We aim to report the ocular phenotype and molecular genetic findings in two Czech families with Sorsby fundus dystrophy and to review all the reported TIMP3 pathogenic variants. Two probands with Sorsby fundus dystrophy and three first-degree relatives underwent ocular examination and retinal imaging, including optical coherence tomography angiography. The DNA of the first proband was screened using a targeted ocular gene panel, while, in the second proband, direct sequencing of the TIMP3 coding region was performed. Sanger sequencing was also used for segregation analysis within the families. All the previously reported TIMP3 variants were reviewed using the American College of Medical Genetics and the Association for Molecular Pathology interpretation framework. A novel heterozygous variant, c.455A>G p.(Tyr152Cys), in TIMP3 was identified in both families and potentially de novo in one. Optical coherence tomography angiography documented in one patient the development of a choroidal neovascular membrane at 54 years. Including this study, 23 heterozygous variants in TIMP3 have been reported as disease-causing. Application of gene-specific criteria denoted eleven variants as pathogenic, eleven as likely pathogenic, and one as a variant of unknown significance. Our study expands the spectrum of TIMP3 pathogenic variants and highlights the importance of optical coherence tomography angiography for early detection of choroidal neovascular membranes.

Department of Ophthalmology 1st Faculty of Medicine and Military University Hospital Prague 162 00 Prague Czech Republic

Department of Ophthalmology 1st Faculty of Medicine Charles University and General University Hospital Prague 128 08 Prague Czech Republic

Department of Paediatrics and Inherited Metabolic Disorders 1st Faculty of Medicine Charles University and General University Hospital Prague 121 08 Prague Czech Republic

Laboratory of Molecular Biology AGEL 741 01 Nový Jíčín Czech Republic

UCL Institute of Ophthalmology University College London and Moorfields Eye Hospital London EC1V 9EL UK

See more in PubMed

Christensen D.R.G., Brown F.E., Cree A.J., Ratnayaka J.A., Lotery A.J. Sorsby fundus dystrophy—A review of pathology and disease mechanisms. Exp. Eye Res. 2017;165:35–46. doi: 10.1016/j.exer.2017.08.014. PubMed DOI

Anand-Apte B., Chao J.R., Singh R., Stohr H. Sorsby fundus dystrophy: Insights from the past and looking to the future. J. Neurosci. Res. 2019;97:88–97. doi: 10.1002/jnr.24317. PubMed DOI PMC

Arpino V., Brock M., Gill S.E. The role of TIMPs in regulation of extracellular matrix proteolysis. Matrix Biol. 2015;44–46:247–254. doi: 10.1016/j.matbio.2015.03.005. PubMed DOI

Qi J.H., Ebrahem Q., Moore N., Murphy G., Claesson-Welsh L., Bond M., Baker A., Anand-Apte B. A novel function for tissue inhibitor of metalloproteinases-3 (TIMP3): Inhibition of angiogenesis by blockage of VEGF binding to VEGF receptor-2. Nat. Med. 2003;9:407–415. doi: 10.1038/nm846. PubMed DOI

Kamei M., Hollyfield J.G. TIMP-3 in Bruch’s membrane: Changes during aging and in age-related macular degeneration. Investig. Ophthalmol. Vis. Sci. 1999;40:2367–2375. PubMed

Gliem M., Muller P.L., Mangold E., Holz F.G., Bolz H.J., Stohr H., Weber B.H., Charbel Issa P. Sorsby Fundus Dystrophy: Novel Mutations, Novel Phenotypic Characteristics, and Treatment Outcomes. Investig. Ophthalmol. Vis. Sci. 2015;56:2664–2676. doi: 10.1167/iovs.14-15733. PubMed DOI

Tsokolas G. Sorsby fundus dystrophy (SFD): A narrative review. Medicine. 2022;101:e30595. doi: 10.1097/MD.0000000000030595. PubMed DOI PMC

de Carlo T.E., Romano A., Waheed N.K., Duker J.S. A review of optical coherence tomography angiography (OCTA) Int. J. Retin. Vitr. 2015;1:5. doi: 10.1186/s40942-015-0005-8. PubMed DOI PMC

Mohla A., Khan K., Kasilian M., Michaelides M. OCT angiography in the management of choroidal neovascular membrane secondary to Sorsby fundus dystrophy. BMJ Case Rep. 2016;2016:bcr2016216453. doi: 10.1136/bcr-2016-216453. PubMed DOI PMC

