2 has multiple binding regions on fibrillins and has covalent periodic association with fibrillin-containing microfibrils. J. Biol. Chem. 279: 29185-29194, 2004. [PubMed: 15131124] [Full Text: https://doi.org/10.1074/jbc.M313672200]
Hatzinikolas, G., Gibson, M. A. The exon structure of the human MAGP-2 gene: similarity with the MAGP-1 gene is confined to two exons encoding a cysteine-rich region. J. Biol. Chem. 273: 29309-29314, 1998. [PubMed: 9792630] [Full Text: https://doi.org/10.1074/jbc.273.45.29309]
Segade, F., Trask, B. C., Broekelmann, T. J., Pierce, R. A., Mecham, R. P. Identification of a matrix-binding domain in MAGP1 and MAGP2 and intracellular localization of alternative splice forms. J. Biol. Chem. 277: 11050-11057, 2002. [PubMed: 11796718] [Full Text: https://doi.org/10.1074/jbc.M110347200]