Molecular Genetics of Sorsby Fundus Dystrophy


Sorsby fundus dystrophy (SFD) is a macular dystrophy caused by mutations in the tissue inhibitor metalloproteinase‐3 (TIMP3) gene on chromosome 22. It is a late‐onset autosomal dominant retinal dystrophy. Patients classically develop night blindness and central visual changes and it is often clinically mistaken for wet age‐related macular degeneration (wet AMD). Although SFD often presents at a younger age than wet AMD, it is currently being managed in a similar manner with intravitreal anti‐VEGF. The molecular mechanisms and pathology underlying SFD are not very well understood. Mutations in TIMP3 alter the homeostatic balance of the extracellular matrix as one of the main physiological function of TIMP3 is to inhibit matrix metalloproteinases (MMPs) which are involved in degradation of the ECM.

Key Concepts

  • Mutations in tissue inhibitor metalloproteinase‐3 impair extracellular matrix degradation.
  • Sorsby fundus dystrophy can result in choroidal neovascularisation.
  • RPE cells derived from induced pluripotent stem cells (iPSCs) can be used to model Sorsby fundus dystrophy for future studies.
  • Sorsby fundus dystrophy with associated choroidal neovascularisation is currently best managed with anti‐VEGF therapy.
  • There is increased tissue inhibitor metalloproteinase‐3 in the retina of Sorsby fundus dystrophy patients.

Keywords: Sorsby fundus dystrophy; tissue inhibitor metalloproteinase‐3; macular; dystrophy; matrix metalloproteinases; retinal pigment epithelium

Figure 1. A right multicolour fundus photograph of a patient with SFD demonstrating extensive areas of macula and peripapillary atrophy.
Figure 2. An OCT Heidelberg image of the right macula of a patient with SFD. The image displays evidence of CNV with associated intra‐retinal fluid and sub‐foveal fibrosis.


Anand‐Apte B, Chao JR, Singh R and Stöhr H (2018) Sorsby fundus dystrophy: insights from the past and looking to the future. Journal of Neuroscience Research 97: 88–97.

Apte SS, Olsen BR and Murphy G (1995) The gene structure of tissue inhibitor of metalloproteinases (TIMP)‐3 and its inhibitory activities define the distinct TIMP gene family. Journal of Biological Chemistry 270: 14313–14318.

Bailey TA, Alexander RA, Dubovy SR, Luthert PJ and Chong NH (2001) Measurement of TIMP‐3 expression and Bruch's membrane thickness in human macula. Experimental Eye Research 73: 851–858.

Balaskas K, Hovan M, Mahmood S and Bishop P (2013) Ranibizumab for the management of Sorsby fundus dystrophy. Eye (London) 27: 101–102.

Barbazetto IA, Hayashi M, Klais CM, Yannuzzi LA and Allikmets R (2005) A novel TIMP3 mutation associated with Sorsby fundus dystrophy. Archives of Ophthalmology 123: 542–543.

Brew K and Nagase H (2010) The tissue inhibitors of metalloproteinases (TIMPs): an ancient family with structural and functional diversity. Biochimica et Biophysica Acta 1803: 55–71.

Buchholz DE, Hikita ST, Rowland TJ, et al. (2009) Derivation of functional retinal pigmented epithelium from induced pluripotent stem cells. Stem Cells 27: 2427–2434.

Capon MR, Marshall J, Krafft JI, et al. (1989) Sorsby's fundus dystrophy. A light and electron microscopic study. Ophthalmology 96: 1769–1777.

Chong NH, Alexander RA, Gin T, Bird AC and Luthert PJ (2000) TIMP‐3, collagen, and elastin immunohistochemistry and histopathology of Sorsby's fundus dystrophy. Investigative Ophthalmolgy & Visual Science 41: 898–902.

Chong NH, Kvanta A, Seregard S, et al. (2003) TIMP‐3 mRNA is not overexpressed in Sorsby fundus dystrophy. American Journal of Ophthalmology 136: 954–955.

Christensen DRG, Brown FE, Cree AJ, Ratnayaka JA and Lotery AJ (2017) Sorsby fundus dystrophy ‐ A review of pathology and disease mechanisms. Experimental Eye Research 165: 35–46.