Spaide R.F. Treatment of Sorsby fundus dystrophy with anti-tumor necrosis factor-alpha medication. Eye. 2022;36:1810–1812. doi: 10.1038/s41433-021-01735-3. PubMed DOI PMC

Tsokolas G., Almuhtaseb H., Lotery A. Evaluation of Pro-re-Nata (PRN) and Treat and Extend Bevacizumab treatment protocols in Sorsby Fundus Dystrophy. Eur. J. Ophthalmol. 2020;30:26–33. doi: 10.1177/1120672118811568. PubMed DOI

Spaide R.F. Long-Term Visual Acuity Preservation in Sorsby Fundus Dystrophy with Corticosteroid Treatment. Retin. Cases Brief Rep. 2022;16:44–47. doi: 10.1097/ICB.0000000000000946. PubMed DOI

Hess K., Raming K., Gliem M., Charbel Issa P., Herrmann P., Holz F.G., Pfau M. Choriocapillaris Flow Signal Impairment in Sorsby Fundus Dystrophy. Ophthalmologica. 2022;245:265–274. doi: 10.1159/000520931. PubMed DOI

Meunier I., Bocquet B., Labesse G., Zeitz C., Defoort-Dhellemmes S., Lacroux A., Mauget-Faysse M., Drumare I., Gamez A.S., Mathieu C., et al. A new autosomal dominant eye and lung syndrome linked to mutations in TIMP3 gene. Sci. Rep. 2016;6:32544. doi: 10.1038/srep32544. PubMed DOI PMC

Bloch S.B. Implementation studies of ranibizumab for neovascular age-related macular degeneration. Acta Ophthalmol. 2013;91:1–22. doi: 10.1111/aos.12272. PubMed DOI

Guan B., Huryn L.A., Hughes A.B., Li Z., Bender C., Blain D., Turriff A., Cukras C.A., Hufnagel R.B. Early-Onset TIMP3-Related Retinopathy Associated with Impaired Signal Peptide. JAMA Ophthalmol. 2022;140:730–733. doi: 10.1001/jamaophthalmol.2022.1822. PubMed DOI PMC

Bakall B., Sohn E.H., Riley J., Brack D., Stone E.M. Novel mutations and change of nomenclature for pathogenic variants in the TIMP3 gene causing Sorsby fundus dystrophy. Investig. Ophthalmol. Vis. Sci. 2014;55:3290.

Naessens S., De Zaeytijd J., Syx D., Vandenbroucke R.E., Smeets F., Van Cauwenbergh C., Leroy B.P., Peelman F., Coppieters F. The N-terminal p.(Ser38Cys) TIMP3 mutation underlying Sorsby fundus dystrophy is a founder mutation disrupting an intramolecular disulfide bond. Hum. Mutat. 2019;40:539–551. doi: 10.1002/humu.23713. PubMed DOI PMC

Schoenberger S.D., Agarwal A. A novel mutation at the N-terminal domain of the TIMP3 gene in Sorsby fundus dystrophy. Retina. 2013;33:429–435. doi: 10.1097/IAE.0b013e318263d3b4. PubMed DOI

Warwick A., Gibson J., Sood R., Lotery A. A rare penetrant TIMP3 mutation confers relatively late onset choroidal neovascularisation which can mimic age-related macular degeneration. Eye. 2016;30:488–491. doi: 10.1038/eye.2015.204. PubMed DOI PMC

DeBenedictis M.J., Gindzin Y., Glaab E., Anand-Apte B. A novel TIMP3 mutation associated with a retinitis pigmentosa-like phenotype. Ophthalmic Genet. 2020;41:480–484. doi: 10.1080/13816810.2020.1795889. PubMed DOI PMC

Tabata Y., Isashiki Y., Kamimura K., Nakao K., Ohba N. 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. 1998;103:179–182. doi: 10.1007/pl00008707. PubMed DOI

Saihan Z., Li Z., Rice J., Rana N.A., Ramsden S., Schlottmann P.G., Jenkins S.A., Blyth C., Black G.C., McKie N., et al. Clinical and biochemical effects of the E139K missense mutation in the TIMP3 gene, associated with Sorsby fundus dystrophy. Mol. Vis. 2009;15:1218–1230. PubMed PMC

