A Review and Update on the Molecular Basis of Pathogenesis of Sorsby Fundus Dystrophy

  • Heidi StöhrEmail author
  • Bela Anand-Apte
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 723)


Sorsby fundus dystrophy (SFD) is a rare autosomal dominant macular degeneration characterized by abnormal thickening of Bruch’s membrane (BM) leading to macular atrophy and choroidal neovascularization (CNV). SFD is caused by mutations in the gene encoding the tissue inhibitor of metalloproteinase-3 (TIMP3), a multifunctional protein component of BM. Disturbed homeostasis in extracellular matrix (ECM) remodeling is likely involved in SFD pathology. Here, we summarize the current findings on the mechanism(s) by which mutant TIMP3 causes the phenotypical expression of SFD. In addition, the association between SFD and complex age-related macular degeneration (AMD) is discussed.


Sorsby fundus dystrophy Choroidal neovascularization Bruch’s membrane TIMP3 Extracellular matrix Angiogenesis VEGF AMD 


  1. Arris CE, Bevitt DJ, Mohamed J et al (2003) Expression of mutant and wild-type TIMP3 in primary gingival fibroblasts from Sorsby’s fundus dystrophy patients. Biochim Biophys Acta 1638:20–28PubMedGoogle Scholar
  2. Barbazetto IA, Hayashi M, Klais CM et al (2005) A novel TIMP3 mutation associated with Sorsby fundus dystrophy. Arch Ophthalmol 123:542–543PubMedCrossRefGoogle Scholar
  3. Brew K, Nagase H (2010) The tissue inhibitors of metalloproteinases (TIMPs): an ancient family with structural and functional diversity. Biochim Biophys Acta 1803:55–71PubMedCrossRefGoogle Scholar
  4. Capon MRC, Marshall J, Krafft JI et al (1989) Sorsby’s fundus dystrophy: a light and electron microscopic study. Ophthalmology 96:1769–1777PubMedGoogle Scholar
  5. Chen W, Stambolian D, Edwards AO et al (2010) Genetic variants near TIMP3 and high-density lipoprotein-associated loci influence susceptibility to age-related macular degeneration. Proc Natl Acad Sci USA 107:7401–7406PubMedCrossRefGoogle Scholar
  6. Chong NH, Alexander RA, Gin T et al (2000) TIMP-3, collagen, and elastin immunohistochemistry and histopathology of Sorsby’s fundus dystrophy. Invest Ophthalmol Vis Sci 41:898–902PubMedGoogle Scholar
  7. Clarke M, Mitchell KW, Goodship J et al (2001) Clinical features of a novel TIMP-3 mutation causing Sorsby’s fundus dystrophy: implications for disease mechanism. Br J Ophthalmol 85:1429–1431PubMedCrossRefGoogle Scholar
  8. Ebrahem Q, Qi J, Sugimoto M et al. (2011) Increased neovascularization in mice lacking tissue inhibitor of metalloproteinases-3. Invest Ophthalmol Vis Sci 52:6117-6123Google Scholar
  9. Fariss RN, Apte SS, Luthert PJ et al (1998) Accumulation of tissue inhibitor of metalloproteinases-3 in human eyes with Sorsby’s fundus dystrophy or retinitis pigmentosa. Br J Ophthalmol 82:1329–1334PubMedCrossRefGoogle Scholar
  10. Fedak PW, Smookler DS, Kassiri Z et al (2004) TIMP-3 deficiency leads to dilated cardiomyopathy. Circulation 110:2401–2409PubMedCrossRefGoogle Scholar
  11. Felbor U, Stöhr H, Amann T et al (1995) A novel Ser156Cys mutation in the tissue inhibitor of metalloproteinases-3 (TIMP3) in Sorsby’s fundus dystrophy with unusual clinical features. Hum Mol Genet 4:2415–2416PubMedCrossRefGoogle Scholar
  12. Felbor U, Benkwitz C, Litt M et al (1997) A founder mutation in TIMP3, Ser181Cys, presents with variable expressivity of Sorsby fundus dystrophy. Arch Ophthalmol 115:1569–1571PubMedCrossRefGoogle Scholar
  13. Fogarasi M, Janssen A, Weber BH et al (2008) Molecular dissection of TIMP3 mutation S156C associated with Sorsby fundus dystrophy. Matrix Biol 27:381–292PubMedCrossRefGoogle Scholar
  14. Fu L, Garland D, Yang Z et al (2007) The R345W mutation in EFEMP1 is pathogenic and causes AMD-like deposits in mice. Hum Mol Genet 16:2411–2422PubMedCrossRefGoogle Scholar
  15. Jacobson SG, Cideciyan AV, Regunath G et al (1995) Night blindness in Sorsby’s fundus dystrophy reversed by vitamin A. Nat Genet 11:27–32PubMedCrossRefGoogle Scholar
  16. Jacobson SG, Cideciyan AV, Bennett J et al (2002) Novel mutation in the TIMP3 gene causes Sorsby fundus dystrophy. Arch Ophthalmol 120:376–379PubMedGoogle Scholar
  17. Janssen A, Hoellenriegel J, Fogarasi M et al (2008) Abnormal vessel formation in the choroid of mice lacking tissue inhibitor of metalloprotease-3. Invest Ophthalmol Vis Sci 49:2812–2822PubMedCrossRefGoogle Scholar
