{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T03:01:27Z","timestamp":1789095687909,"version":"build-2803163510"},"reference-count":43,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,8,16]],"date-time":"2025-08-16T00:00:00Z","timestamp":1755302400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"},{"start":{"date-parts":[[2025,8,16]],"date-time":"2025-08-16T00:00:00Z","timestamp":1755302400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"funder":[{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"publisher","award":["R01-EY027785"],"award-info":[{"award-number":["R01-EY027785"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Larson Endowed Chair for Macular Degeneration"},{"name":"Helen Lindsay Family Foundation"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"DOI":"10.1038\/s41598-025-14561-4","type":"journal-article","created":{"date-parts":[[2025,8,16]],"date-time":"2025-08-16T17:26:36Z","timestamp":1755365196000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["A spectrum of cysteine mutations in fibulin-3 highlight its disulfide bonding complexity and potential to induce ER stress"],"prefix":"10.1038","volume":"15","author":[{"given":"Gracen E.","family":"Collier","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna L.","family":"Roovers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John D.","family":"Hulleman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,8,16]]},"reference":[{"issue":"24","key":"14561_CR1","doi-asserted-by":"publisher","first-page":"6850","DOI":"10.1111\/febs.15776","volume":"288","author":"NK Karamanos","year":"2021","unstructured":"Karamanos, N. K. et al. A guide to the composition and functions of the extracellular matrix. FEBS J. 288 (24), 6850\u20136912 (2021).","journal-title":"FEBS J."},{"issue":"4","key":"14561_CR2","doi-asserted-by":"publisher","first-page":"597","DOI":"10.1016\/S0092-8674(00)81259-3","volume":"85","author":"AK Downing","year":"1996","unstructured":"Downing, A. K. et al. Solution structure of a pair of calcium-binding epidermal growth factor-like domains: implications for the Marfan syndrome and other genetic disorders. Cell 85 (4), 597\u2013605 (1996).","journal-title":"Cell"},{"issue":"3","key":"14561_CR3","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1002\/(SICI)1096-8628(19960329)62:3<233::AID-AJMG7>3.0.CO;2-U","volume":"62","author":"EA Putnam","year":"1996","unstructured":"Putnam, E. A. et al. Delineation of the Marfan phenotype associated with mutations in exons 23\u201332 of the FBN1 gene. Am. J. Med. Genet. 62 (3), 233\u2013242 (1996).","journal-title":"Am. J. Med. Genet."},{"issue":"5","key":"14561_CR4","doi-asserted-by":"publisher","first-page":"103869","DOI":"10.1016\/j.ejmg.2020.103869","volume":"63","author":"S Bizzari","year":"2020","unstructured":"Bizzari, S. et al. Recessive marfanoid syndrome with herniation associated with a homozygous mutation in Fibulin-3. Eur. J. Med. Genet. 63 (5), 103869 (2020).","journal-title":"Eur. J. Med. Genet."},{"key":"14561_CR5","doi-asserted-by":"publisher","first-page":"1945","DOI":"10.1002\/humu.24452","volume":"43","author":"DR Woodard","year":"2022","unstructured":"Woodard, D. R. et al. A loss-of-function cysteine mutant in fibulin-3 (EFEMP1) forms aberrant extracellular disulfide-linked homodimers and alters extracellular matrix composition. Hum. Mutat. 43, 1945\u20131955 (2022).","journal-title":"Hum. Mutat."},{"key":"14561_CR6","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1016\/B978-0-12-386471-0.00009-2","volume":"499","author":"Y Ishida","year":"2011","unstructured":"Ishida, Y. & Nagata, K. Hsp47 as a collagen-specific molecular chaperone. Methods Enzymol. 