Alternative titles; symbols
HGNC Approved Gene Symbol: SERPINF1
Cytogenetic location: 17p13.3 Genomic coordinates (GRCh38): 17:1,762,060-1,777,565 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17p13.3 | Osteogenesis imperfecta, type VI | 613982 | Autosomal recessive | 3 |
The SERPINF1 gene is a member of the serpin gene family. Serpins are a group of serine protease inhibitors, some of which have also been reported to exhibit neurotrophic activity.
By the analysis of 3 independent somatic cell hybrid panels, Tombran-Tink et al. (1994) assigned the PEDF gene to chromosome 17. Fluorescence in situ hybridization showed localization at the terminal portion of 17p. PCR analysis of somatic cell hybrids containing specific regions of 17 were subsequently used to sublocalize PEDF to 17pter-p13.1. Greenberg et al. (1997) used linkage analysis to narrow the localization of the PEDF gene to 17p13.3, the same region as that carrying the autosomal dominant retinitis pigmentosa locus (RP13; 600059) identified in a South African family.
Pigment epithelium-derived factor, originally identified in conditioned medium of cultured human fetal retinal pigment epithelial (RPE) cells, induces extensive neuronal differentiation in human Y79 retinoblastoma cells, a neoplastic counterpart of normal retinoblasts. Steele et al. (1993) suggested that PEDF is synthesized by RPE cells and secreted into the retina interphotoreceptor matrix where it may influence development/differentiation of the neural retina.
In studies aimed at identifying antiangiogenic factors in the eye, Dawson et al. (1999) identified PEDF. Biochemically purified as well as recombinant forms of PEDF potently inhibited neovascularization in the rat cornea. In vitro, PEDF inhibited endothelial cell migration in a dose-dependent manner with a median effective dose of 0.4 nanomolar, placing it among the most potent natural inhibitors of angiogenesis in this assay, slightly more active than pure angiostatin (see 173350), thrombospondin I (188060), and endostatin (see 120328). At doses of 1.0 nanomolar or greater, PEDF also inhibited basic fibroblast growth factor (see 131220)-induced proliferation of capillary endothelial cells by 40%. The amount of inhibitory PEDF produced by retinal cells was positively correlated with oxygen concentrations, suggesting that its loss plays a permissive role in ischemia-driven retinal neovascularization. These results suggested that PEDF may be of therapeutic use, especially in retinopathies where pathologic neovascularization compromises vision and leads to blindness. PEDF may also prove to be a useful therapeutic for retinoblastomas, where its dual activities in reducing cell differentiation and inhibiting angiogenesis may be particularly effective.
King and Suzuma (2000) reviewed the role of pigment epithelium-derived factor as a key coordinator of retinal neuronal and vascular functions. Aymerich et al. (2001) examined native neural retinas from adult steers for the expression of PEDF receptors and conclusively demonstrated the existence of PEDF receptors discretely distributed on the surface of cells from the adult retinal cells. They suggested that the results also provided evidence for the direct action of PEDF on photoreceptor and ganglion cell neurons and an anatomic basis for studies to assess PEDF neurotrophic effects on the adult retina.
Simonovic et al. (2001) pointed out that PEDF is the most potent inhibitor of angiogenesis in the mammalian ocular compartment. It also has neurotrophic activity, both in the retina and in the central nervous system, and is highly upregulated in young versus senescent fibroblasts. To provide a structural basis for understanding its many biologic roles, Simonovic et al. (2001) solved the crystal structure of glycosylated human PEDF. The structure revealed the organization of possible receptor and heparin-binding sites, and showed that, unlike any other previously characterized serpins, PEDF has a striking asymmetric charge distribution that might be of functional importance.
Natural inhibitors of angiogenesis are able to block pathologic neovascularization without harming the preexisting vasculature. Volpert et al. (2002) demonstrated that 2 such inhibitors, thrombospondin I and pigment epithelium-derived factor, derive specificity for remodeling vessels from their dependence on Fas/Fas ligand (134637; FasL, 134638)-mediated apoptosis to block angiogenesis. Both inhibitors upregulated FasL on endothelial cells. Expression of the essential partner of FasL, Fas receptor, was low on quiescent endothelial cells and vessels but greatly enhanced by inducers of angiogenesis, thereby specifically sensitizing the stimulated cells to apoptosis by inhibitor-generated FasL. The antiangiogenic activity of thrombospondin I and pigment epithelium-derived factor both in vitro and in vivo was dependent on this dual induction of Fas and FasL and the resulting apoptosis. Volpert et al. (2002) concluded that this example of cooperation between pro- and antiangiogenic factors in the inhibition of angiogenesis provides one explanation for the ability of inhibitors to select remodeling capillaries for destruction.
Ogata et al. (2002) found that lower vitreous levels of PEDF and higher levels of vascular endothelial growth factor (VEGF; 192240) in vivo might be related to the angiogenesis in proliferative diabetic retinopathy (see 603933).
