Malattia Leventinese/Doyne Honeycomb Retinal Dystrophy: Similarities to Age-Related Macular Degeneration and Potential Therapies

  • John D. HullemanEmail author
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 854)


Fibulin-3 (F3) is a secreted, disulfide-rich glycoprotein which is expressed in a variety of tissues within the body, including the retina. An Arg345Trp (R345W) mutation in F3 was identified as the cause of a rare retinal dystrophy, Malattia Leventinese/Doyne Honeycomb Retinal Dystrophy (ML/DHRD). ML/DHRD shares many phenotypic similarities with age-related macular degeneration (AMD). The most prominent feature of ML/DHRD is the development of radial or honeycomb patterns of drusen which can develop as early as adolescence. Two independent mouse models of ML/DHRD show evidence of complement activation as well as retinal pigment epithelium (RPE) atrophy, strengthening the phenotypic connection with AMD. Because of its similarities with AMD, ML/DHRD is receiving increasing interest as a potential surrogate disease to study the underpinnings of AMD. This mini-review summarizes the current knowledge of F3 and points toward potential therapeutic strategies which directly or indirectly target cellular dysfunction associated with R345W F3.


Fibulin-3 Malattia leventinese/Doyne honeycomb retinal dystrophy Protein misfolding Age-related macular degeneration Retinal degeneration Drusen Therapeutics 



This work was funded by an endowment from the Roger and Dorothy Hirl Research Fund, an NEI core grant (EY020799), a career development award from Research to Prevent Blindness (RPB), and an unrestricted grant from RPB. The author thanks Bonnie Miller and Rafael Ufret-Vincenty for their review of this manuscript


