{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T23:50:20Z","timestamp":1789429820809,"version":"build-2803163510"},"reference-count":57,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2022,8,9]],"date-time":"2022-08-09T00:00:00Z","timestamp":1660003200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100015311","name":"Novartis Institutes for BioMedical Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100015311","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,1,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>EFEMP1 R345W is a dominant mutation causing Doyne honeycomb retinal dystrophy\/malattia leventinese (DHRD\/ML), a rare blinding disease with clinical pathology similar to age-related macular degeneration (AMD). Aged Efemp1 \u00a0R345W\/R345W knock-in mice (Efemp1ki\/ki) develop microscopic deposits on the basal side of retinal pigment epithelial cells (RPE), an early feature in DHRD\/ML and AMD. Here, we assessed the role of alternative complement pathway component factor B (FB) in the formation of these deposits. RNA-seq analysis of the posterior eyecups revealed increased unfolded protein response, decreased mitochondrial function in the neural retina (by 3\u00a0months of age) and increased inflammatory pathways in both neural retina and posterior eyecups (at 17\u00a0months of age) of Efemp1ki\/ki mice compared with wild-type littermate controls. Proteomics analysis of eye lysates confirmed similar dysregulated pathways as detected by RNA-seq. Complement activation was increased in aged Efemp1ki\/ki eyes with an approximately 2-fold elevation of complement breakdown products iC3b and Ba (P\u2009&amp;lt;\u20090.05). Deletion of the Cfb gene in female Efemp1ki\/ki mice partially normalized the above dysregulated biological pathway changes and oral dosing of a small molecule FB inhibitor from 10 to 12 months of age reduced sub-RPE deposits by 65% (P\u2009=\u20090.029). In contrast, male Efemp1ki\/ki mice had fewer sub-RPE deposits than age-matched females, no elevation of ocular complement activation and no effect of FB inhibition on sub-RPE deposits. The effects of FB deletion or inhibition on Efemp1ki\/ki mice supports systemic inhibition of the alternative complement pathway as a potential treatment of dry AMD and DHRD\/ML.<\/jats:p>","DOI":"10.1093\/hmg\/ddac187","type":"journal-article","created":{"date-parts":[[2022,8,9]],"date-time":"2022-08-09T15:50:14Z","timestamp":1660060214000},"page":"204-217","source":"Crossref","is-referenced-by-count":22,"title":["Complement factor B is critical for sub-RPE deposit accumulation in a model of Doyne honeycomb retinal dystrophy with features of age-related macular degeneration"],"prefix":"10.1093","volume":"32","author":[{"given":"Maura A","family":"Crowley","sequence":"first","affiliation":[{"name":"Ophthalmology, Novartis Institutes for BioMedical Research , Cambridge, MA 02319 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donita L","family":"Garland","sequence":"additional","affiliation":[{"name":"Ocular Genomics Institute at Massachusetts Eye and Ear, Harvard Medical School , Boston, MA 02114 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Holger","family":"Sellner","sequence":"additional","affiliation":[{"name":"Global Discovery Chemistry, Novartis Institutes for BioMedical Research , Basel , Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Banks","sequence":"additional","affiliation":[{"name":"Ophthalmology, Novartis Institutes for BioMedical Research , Cambridge, MA 02319 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Fan","sequence":"additional","affiliation":[{"name":"Analytical Sciences and Imaging, Novartis Institutes for BioMedical Research , Cambridge, MA 02319 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomas","family":"Rejtar","sequence":"additional","affiliation":[{"name":"Analytical Sciences and Imaging, Novartis Institutes for BioMedical Research , Cambridge, MA 02319 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natasha","family":"Buchanan","sequence":"additional","affiliation":[{"name":"Ophthalmology, Novartis Institutes for BioMedical Research , Cambridge, MA 02319 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Omar","family":"Delgado","sequence":"additional","affiliation":[{"name":"Ophthalmology, Novartis Institutes for BioMedical Research , Cambridge, MA 02319 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong Yao","family":"Xu","sequence":"additional","affiliation":[{"name":"Ophthalmology, Novartis Institutes for BioMedical Research , Cambridge, MA 02319 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Jose","sequence":"additional","affiliation":[{"name":"Ophthalmology, Novartis Institutes for BioMedical Research , Cambridge, MA 02319 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher M","family":"Adams","sequence":"additional","affiliation":[{"name":"Global Discovery Chemistry, Novartis Institutes for BioMedical Research , Cambridge, MA 02319 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muneto","family":"Mogi","sequence":"additional","affiliation":[{"name":"Global Discovery Chemistry, Novartis Institutes for BioMedical Research , Cambridge, MA 02319 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Wang","sequence":"additional","affiliation":[{"name":"Analytical Sciences and Imaging, Novartis Institutes for BioMedical Research , Cambridge, MA 02319 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chad E","family":"Bigelow","sequence":"additional","affiliation":[{"name":"Ophthalmology, Novartis Institutes for BioMedical Research , Cambridge, MA 02319 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Poor","sequence":"additional","affiliation":[{"name":"Ophthalmology, Novartis Institutes for BioMedical Research , Cambridge, MA 02319 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Anderson","sequence":"additional","affiliation":[{"name":"Ophthalmology, Novartis Institutes for BioMedical Research , Cambridge, MA 02319 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce D","family":"Jaffee","sequence":"additional","affiliation":[{"name":"Ophthalmology, Novartis Institutes for BioMedical Research , Cambridge, MA 02319 