Fariss RN, Apte SS, Luthert PJ, Bird AC and Milam AH (1998) Accumulation of tissue inhibitor of metalloproteinases‐3 in human eyes with Sorsby's fundus dystrophy or retinitis pigmentosa. British Journal of Ophthalmology 82: 1329–1334.

Fata JE, Leco KJ, Voura EB, et al. (2001) Accelerated apoptosis in the Timp‐3‐deficient mammary gland. Journal of Clinical Investigation 108: 831–841.

Felbor U, Stohr H, Amann T, Schonherr U and Weber BH (1995) A novel Ser156Cys mutation in the tissue inhibitor of metalloproteinases‐3 (TIMP3) in Sorsby's fundus dystrophy with unusual clinical features. Human Molecular Genetics 4: 2415–2416.

Felbor U, Suvanto EA, Forsius HR, Eriksson AW and Weber BH (1997) Autosomal recessive Sorsby fundus dystrophy revisited: molecular evidence for dominant inheritance. American Journal of Human Genetics 60: 57–62.

Fritsche LG, Igl W, Bailey JN, et al. (2016) A large genome‐wide association study of age‐related macular degeneration highlights contributions of rare and common variants. Nature Genetics 48: 134–143.

Gemenetzi MK, Luff AJ and Lotery AJ (2011) Successful treatment of choroidal neovascularization secondary to Sorsby fundus dystrophy with intravitreal bevacizumab. Retinal Cases and Brief Reports 5: 132–135.

Gliem M, Muller PL, Mangold E, et al. (2015a) Reticular pseudodrusen in Sorsby fundus dystrophy. Ophthalmology 122: 1555–1562.

Gliem M, Muller PL, Mangold E, et al. (2015b) Sorsby fundus dystrophy: novel mutations, novel phenotypic characteristics, and treatment outcomes. Investigative Ophthalmology & Visual Science 56: 2664–2676.

Golestaneh N, Chu Y, Cheng SK, et al. (2016) Repressed SIRT1/PGC‐1alpha pathway and mitochondrial disintegration in iPSC‐derived RPE disease model of age‐related macular degeneration. Journal of Translational Medicine 14: 344.

Jacobson SG, Cideciyan AV, Regunath G, et al. (1995) Night blindness in Sorsby's fundus dystrophy reversed by vitamin A. Nature Genetics 11: 27–32.

Jacobson SG, Cideciyan AV, Bennett J, et al. (2002) Novel mutation in the TIMP3 gene causes Sorsby fundus dystrophy. Archives of Ophthalmology 120: 376–379.

Joutel A, Vahedi K, Corpechot C, et al. (1997) Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients. Lancet 350: 1511–1515.

Kamei M and Hollyfield J (1999) TIMP‐3 in Bruch's membrane: changes during aging and in age‐related macular degeneration. Investigative Ophthalmology & Visual Science 40: 2367–2375.

Kashiwagi M, Tortorella M, Nagase H and Brew K (2001) TIMP‐3 is a potent inhibitor of aggrecanase 1 (ADAM‐TS4) and aggrecanase 2 (ADAM‐TS5). Journal of Biological Chemistry 276: 12501–12504.

Kaye R and Lotery AJ (2017) ARVO e‐abstract: B0260: long‐term outcome of bevacizumab therapy in Sorsby fundus dystrophy, a case series. Investigative Ophthalmology & Visual Science 58 (8): 229.

Langton KP, McKie N, Curtis A, et al. (2000) A novel tissue inhibitor of metalloproteinases‐3 mutation reveals a common molecular phenotype in Torsby's fundus dystrophy. Journal of Biological Chemistry 275: 27027–27031.

Langton KP, McKie N, Smith BM, Brown NJ and Barker MD (2005) Sorsby's fundus dystrophy mutations impair turnover of TIMP‐3 by retinal pigment epithelial cells. Human Molecular Genetics 14: 3579–3586.

Li Y, Zhang Y, Xu Y, et al. (2017) Patient‐specific mutations impair BESTROPHIN1's essential role in mediating Ca(2+)‐dependent Cl(‐) currents in human RPE. eLife 6.

Lin RJ, Blumenkranz MS, Binkley J, Wu K and Vollrath D (2006) A novel His158Arg mutation in TIMP3 causes a late‐onset form of Sorsby fundus dystrophy. American Journal of Ophthalmology 142: 839–848.