Osteogenesis Imperfecta Type VI
In 2 male sibs, born to second-cousin parents from the United Arab Emirates, with osteogenesis imperfecta type VI (OI6; 613982), Becker et al. (2011) identified a homozygous truncating mutation in the SERPINF1 gene (172860.0001). The parents and 2 unaffected sisters were heterozygous carriers. In 2 unrelated Turkish patients with OI VI, both from consanguineous families, Becker et al. (2011) identified homozygosity for 2 different truncating SERPINF1 mutations (172860.0002-172860.0003). Collagen analyses with cultured dermal fibroblasts displayed no evidence for impaired collagen folding, posttranslational modification, or secretion.
In affected members of 3 Saudi families with OI, Shaheen et al. (2012) identified homozygous mutations in the SERPINF1 gene (172860.0004-172860.0006). All of those affected had early childhood onset of fractures, and affected individuals in 2 families had blue sclera. There was no apparent involvement of the teeth or other organs. All responded well to bisphosphonate therapy.
Associations Pending Confirmation
For discussion of a possible association between microvascular complications of diabetes and variation in the SERPINF1 gene, see MVCD1 (603933).
Doll et al. (2003) generated Pedf-deficient by targeted disruption. Pedf -/- mice were viable and fertile with litters of normal size. Mice deficient in Pedf had retinas with malpositioned vessels, irregular pigmentation, a reduced number of ganglion cells, and increased microvessel density. Doll et al. (2003) identified Pedf as a key inhibitor of stromal vasculature and epithelial tissue growth in mouse prostate and pancreas. In Pedf-deficient mice, stromal cells were increased and associated with epithelial cell hyperplasia. Androgens inhibited prostatic Pedf expression in cultured cells. In vivo, androgen ablation increased PEDF in normal rat prostates and in human cancer biopsies. Exogenous PEDF induced tumor epithelial apoptosis in vitro and limited in vivo tumor xenograft growth, triggering endothelial apoptosis. Thus, Doll et al. (2003) concluded that PEDF regulates normal pancreas and prostate mass and suggested that its androgen sensitivity makes PEDF a likely contributor to the anticancer effects of androgen ablation.
In 2 male sibs with osteogenesis imperfecta type VI (OI6; 613982), offspring of second-cousin parents from the United Arab Emirates, Becker et al. (2011) identified homozygosity for a 696C-G transversion in exon 6 of the SERPINF1 gene (g.1,625,154, NCBI36), resulting in a tyr232-to-ter (Y232X) substitution. The mutation is predicted to be null because of nonsense-mediated decay. The parents and 2 unaffected sisters were heterozygous carriers. The mutation was not found in 460 control chromosomes from individuals with the same regional ancestry as the index patient.
In an affected patient from a consanguineous Turkish family segregating osteogenesis imperfecta type VI (OI6; 613982), Becker et al. (2011) identified a homozygous 2-bp duplication in exon 4 of the SERPINF1 gene (324_325dupCT), resulting in a frameshift and a premature stop codon (Tyr109SerfsTer5). The mutation is predicted to be null because of nonsense-mediated decay. The patient's parents and 2 healthy sisters were heterozygous for the mutation. The mutation was not found in 460 Turkish control chromosomes.
In an affected patient from a consanguineous Turkish family segregating osteogenesis imperfecta type VI (OI6; 613982), Becker et al. (2011) identified homozygosity for a 1132C-T transition in exon 8 of the SERPINF1 gene, resulting in a gln378-to-ter (Q378X) substitution. The mutation occurs in a highly conserved region of the C-terminus within the reactive center loop of the protein. The patient's parents were heterozygous for the mutation, which was not found in 272 Turkish control alleles.
In affected members of a Saudi family with osteogenesis imperfecta type VI (OI6; 613982), Shaheen et al. (2012) identified a homozygous 2-bp deletion (1118_1119del) in the SERPINF1 gene, resulting in a frameshift (Pro373GlnfsTer18, P373QfsX18). All of those affected had early childhood onset of fractures and blue sclera. There was no apparent involvement of the teeth or other organs. All responded well to bisphosphonate therapy.
In affected members of a Saudi family with osteogenesis imperfecta type VI (OI6; 613982), Shaheen et al. (2012) identified a homozygous mutation at the donor splice site of exon 1, a 1-bp duplication (T) at position +2 (-9+2dup), in the SERPINF1 gene. All of those affected had early childhood onset of fractures and blue sclera. There was no apparent involvement of the teeth or other organs. All responded well to bisphosphonate therapy. Shaheen et al. (2012) notated this mutation as 1-4796dupT; the notation used here was provided by Shaheen (2013).
In affected members of a Saudi family with osteogenesis imperfecta type VI (OI6; 613982), Shaheen et al. (2012) identified a homozygous 1-bp deletion in the SEFPINF1 gene (653delT). All of those affected had early childhood onset of fractures. There was no apparent involvement of the teeth or other organs. All responded well to bisphosphonate therapy.