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ganesh","family":"Prasanna","sequence":"additional","affiliation":[{"name":"Ophthalmology, Novartis Institutes for BioMedical Research , Cambridge, MA 02319 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cynthia","family":"Grosskreutz","sequence":"additional","affiliation":[{"name":"Ophthalmology, Novartis Institutes for BioMedical Research , Cambridge, MA 02319 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosario","family":"Fernandez-Godino","sequence":"additional","affiliation":[{"name":"Ocular Genomics Institute at Massachusetts Eye and Ear, Harvard Medical School , Boston, MA 02114 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric A","family":"Pierce","sequence":"additional","affiliation":[{"name":"Ocular Genomics Institute at Massachusetts Eye and Ear, Harvard Medical School , Boston, MA 02114 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thaddeus P","family":"Dryja","sequence":"additional","affiliation":[{"name":"Ophthalmology, Novartis Institutes for BioMedical Research , Cambridge, MA 02319 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3991-2352","authenticated-orcid":false,"given":"Sha-Mei","family":"Liao","sequence":"additional","affiliation":[{"name":"Ophthalmology, Novartis Institutes for BioMedical Research , Cambridge, MA 02319 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,8,9]]},"reference":[{"key":"2023011411263287300_ref1","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1038\/ng.3448","article-title":"A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants","volume":"48","author":"Fritsche","year":"2016","journal-title":"Nat. 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Primers."},{"key":"2023011411263287300_ref5","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.preteyeres.2009.11.003","article-title":"The pivotal role of the complement system in aging and age-related macular degeneration: hypothesis re-visited","volume":"29","author":"Anderson","year":"2010","journal-title":"Prog. Retin. Eye Res."},{"key":"2023011411263287300_ref6","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1007\/978-1-4615-0067-4_11","article-title":"Proteomic approaches to understanding age-related macular degeneration","volume":"533","author":"Hollyfield","year":"2003","journal-title":"Adv. Exp. Med. Biol."},{"key":"2023011411263287300_ref7","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1038\/9722","article-title":"A single EFEMP1 mutation associated with both Malattia Leventinese and Doyne honeycomb retinal dystrophy","volume":"22","author":"Stone","year":"1999","journal-title":"Nat. Genet."},{"key":"2023011411263287300_ref8","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.preteyeres.2013.11.001","article-title":"Macular dystrophies mimicking age-related macular degeneration","volume":"39","author":"Saksens","year":"2014","journal-title":"Prog. Retin. Eye Res."},{"key":"2023011411263287300_ref9","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1007\/978-3-319-17121-0_21","article-title":"Malattia Leventinese\/Doyne honeycomb retinal dystrophy: similarities to age-related macular degeneration and potential therapies","volume":"854","author":"Hulleman","year":"2016","journal-title":"Adv. Exp. Med. Biol."},{"key":"2023011411263287300_ref10","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1080\/13816810490498305","article-title":"Association of EFEMP1 with malattia leventinese and age-related macular degeneration: a mini-review","volume":"25","author":"Marmorstein","year":"2004","journal-title":"Ophthalmic Genet."},{"key":"2023011411263287300_ref11","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1093\/hmg\/ddt395","article-title":"Mouse genetics and proteomic analyses demonstrate a critical role for complement in a model of DHRD\/ML, an inherited macular degeneration","volume":"23","author":"Garland","year":"2014","journal-title":"Hum. Mol. Genet."},{"key":"2023011411263287300_ref12","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1097\/IAE.0000000000000263","article-title":"Comparison of drusen and modifying genes in autosomal dominant radial drusen and age-related macular degeneration","volume":"35","author":"Sohn","year":"2015","journal-title":"Retina"},{"key":"2023011411263287300_ref13","doi-asserted-by":"crossref","first-page":"108422","DOI":"10.1016\/j.exer.2020.108422","article-title":"Descriptive analysis of Fibulin-3 and the extracellular vesicle marker, Alix, in drusen from a small cohort of postmortem human eyes","volume":"203","author":"Grillo","year":"2021","journal-title":"Exp. 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Mol. Genet."},{"key":"2023011411263287300_ref19","first-page":"2901","article-title":"Analysis of carbohydrate structures in basal laminar deposit in aging human maculae","volume":"35","author":"Kliffen","year":"1994","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"2023011411263287300_ref20","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/S1047-8477(02)00534-8","article-title":"Collagen VI assemblies in age-related macular degeneration","volume":"139","author":"Knupp","year":"2002","journal-title":"J. Struct. Biol."},{"key":"2023011411263287300_ref21","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1093\/aje\/kws031","article-title":"The association between complement component 2\/complement factor B polymorphisms and age-related macular degeneration: a HuGE review and meta-analysis","volume":"176","author":"Thakkinstian","year":"2012","journal-title":"Am. J. Epidemiol."},{"key":"2023011411263287300_ref22","doi-asserted-by":"crossref","first-page":"10416","DOI":"10.1038\/s41598-021-89978-8","article-title":"Complement C5 is not critical for the formation of sub-RPE deposits in Efemp1 mutant mice","volume":"11","author":"Garland","year":"2021","journal-title":"Sci. Rep."},{"key":"2023011411263287300_ref23","doi-asserted-by":"crossref","first-page":"1455","DOI":"10.1167\/iovs.16-20955","article-title":"Deletion of Efemp1 Is Protective Against the Development of Sub-RPE Deposits in Mouse Eyes","volume":"58","author":"Stanton","year":"2017","journal-title":"Invest. Ophthalmol. Vis. 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