Lukovic D, Artero Castro A, Delgado A, et al. (2015) Human iPSC derived disease model of MERTK associated retinitis pigmentosa. Scientific Reports 5: 12910.

Majid MA, Smith VA, Newby AC and Dick AD (2007) Matrix bound SFD mutant TIMP‐3 is more stable than wild type TIMP‐3. British Journal of Ophthalmology 91 (8): 1073–1076.

Meunier I, Bocquet B, Labesse G, et al. (2016) A new autosomal dominant eye and lung syndrome linked to mutations in TIMP3 gene. Scientific Reports 6: 32544.

Murphy G, Houbrechts A, Cockett MI, et al. (1991) The N‐terminal domain of tissue inhibitor of metalloproteinases retains metalloproteinase inhibitory activity. Biochemistry 30: 8097–8102.

Prager F, Michels S, Geitzenauer W and Schmidt‐Erfurth U (2007) Choroidal neovascularization secondary to Sorsby fundus dystrophy treated with systemic bevacizumab (Avastin®). Acta Ophthalmologica Scandinavica 85: 904–906.

Riera M, Navarro R, Ruiz‐Nogales S, et al. (2017) Whole exome sequencing using Ion Proton system enables reliable genetic diagnosis of inherited retinal dystrophies. Scientific Reports 7: 42078.

Saihan Z, Li Z, Rice J, et al. (2009) Clinical and biochemical effects of the E139K missense mutation in the TIMP3 gene, associated with Sorsby fundus dystrophy. Molecular Vision 15: 1218–1230.

Sivaprasad S, Webster AR, Egan CA, Bird AC and Tufail A (2008) Clinical course and treatment outcomes of Sorsby fundus dystrophy. American Journal of Ophthalmology 146: 228–234.

Schoenberger SD and Agarwal A (2013) A novel mutation at the N‐terminal domain of the TIMP3 gene in Sorsby fundus dystrophy. Retina 33: 429–435.

Smookler DS, Mohammed FF, Kassiri Z, et al. (2006) Tissue inhibitor of metalloproteinase 3 regulates TNF‐dependent systemic inflammation. The Journal of Immunology 176: 721–725.

Songstad AE, Wiley LA, Duong K, et al. (2015) Generating iPSC‐derived choroidal endothelial cells to study age‐related macular degeneration. Investigative Ophthalmology & Visual Science 56: 8258–8267.

Sorsby A and Joll Mason ME (1949) A fundus dystrophy with unusual features. British Journal of Ophthalmology: 67–97.

Tabata Y, Isashiki Y, Kamimura K, Nakao K and Ohba N (1998) A novel splice site mutation in the tissue inhibitor of the metalloproteinases‐3 gene in Sorsby's fundus dystrophy with unusual clinical features. Human Genetics 103: 179–182.

Tsokolas G, Almuhtaseb H and Lotery A (2018) Evaluation of Pro‐re‐Nata (PRN) and Treat and Extend Bevacizumab treatment protocols in Sorsby Fundus Dystrophy. European Journal of Ophthalmology 00: 1–8.

Qi JH, Ebrahem Q, Yeow K, et al. (2002) Expression of Sorsby's fundus dystrophy mutations in human retinal pigment epithelial cells reduces matrix metalloproteinase inhibition and may promote angiogenesis. Journal of Biological Chemistry 30: 30.

Qi JH, Ebrahem Q, Moore N, et al. (2003) A novel function for tissue inhibitor of metalloproteinases‐3 (TIMP3): inhibition of angiogenesis by blockage of VEGF binding to VEGF receptor‐2. Nature Medicine 9: 407–415.

Warwick A, Gibson J, Sood R and Lotery A (2016) A rare penetrant TIMP3 mutation confers relatively late onset choroidal neovascularisation which can mimic age‐related macular degeneration. Eye 30: 488–491.

Weber BH, Vogt G, Pruett RC, Stohr H and Felbor U (1994) Mutations in the tissue inhibitor of metalloproteinase‐3 (TIMP‐3) in patients with Sorsby's fundus dystrophy. Nature Genetics 8: 352–356.

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How to Cite close
Akyol, Engin, and Lotery, Andrew(Jul 2019) Molecular Genetics of Sorsby Fundus Dystrophy. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0028558]