  1. 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 16:2411–2422CrossRefPubMedGoogle Scholar
  2. Garland DL, Fernandez-Godino R, Kaur I et al (2014) Mouse genetics and proteomic analyses demonstrate a critical role for complement in a model of DHRD/ML, an inherited macular degeneration. Hum Mol Genet 23:52–68CrossRefPubMedPubMedCentralGoogle Scholar
  3. Hulleman JD, Kelly JW (2015) Genetic ablation of N-linked glycosylation reveals two key folding pathways for R345W fibulin-3, a secreted protein associated with retinal degeneration. FASEB J 29:565–575CrossRefPubMedPubMedCentralGoogle Scholar
  4. Hulleman JD, Kaushal S, Balch WE et al (2011) Compromised mutant EFEMP1 secretion associated with macular dystrophy remedied by proteostasis network alteration. Mol Biol Cell 22:4765–4775CrossRefPubMedPubMedCentralGoogle Scholar
  5. Hulleman JD, Balch WE, Kelly JW (2012) Translational attenuation differentially alters the fate of disease-associated fibulin proteins. FASEB J 26:4548–4560CrossRefPubMedPubMedCentralGoogle Scholar
  6. Hulleman JD, Brown SJ, Rosen H et al (2013) A high-throughput cell-based Gaussia luciferase reporter assay for identifying modulators of fibulin-3 secretion. J Biomol Screen 18:647–658CrossRefPubMedPubMedCentralGoogle Scholar
  7. Jessop CE, Chakravarthi S, Garbi N et al (2007) ERp57 is essential for efficient folding of glycoproteins sharing common structural domains. EMBO J 26:28–40CrossRefPubMedPubMedCentralGoogle Scholar
  8. Klein ML, Schultz DW, Edwards A et al (1998) Age-related macular degeneration. Clinical features in a large family and linkage to chromosome 1q. Arch Ophthalmol 116:1082–1088CrossRefPubMedGoogle Scholar
  9. 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. The J Biol Chem 279:30469–30473CrossRefPubMedGoogle Scholar
  10. Lenassi E, Troeger E, Wilke R et al (2013) Laser clearance of drusen deposit in patients with autosomal dominant drusen (p.Arg345Trp in EFEMP1). Am J Ophthalmol 155:190–198CrossRefPubMedGoogle Scholar
  11. Marmorstein LY, Munier FL, Arsenijevic Y et al (2002) Aberrant accumulation of EFEMP1 underlies drusen formation in malattia leventinese and age-related macular degeneration. Proc Natl Acad Sci U S A 99:13067–13072CrossRefPubMedPubMedCentralGoogle Scholar
  12. Marmorstein LY, McLaughlin PJ, Peachey NS et al (2007) Formation and progression of sub-retinal pigment epithelium deposits in Efemp1 mutation knock-in mice: a model for the early pathogenic course of macular degeneration. Hum Mol Genet 16:2423–2432CrossRefPubMedGoogle Scholar
  13. McLaughlin PJ, Bakall B, Choi J et al (2007) Lack of fibulin-3 causes early aging and herniation, but not macular degeneration in mice. Hum Mol Genet 16:3059–3070CrossRefPubMedGoogle Scholar
  14. Michaelides M, Jenkins SA, Brantley MA Jr et al (2006) Maculopathy due to the R345W substitution in fibulin-3: distinct clinical features, disease variability, and extent of retinal dysfunction. Invest Ophthalmol Vis Sci 47:3085–3097CrossRefPubMedGoogle Scholar
  15. Oka OB, Pringle MA, Schopp IM et al (2013) ERdj5 is the ER reductase that catalyzes the removal of non-native disulfides and correct folding of the LDL receptor. Mol Cell 50:793–804CrossRefPubMedPubMedCentralGoogle Scholar
  16. Parodi MB, Virgili G, Evans JR (2009) Laser treatment of drusen to prevent progression to advanced age-related macular degeneration. Cochrane Database Syst Rev 8(3):CD006537Google Scholar
  17. Ricklin D, Lambris JD (2008) Compstatin: a complement inhibitor on its way to clinical application. Adv Exp Med Biol 632:273–292PubMedPubMedCentralGoogle Scholar
  18. Roybal CN, Marmorstein LY, Vander Jagt DL et al (2005) Aberrant accumulation of fibulin-3 in the endoplasmic reticulum leads to activation of the unfolded protein response and VEGF expression. Invest Ophthalmol Vis Sci 46:3973–3979CrossRefPubMedGoogle Scholar
  19. Ruggiano A, Foresti O, Carvalho P (2014) Quality control: ER-associated degradation: protein quality control and beyond. J Cell Biol 204:869–879CrossRefPubMedPubMedCentralGoogle Scholar
  20. Schultz DW, Weleber RG, Lawrence G et al (2005) HEMICENTIN-1 (FIBULIN-6) and the 1q31 AMD locus in the context of complex disease: review and perspective. Ophthalmic Genet 26:101–105CrossRefPubMedGoogle Scholar
  21. Sercu S, Lambeir AM, Steenackers E et al (2009) ECM1 interacts with fibulin-3 and the beta 3 chain of laminin 332 through its serum albumin subdomain-like 2 domain. Matrix Biol 28:160–169CrossRefPubMedGoogle Scholar
  22. Shoulders MD, Ryno LM, Genereux JC et al (2013) Stress-independent activation of XBP1s and/or ATF6 reveals three functionally diverse ER proteostasis environments. Cell Rep 3:1279–1292CrossRefPubMedPubMedCentralGoogle Scholar
  23. Sohn EH, Wang K, Thompson S et al (2014) Comparison of drusen and modifying genes in autosomal dominant radial drusen and age-related macular degeneration. Retina 35(1):48-57CrossRefGoogle Scholar
  24. Stone EM, Lotery AJ, Munier FL et al (1999) A single EFEMP1 mutation associated with both malattia leventinese and Doyne honeycomb retinal dystrophy. Nat Genet 22:199–202CrossRefPubMedGoogle Scholar
  25. Stone EM, Braun TA, Russell SR et al (2004) Missense variations in the fibulin 5 gene and age-related macular degeneration. N Engl J Med 351:346–353CrossRefPubMedGoogle Scholar
  26. Thompson CL, Klein BE, Klein R et al (2007) Complement factor H and hemicentin-1 in age-related macular degeneration and renal phenotypes. Hum Mol Genet 16:2135–2148CrossRefPubMedGoogle Scholar
  27. Wyatt MK, Tsai JY, Mishra S et al (2013) Interaction of complement factor h and fibulin3 in age-related macular degeneration. PLoS ONE 8:e68088CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Departments of Ophthalmology and PharmacologyUniversity of Texas Southwestern Medical CenterDallasUSA

Personalised recommendations