Aymerich, M. S., Alberdi, E. M., Martinez, A., Becerra, S. P. Evidence for pigment epithelium-derived factor receptors in the neural retina. Invest. Ophthal. Vis. Sci. 42: 3287-3293, 2001. [PubMed: 11726635]
Becker, J., Semler, O., Gilissen, C., Li, Y., Bolz, H. J., Giunta, C., Bergmann, C., Rohrbach, M., Koerber, F., Zimmermann, K., de Vries, P., Wirth, B., Schoenau, E., Wollnik, B., Veltman, J. A., Hoischen, A., Netzer, C. Exome sequencing identifies truncating mutations in human SERPINF1 in autosomal-recessive osteogenesis imperfecta. Am. J. Hum. Genet. 88: 362-371, 2011. [PubMed: 21353196] [Full Text: https://doi.org/10.1016/j.ajhg.2011.01.015]
Dawson, D. W., Volpert, O. V., Gillis, P., Crawford, S. E., Xu, H.-J., Benedict, W., Bouck, N. P. Pigment epithelium-derived factor: a potent inhibitor of angiogenesis. Science 285: 245-248, 1999. [PubMed: 10398599] [Full Text: https://doi.org/10.1126/science.285.5425.245]
Doll, J. A., Stellmach, V. M., Bouck, N. P., Bergh, A. R. J., Lee, C., Abramson, L. P., Cornwell, M. L., Pins, M. R., Borensztajn, J., Crawford, S. E. Pigment epithelium-derived factor regulates the vasculature and mass of the prostate and pancreas. Nature Med. 9: 774-780, 2003. [PubMed: 12740569] [Full Text: https://doi.org/10.1038/nm870]
Greenberg, J., Goliath, R., Tombran-Tink, J., Chader, G., Ramesar, R. Growth factors in the retina: pigment epithelium-derived factor (PEDF) now fine mapped to 17p13.3 and tightly linked to the RP13 locus.In: La Vail, M. M.; Hollyfield, J. G.; Anderson, R. E. (eds.) : Degenerative Retinal Diseases New York: Plenum Press 1997. Pp. 291-294.
King, G. L., Suzuma, K. Pigment-epithelium-derived factor: a key coordinator of retinal neuronal and vascular functions. New Eng. J. Med. 342: 349-351, 2000. [PubMed: 10655537] [Full Text: https://doi.org/10.1056/NEJM200002033420511]
Ogata, N., Nishikawa, M., Nishimura, T., Mitsuma, Y., Matsumura, M. Unbalanced vitreous levels of pigment epithelium-derived factor and vascular endothelial growth factor in diabetic retinopathy. Am. J. Ophthal. 134: 348-353, 2002. [PubMed: 12208245] [Full Text: https://doi.org/10.1016/s0002-9394(02)01568-4]
Shaheen, R. Personal Communication. Riyadh, Saudi Arabia 4/8/2013.
Shaheen, R., Alazami, A. M., Alshammari, M. J., Faqeih, E., Alhashmi, N., Mousa, N., Alsinani, A., Ansari, S., Alzahrani, F., Al-Owain, M., Alzayed, Z. S., Alkuraya, F. S. Study of autosomal recessive osteogenesis imperfecta in Arabia reveals a novel locus defined by TMEM38B mutation. J. Med. Genet. 49: 630-635, 2012. [PubMed: 23054245] [Full Text: https://doi.org/10.1136/jmedgenet-2012-101142]
Simonovic, M., Gettins, P. G. W., Volz, K. Crystal structure of human PEDF, a potent antiangiogenic and neurite growth-promoting factor. Proc. Nat. Acad. Sci. 98: 11131-11135, 2001. [PubMed: 11562499] [Full Text: https://doi.org/10.1073/pnas.211268598]
Steele, F. R., Chader, G. J., Johnson, L. V., Tombran-Tink, J. Pigment epithelium-derived factor: neurotrophic activity and identification as a member of the serine protease inhibitor gene family. Proc. Nat. Acad. Sci. 90: 1526-1530, 1993. [PubMed: 8434014] [Full Text: https://doi.org/10.1073/pnas.90.4.1526]
Tombran-Tink, J., Pawar, H., Swaroop, A., Rodriguez, I., Chader, G. J. Localization of the gene for pigment epithelium-derived factor (PEDF) to chromosome 17p13.1 and expression in cultured human retinoblastoma cells. Genomics 19: 266-272, 1994. [PubMed: 8188257] [Full Text: https://doi.org/10.1006/geno.1994.1057]
Volpert, O. V., Zaichuk, T., Zhou, W., Reiher, F., Ferguson, T. A., Stuart, P. M., Amin, M., Bouck, N. P. Inducer-stimulated Fas targets activated endothelium for destruction by anti-angiogenic thrombospondin-1 and pigment epithelium-derived factor. Nature Med. 8: 349-357, 2002. [PubMed: 11927940] [Full Text: https://doi.org/10.1038/nm0402-349]