Langton K.P., McKie N., Curtis A., Goodship J.A., Bond P.M., Barker M.D., Clarke M. A novel tissue inhibitor of metalloproteinases-3 mutation reveals a common molecular phenotype in Sorsby’s fundus dystrophy. J. Biol. Chem. 2000;275:27027–27031. doi: 10.1016/S0021-9258(19)61475-4. PubMed DOI

Clarke M., Mitchell K.W., Goodship J., McDonnell S., Barker M.D., Griffiths I.D., McKie N. Clinical features of a novel TIMP-3 mutation causing Sorsby’s fundus dystrophy: Implications for disease mechanism. Br. J. Ophthalmol. 2001;85:1429–1431. doi: 10.1136/bjo.85.12.1429. PubMed DOI PMC

Riera M., Navarro R., Ruiz-Nogales S., Mendez P., Bures-Jelstrup A., Corcostegui B., Pomares E. Whole exome sequencing using Ion Proton system enables reliable genetic diagnosis of inherited retinal dystrophies. Sci. Rep. 2017;7:42078. doi: 10.1038/srep42078. PubMed DOI PMC

Felbor U., Stohr H., Amann T., Schonherr U., Weber B.H. A novel Ser156Cys mutation in the tissue inhibitor of metalloproteinases-3 (TIMP3) in Sorsby’s fundus dystrophy with unusual clinical features. Hum. Mol. Genet. 1995;4:2415–2416. doi: 10.1093/hmg/4.12.2415. PubMed DOI

Lin R.J., Blumenkranz M.S., Binkley J., Wu K., Vollrath D. A novel His158Arg mutation in TIMP3 causes a late-onset form of Sorsby fundus dystrophy. Am. J. Ophthalmol. 2006;142:839–848. doi: 10.1016/j.ajo.2006.06.003. PubMed DOI

Fung A.T., Stohr H., Weber B.H., Holz F.G., Yannuzzi L.A. Atypical sorsby fundus dystrophy with a novel tyr159cys timp-3 mutation. Retin. Cases Brief Rep. 2013;7:71–74. doi: 10.1097/ICB.0b013e318267101e. PubMed DOI

Felbor U., Suvanto E.A., Forsius H.R., Eriksson A.W., Weber B.H. Autosomal recessive Sorsby fundus dystrophy revisited: Molecular evidence for dominant inheritance. Am. J. Hum. Genet. 1997;60:57–62. PubMed PMC

Jacobson S.G., Cideciyan A.V., Bennett J., Kingsley R.M., Sheffield V.C., Stone E.M. Novel mutation in the TIMP3 gene causes Sorsby fundus dystrophy. Arch. Ophthalmol. 2002;120:376–379. doi: 10.1001/archopht.120.3.376. PubMed DOI

Weber B.H., Vogt G., Pruett R.C., Stohr H., Felbor U. Mutations in the tissue inhibitor of metalloproteinases-3 (TIMP3) in patients with Sorsby’s fundus dystrophy. Nat. Genet. 1994;8:352–356. doi: 10.1038/ng1294-352. PubMed DOI

Barbazetto I.A., Hayashi M., Klais C.M., Yannuzzi L.A., Allikmets R. A novel TIMP3 mutation associated with Sorsby fundus dystrophy. Arch. Ophthalmol. 2005;123:542–543. doi: 10.1001/archopht.123.4.542. PubMed DOI

Weber B.H., Vogt G., Wolz W., Ives E.J., Ewing C.C. Sorsby’s fundus dystrophy is genetically linked to chromosome 22q13-qter. Nat. Genet. 1994;7:158–161. doi: 10.1038/ng0694-158. PubMed DOI

Iyer P.G., Zhou H., Zhang Q., Chu Z., Shen M., Shi Y., Liu J., Trivizki O., Lam B.L., Wang R.K., et al. Swept-Source Optical Coherence Tomography Detection of Bruch Membrane and Choriocapillaris Abnormalities in Sorsby Macular Dystrophy. Retina. 2022;42:1645–1654. doi: 10.1097/IAE.0000000000003515. PubMed DOI

Yannuzzi L.A., Rohrer K.T., Tindel L.J., Sobel R.S., Costanza M.A., Shields W., Zang E. Fluorescein angiography complication survey. Ophthalmology. 1986;93:611–617. doi: 10.1016/S0161-6420(86)33697-2. PubMed DOI

Wang M., Gao S., Zhang Y., Zhang M. Sensitivity and specificity of optical coherence tomography angiography in the diagnosis of active choroidal neovascularization: A systematic review and meta-analysis. Graefes Arch. Clin. Exp. Ophthalmol. 2021;259:3529–3536. doi: 10.1007/s00417-021-05239-4. PubMed DOI