499, 167\u2013182 (2011).","journal-title":"Methods Enzymol."},{"key":"14561_CR7","doi-asserted-by":"publisher","first-page":"17052","DOI":"10.1038\/nrdp.2017.52","volume":"3","author":"JC Marini","year":"2017","unstructured":"Marini, J. C. et al. Osteogenesis imperfecta. Nat. Rev. Dis. Primers 3, 17052 (2017).","journal-title":"Nat. Rev. Dis. Primers"},{"issue":"5801","key":"14561_CR8","doi-asserted-by":"publisher","first-page":"992","DOI":"10.1126\/science.1133811","volume":"314","author":"Z Yang","year":"2006","unstructured":"Yang, Z. et al. A variant of the HTRA1 gene increases susceptibility to age-related macular degeneration. Science 314 (5801), 992\u2013993 (2006).","journal-title":"Science"},{"key":"14561_CR9","doi-asserted-by":"crossref","unstructured":"Williams BL, Seager NA, Gardiner JD, Pappas CM, Cronin MC, Amat di San Filippo C, et al. Chromosome 10q26-driven age-related macular degeneration is associated with reduced levels of HTRA1 in human retinal pigment epithelium. Proceedings of the National Academy of Sciences of the United States of America 118 (30) (2021).","DOI":"10.1073\/pnas.2103617118"},{"issue":"4","key":"14561_CR10","doi-asserted-by":"publisher","first-page":"346","DOI":"10.1056\/NEJMoa040833","volume":"351","author":"EM Stone","year":"2004","unstructured":"Stone, E. M. et al. Missense variations in the fibulin 5 gene and age-related macular degeneration. N. Engl. J. Med. 351 (4), 346\u2013353 (2004).","journal-title":"N. Engl. J. Med."},{"issue":"1","key":"14561_CR11","doi-asserted-by":"publisher","first-page":"17429","DOI":"10.1038\/s41598-019-53433-6","volume":"9","author":"JH Qi","year":"2019","unstructured":"Qi, J. H. et al. Sorsby fundus dystrophy mutation in tissue inhibitor of metalloproteinase 3 (TIMP3) promotes choroidal neovascularization via a fibroblast growth factor-dependent mechanism. Sci. Rep. 9 (1), 17429 (2019).","journal-title":"Sci. Rep."},{"issue":"4","key":"14561_CR12","doi-asserted-by":"publisher","first-page":"352","DOI":"10.1038\/ng1294-352","volume":"8","author":"BH Weber","year":"1994","unstructured":"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\u2019s fundus dystrophy. Nat. Genet. 8 (4), 352\u2013356 (1994).","journal-title":"Nat. Genet."},{"issue":"20","key":"14561_CR13","doi-asserted-by":"publisher","first-page":"2411","DOI":"10.1093\/hmg\/ddm198","volume":"16","author":"L Fu","year":"2007","unstructured":"Fu, L. et al. The R345W mutation in EFEMP1 is pathogenic and causes AMD-like deposits in mice. Hum. Mol. Genet. 16 (20), 2411\u20132422 (2007).","journal-title":"Hum. Mol. Genet."},{"issue":"2","key":"14561_CR14","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1038\/9722","volume":"22","author":"EM Stone","year":"1999","unstructured":"Stone, E. M. et al. A single EFEMP1 mutation associated with both Malattia Leventinese and Doyne honeycomb retinal dystrophy. Nat. Genet. 22 (2), 199\u2013202 (1999).","journal-title":"Nat. Genet."},{"key":"14561_CR15","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1007\/978-3-319-17121-0_21","volume":"854","author":"JD Hulleman","year":"2016","unstructured":"Hulleman, J. D. Malattia leventinese\/doyne honeycomb retinal dystrophy: Similarities to age-related macular degeneration and potential therapies. Adv. Exp. Med. Biol. 854, 153\u2013158 (2016).","journal-title":"Adv. Exp. Med. Biol."