  18. Kamei M, Hollyfield JG (1999). Invest Ophthalmol Vis Sci 40:2367–2375Google Scholar
  19. Klenotic PA, Munier FL, Marmorstein LY et al (2004) 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. J Biol Chem 279:30469–30473PubMedCrossRefGoogle Scholar
  20. Langton KP, McKie N, Curtis A et al (2000) A novel tissue inhibitor of metalloproteinases-3 mutation reveals a common molecular phenotype in Sorsby’s fundus dystrophy. J Biol Chem 275:27027–27031PubMedGoogle Scholar
  21. Langton KP, McKie N, Smith BM et al (2005) Sorsby’s fundus dystrophy mutations impair turnover of TIMP-3 by retinal pigment epithelial cells. Hum Mol Genet 14:3579–3586PubMedCrossRefGoogle Scholar
  22. Leco KJ, Waterhouse P, Sanchez OH et al (2001) Spontaneous air space enlargement in the lungs of mice lacking tissue inhibitor of metalloproteinases-3 (TIMP-3). J Clin Invest 108:817–829PubMedGoogle Scholar
  23. Lin RJ, Blumenkranz MS, Binkley J et al (2006) A novel His158Arg mutation in TIMP3 causes a late-onset form of Sorsby fundus dystrophy. Am J Ophthalmol 142:839–848PubMedCrossRefGoogle Scholar
  24. Mahmoodi M, Sahebjam S, Smookler D et al (2005) Links Lack of tissue inhibitor of metalloproteinases-3 results in an enhanced inflammatory response in antigen-induced arthritis. Am J Pathol 166:1733–1740PubMedCrossRefGoogle Scholar
  25. Mohammed FF, Smookler DS, Taylor SE et al (2004) Abnormal TNF activity in Timp3 −/− mice leads to chronic hepatic inflammation and failure of liver regeneration. Nat Genet 36:969-977PubMedCrossRefGoogle Scholar
  26. Polkinghorne PJ, Capon MRC, Berninger T et al (1989) Sorsby’s fundus dystrophy: a clinical study. Ophthalmology 96: 1763–1768PubMedGoogle Scholar
  27. Qi JH, Dai G, Luthert P et al (2009) S156C mutation in tissue inhibitor of metalloproteinases-3 induces increased angiogenesis. J Biol Chem 284:19927–19936PubMedCrossRefGoogle Scholar
  28. 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. Nat Med 9:407–415PubMedCrossRefGoogle Scholar
  29. 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. J Biol Chem 277:13394–13400PubMedCrossRefGoogle Scholar
  30. 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. Mol Vis 15:1218–1230PubMedGoogle Scholar
  31. Sivaprasad S. Webster AR, Egan CA et al (2008) Clinical Course and Treatment Outcomes of Sorsby Fundus Dystrophy. Am J Ophthalmol 146:228–234PubMedCrossRefGoogle Scholar
  32. Soboleva G, Geis B, Schrewe H et al (2003) Sorsby fundus dystrophy mutation Timp3(S156C) affects the morphological and biochemical phenotype but not metalloproteinase homeostasis. J Cell Physiol 197:149–156PubMedCrossRefGoogle Scholar
  33. Sorsby A, Mason MEJ, Gardner N (1949) A fundus dystrophy with unusual features (late onset and dominant inheritance of a central retinal lesion showing oedema, haemorrhage and exudates developing into generalised choroidal atrophy with massive pigment proliferation). Br J Ophthalmol 33: 67–97PubMedCrossRefGoogle Scholar
  34. Tabata Y, Isashiki Y, Kamimura K et al (1998) A novel splice site mutation in the tissue inhibitor of the metalloproteinases-3 gene in Sorsby’s fundus dystrophy with unusual clinical features. Hum Genet 103:179–182PubMedGoogle Scholar
  35. Troeberg L, Fushimi K, Khokha R et al (2008) Calcium pentosan polysulfate is a multifaceted exosite inhibitor of aggrecanases. FASEB J 22:3515–3524PubMedCrossRefGoogle Scholar
  36. Weber B, Vogt G, Pruett RC et al (1994) Mutations in the tissue inhibitor of metalloproteinases-3 (TIMP3) in patients with Sorsby’s fundus dystrophy. Nat Genet 8:352–356PubMedCrossRefGoogle Scholar
  37. Weber BH, Lin B, White K et al (2002) A mouse model for Sorsby fundus dystrophy. Invest Ophthalmol Vis Sci 43:2732–2740PubMedGoogle Scholar
  38. Yeow KM, Kishnani NS, Hutton M et al (2002) Sorsby’s fundus dystrophy tissue inhibitor of metalloproteinases-3 (TIMP-3) mutants have unimpaired matrix metalloproteinase inhibitory activities, but affect cell adhesion to the extracellular matrix. Matrix Biol 21:75–88PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Institute of Human GeneticsUniversity RegensburgRegensburgGermany
  2. 2.Department of Ophthalmic ResearchCole Eye InstituteClevelandUSA

Personalised recommendations