Arris C.E., Bevitt D.J., Mohamed J., Li Z., Langton K.P., Barker M.D., Clarke M.P., McKie N. Expression of mutant and wild-type TIMP3 in primary gingival fibroblasts from Sorsby’s fundus dystrophy patients. Biochim. Biophys. Acta. 2003;1638:20–28. doi: 10.1016/S0925-4439(03)00036-X. PubMed DOI

Langton K.P., Barker M.D., McKie N. Localization of the functional domains of human tissue inhibitor of metalloproteinases-3 and the effects of a Sorsby’s fundus dystrophy mutation. J. Biol. Chem. 1998;273:16778–16781. doi: 10.1074/jbc.273.27.16778. PubMed DOI

Langton K.P., McKie N., Smith B.M., Brown N.J., Barker M.D. Sorsby’s fundus dystrophy mutations impair turnover of TIMP-3 by retinal pigment epithelial cells. Hum. Mol. Genet. 2005;14:3579–3586. doi: 10.1093/hmg/ddi385. PubMed DOI

Soboleva G., Geis B., Schrewe H., Weber B.H. Sorsby fundus dystrophy mutation Timp3(S156C) affects the morphological and biochemical phenotype but not metalloproteinase homeostasis. J. Cell Physiol. 2003;197:149–156. doi: 10.1002/jcp.10361. PubMed DOI

Weber B.H., Lin B., White K., Kohler K., Soboleva G., Herterich S., Seeliger M.W., Jaissle G.B., Grimm C., Reme C., et al. A mouse model for Sorsby fundus dystrophy. Investig. Ophthalmol. Vis. Sci. 2002;43:2732–2740. PubMed

Rocholz R., Corvi F., Weichsel J., Schmidt S., Staurenghi G. OCT Angiography (OCTA) in Retinal Diagnostics. In: Bille J.F., editor. High Resolution Imaging in Microscopy and Ophthalmology: New Frontiers in Biomedical Optics. Springer; Cham, Switzerland: 2019. pp. 135–160. PubMed DOI

Ensenberger M.G., Thompson J., Hill B., Homick K., Kearney V., Mayntz-Press K.A., Mazur P., McGuckian A., Myers J., Raley K., et al. Developmental validation of the PowerPlex 16 HS System: An improved 16-locus fluorescent STR multiplex. Forensic Sci. Int. Genet. 2010;4:257–264. doi: 10.1016/j.fsigen.2009.10.007. PubMed DOI

De Bonis P., Laborante A., Pizzicoli C., Stallone R., Barbano R., Longo C., Mazzilli E., Zelante L., Bisceglia L. Mutational screening of VSX1, SPARC, SOD1, LOX, and TIMP3 in keratoconus. Mol. Vis. 2011;17:2482–2494. PubMed PMC

Gelb B.D., Cave H., Dillon M.W., Gripp K.W., Lee J.A., Mason-Suares H., Rauen K.A., Williams B., Zenker M., Vincent L.M., et al. ClinGen’s RASopathy Expert Panel consensus methods for variant interpretation. Genet. Med. 2018;20:1334–1345. doi: 10.1038/gim.2018.3. PubMed DOI PMC

Mester J.L., Ghosh R., Pesaran T., Huether R., Karam R., Hruska K.S., Costa H.A., Lachlan K., Ngeow J., Barnholtz-Sloan J., et al. Gene-specific criteria for PTEN variant curation: Recommendations from the ClinGen PTEN Expert Panel. Hum. Mutat. 2018;39:1581–1592. doi: 10.1002/humu.23636. PubMed DOI PMC

Biesecker L.G., Harrison S.M., ClinGen Sequence Variant Interpretation Working G. The ACMG/AMP reputable source criteria for the interpretation of sequence variants. Genet. Med. 2018;20:1687–1688. doi: 10.1038/gim.2018.42. PubMed DOI PMC

Nagase H., Visse R., Murphy G. Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc. Res. 2006;69:562–573. doi: 10.1016/j.cardiores.2005.12.002. PubMed DOI

Li Z., Clarke M.P., Barker M.D., McKie N. TIMP3 mutation in Sorsby’s fundus dystrophy: Molecular insights. Expert Rev. Mol. Med. 2005;7:1–15. doi: 10.1017/S1462399405010045. PubMed DOI