},{"key":"14561_CR16","doi-asserted-by":"crossref","unstructured":"Collantes, E. R. A., et al. EFEMP1 rare variants cause familial juvenile-onset open-angle glaucoma. Hum Mutat. (2021).","DOI":"10.22541\/au.162673232.22241174\/v1"},{"issue":"4","key":"14561_CR17","doi-asserted-by":"publisher","first-page":"445","DOI":"10.1038\/s41431-019-0546-7","volume":"28","author":"SGW Driver","year":"2020","unstructured":"Driver, S. G. W. et al. Biallelic variants in EFEMP1 in a man with a pronounced connective tissue phenotype. Eur. J. Hum. Genet. EJHG 28 (4), 445\u2013452 (2020).","journal-title":"Eur. J. Hum. Genet. EJHG"},{"issue":"4","key":"14561_CR18","doi-asserted-by":"publisher","first-page":"510","DOI":"10.3390\/genes12040510","volume":"12","author":"M Verlee","year":"2021","unstructured":"Verlee, M. et al. Loss-of-function variants in EFEMP1 cause a recognizable connective tissue disorder characterized by cutis laxa and multiple herniations. Genes (Basel) 12 (4), 510 (2021).","journal-title":"Genes (Basel)"},{"issue":"6","key":"14561_CR19","doi-asserted-by":"publisher","first-page":"e63556","DOI":"10.1002\/ajmg.a.63556","volume":"194","author":"I Forghani","year":"2024","unstructured":"Forghani, I. et al. EFEMP1 haploinsufficiency causes a Marfan-like hereditary connective tissue disorder. Am. J. Med. Genet. A 194 (6), e63556 (2024).","journal-title":"Am. J. Med. Genet. A"},{"issue":"11","key":"14561_CR20","doi-asserted-by":"publisher","first-page":"4548","DOI":"10.1096\/fj.11-202861","volume":"26","author":"JD Hulleman","year":"2012","unstructured":"Hulleman, J. D., Balch, W. E. & Kelly, J. W. Translational attenuation differentially alters the fate of disease-associated fibulin proteins. FASEB J. 26 (11), 4548\u20134560 (2012).","journal-title":"FASEB J."},{"issue":"24","key":"14561_CR21","doi-asserted-by":"publisher","first-page":"4765","DOI":"10.1091\/mbc.e11-08-0695","volume":"22","author":"JD Hulleman","year":"2011","unstructured":"Hulleman, J. D., Kaushal, S., Balch, W. E. & Kelly, J. W. Compromised mutant EFEMP1 secretion associated with macular dystrophy remedied by proteostasis network alteration. Mol. Biol. Cell 22 (24), 4765\u20134775 (2011).","journal-title":"Mol. Biol. Cell"},{"issue":"2","key":"14561_CR22","doi-asserted-by":"publisher","first-page":"565","DOI":"10.1096\/fj.14-255414","volume":"29","author":"JD Hulleman","year":"2015","unstructured":"Hulleman, J. D. & Kelly, J. W. 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 (2), 565\u2013575 (2015).","journal-title":"FASEB J."},{"issue":"6","key":"14561_CR23","doi-asserted-by":"publisher","first-page":"479","DOI":"10.1038\/nrm1130","volume":"4","author":"R Timpl","year":"2003","unstructured":"Timpl, R., Sasaki, T., Kostka, G. & Chu, M. L. Fibulins: a versatile family of extracellular matrix proteins. Nat. Rev. 4 (6), 479\u2013489 (2003).","journal-title":"Nat. Rev."},{"issue":"1","key":"14561_CR24","doi-asserted-by":"publisher","first-page":"2998","DOI":"10.1038\/s41598-020-79570-x","volume":"11","author":"DR Woodard","year":"2021","unstructured":"Woodard, D. R., Nakahara, E. & Hulleman, J. D. Clinically-identified C-terminal mutations in fibulin-3 are prone to misfolding and destabilization. Sci. Rep. 11 (1), 2998 (2021).","journal-title":"Sci. Rep."},{"key":"14561_CR25","first-page":"179","volume":"27","author":"DR Woodard","year":"2021","unstructured":"Woodard, D. R. et al. A novel homozygous missense mutation p.P388S in TULP1 causes protein instability and retinitis pigmentosa. Mol. Vis. 27, 179\u2013190 (2021).","journal-title":"Mol. Vis."},{"issue":"2","key":"14561_CR26","doi-asserted-by":"publisher","first-page":"103000","DOI":"10.1016\/j.xpro.2024.103000","volume":"5","author":"KP Lankford","year":"2024","unstructured":"Lankford, K. P. & Hulleman, J. D. Protocol for HiBiT tagging endogenous proteins using CRISPR-Cas9 gene editing. STAR Protoc. 5 (2), 103000 (2024).","journal-title":"STAR Protoc."},{"key":"14561_CR27","doi-asserted-by":"crossref","unstructured":"DiCesare, S. M., Ortega, A. J., Collier, G. E., Daniel, S., Thompson, K. N., McCoy, M. K., et al. GSK3 inhibition reduces ECM production and prevents age-related macular degeneration-like pathology. bioRxiv. (2023).","DOI":"10.1101\/2023.12.14.571757"},{"issue":"7","key":"14561_CR28","doi-asserted-by":"publisher","first-page":"4845","DOI":"10.1074\/jbc.M005160200","volume":"276","author":"JY Chang","year":"2001","unstructured":"Chang, J. Y., Li, L. & Lai, P. H. A major kinetic trap for the oxidative folding of human epidermal growth factor. J. Biol. Chem. 276 (7), 4845\u20134852 (2001).","journal-title":"J. Biol. Chem."},{"issue":"16","key":"14561_CR29","doi-asserted-by":"publisher","first-page":"9207","DOI":"10.1074\/jbc.270.16.9207","volume":"270","author":"JY Chang","year":"1995","unstructured":"Chang, J. Y., Schindler, P., Ramseier, U. & Lai, P. H. The disulfide folding pathway of human epidermal growth factor. J. Biol. Chem. 270 (16), 9207\u20139216 (1995).","journal-title":"J. Biol. Chem."},{"issue":"11","key":"14561_CR30","doi-asserted-by":"publisher","first-page":"1639","DOI":"10.1007\/s00109-020-01974-z","volume":"98","author":"S Daniel","year":"2020","unstructured":"Daniel, S. et al. Fibulin-3 knockout mice demonstrate corneal dysfunction but maintain normal retinal integrity. J. Mol. Med. 98 (11), 1639\u20131656 (2020).","journal-title":"J. Mol. Med."},{"key":"14561_CR31","first-page":"167239","volume":"2024","author":"S Daniel","year":"1870","unstructured":"Daniel, S. & Hulleman, J. D. Exploring ocular fibulin-3 (EFEMP1): Anatomical, age-related, and species perspectives. Biochim. Biophys. Acta Mol. Basis Dis. 2024, 167239 (1870).","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"issue":"2","key":"14561_CR32","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1006\/exer.1996.0020","volume":"62","author":"KC Dunn","year":"1996","unstructured":"Dunn, K. C., Aotaki-Keen, A. E., Putkey, F. R. & Hjelmeland, L. M. ARPE-19, a human retinal pigment epithelial cell line with differentiated properties. Exp. Eye Res. 62 (2), 155\u2013169 (1996).","journal-title":"Exp. Eye Res."},{"issue":"1","key":"14561_CR33","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1093\/hmg\/ddx392","volume":"27","author":"R Fernandez-Godino","year":"2018","unstructured":"Fernandez-Godino, R., Bujakowska, K. M. & Pierce, E. A. Changes in extracellular matrix cause RPE cells to make basal deposits and activate the alternative complement pathway. Hum. Mol. Genet. 27 (1), 147\u2013159 (2018).","journal-title":"Hum. Mol. Genet."},{"issue":"4","key":"14561_CR34","doi-asserted-by":"publisher","first-page":"1279","DOI":"10.1016\/j.celrep.2013.03.024","volume":"3","author":"MD Shoulders","year":"2013","unstructured":"Shoulders, M. D. et al. Stress-independent activation of XBP1s and\/or ATF6 reveals three functionally diverse ER proteostasis environments. Cell Rep. 3 (4), 1279\u20131292 (2013).","journal-title":"Cell Rep."},{"issue":"6","key":"14561_CR35","doi-asserted-by":"publisher","first-page":"647","DOI":"10.1177\/1087057112469405","volume":"18","author":"JD Hulleman","year":"2013","unstructured":"Hulleman, J. D., Brown, S. J., Rosen, H. & Kelly, J. W. A high-throughput cell-based Gaussia luciferase reporter assay for identifying modulators of fibulin-3 secretion. J. Biomol. Screen. 18 (6), 647\u2013658 (2013).","journal-title":"J. Biomol. Screen."},{"issue":"9","key":"14561_CR36","doi-asserted-by":"publisher","first-page":"1294","DOI":"10.3390\/biom10091294","volume":"10","author":"I Livingstone","year":"2020","unstructured":"Livingstone, I., Uversky, V. N., Furniss, D. & Wiberg, A. The pathophysiological significance of fibulin-3. Biomolecules 10 (9), 1294 (2020).","journal-title":"Biomolecules"},{"issue":"20","key":"14561_CR37","doi-asserted-by":"publisher","first-page":"13067","DOI":"10.1073\/pnas.202491599","volume":"99","author":"LY Marmorstein","year":"2002","unstructured":"Marmorstein, L. Y. et al. Aberrant accumulation of EFEMP1 underlies drusen formation in Malattia Leventinese and age-related macular degeneration. Proc. Natl. Acad. Sci. USA 99 (20), 13067\u201313072 (2002).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"issue":"7","key":"14561_CR38","doi-asserted-by":"publisher","first-page":"e0132529","DOI":"10.1371\/journal.pone.0132529","volume":"10","author":"DS Mackay","year":"2015","unstructured":"Mackay, D. S., Bennett, T. M. & Shiels, A. Exome sequencing identifies a missense variant in EFEMP1 co-segregating in a family with autosomal dominant primary open-angle glaucoma. PLoS ONE 10 (7), e0132529 (2015).","journal-title":"PLoS ONE"},{"issue":"31","key":"14561_CR39","doi-asserted-by":"publisher","first-page":"22821","DOI":"10.1074\/jbc.M112.439158","volume":"288","author":"J Djokic","year":"2013","unstructured":"Djokic, J., Fagotto-Kaufmann, C., Bartels, R., Nelea, V. & Reinhardt, D. P. Fibulin-3, -4, and -5 are highly susceptible to proteolysis, interact with cells and heparin, and form multimers. J. Biol. Chem. 288 (31), 22821\u201322835 (2013).","journal-title":"J. Biol. Chem."},{"issue":"3","key":"14561_CR40","doi-asserted-by":"publisher","first-page":"791","DOI":"10.3233\/JPD-201965","volume":"10","author":"R Kayed","year":"2020","unstructured":"Kayed, R., Dettmer, U. & Lesne, S. E. Soluble endogenous oligomeric alpha-synuclein species in neurodegenerative diseases: Expression, spreading, and cross-talk. J. Parkinsons Dis. 10 (3), 791\u2013818 (2020).","journal-title":"J. Parkinsons Dis."},{"issue":"2","key":"14561_CR41","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1038\/nrm2101","volume":"8","author":"C Haass","year":"2007","unstructured":"Haass, C. & Selkoe, D. J. Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer\u2019s amyloid beta-peptide. Nat. Rev. 8 (2), 101\u2013112 (2007).","journal-title":"Nat. Rev."},{"issue":"4","key":"14561_CR42","doi-asserted-by":"publisher","first-page":"444","DOI":"10.1002\/path.5203","volume":"247","author":"M Tasaki","year":"2019","unstructured":"Tasaki, M. et al. A novel age-related venous amyloidosis derived from EGF-containing fibulin-like extracellular matrix protein 1. J. Pathol. 247 (4), 444\u2013455 (2019).","journal-title":"J. Pathol."},{"issue":"3","key":"14561_CR43","doi-asserted-by":"publisher","first-page":"459","DOI":"10.1111\/his.14276","volume":"78","author":"LN Dao","year":"2021","unstructured":"Dao, L. N. et al. The novel form of amyloidosis derived from EGF-containing fibulin-like extracellular matrix protein 1 (EFEMP1) preferentially affects the lower gastrointestinal tract of elderly females(a). Histopathology 78 (3), 459\u2013463 (2021).","journal-title":"Histopathology"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-14561-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-14561-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-14561-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,9]],"date-time":"2025-09-09T15:14:21Z","timestamp":1757430861000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-14561-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,16]]},"references-count":43,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["14561"],"URL":"https:\/\/doi.org\/10.1038\/s41598-025-14561-4","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,16]]},"assertion":[{"value":"10 October 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 August 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 August 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"30028"}}