{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T15:32:01Z","timestamp":1785166321582,"version":"3.55.0"},"reference-count":42,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2023,9,22]],"date-time":"2023-09-22T00:00:00Z","timestamp":1695340800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Alberta Prion Research Institute"},{"name":"Fighting Blindness Canada. E.D.H."},{"name":"Alberta Graduate Excellence Scholarship"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Pigmentary glaucoma has recently been associated with missense mutations in PMEL that are dominantly inherited and enriched in the protein\u2019s fascinating repeat domain. PMEL pathobiology is intriguing because PMEL forms functional amyloid in healthy eyes, and this PMEL amyloid acts to scaffold melanin deposition. This is an informative contradistinction to prominent neurodegenerative diseases where amyloid formation is neurotoxic and mutations cause a toxic gain of function called \u201camyloidosis\u201d. Preclinical animal models have failed to model this PMEL \u201cdysamyloidosis\u201d pathomechanism and instead cause recessively inherited ocular pigment defects via PMEL loss of function; they have not addressed the consequences of disrupting PMEL\u2019s repetitive region. Here, we use CRISPR to engineer a small in-frame mutation in the zebrafish homolog of PMEL that is predicted to subtly disrupt the protein\u2019s repetitive region. Homozygous mutant larvae displayed pigmentation phenotypes and altered eye morphogenesis similar to presumptive null larvae. Heterozygous mutants had disrupted eye morphogenesis and disrupted pigment deposition in their retinal melanosomes. The deficits in the pigment deposition of these young adult fish were not accompanied by any detectable glaucomatous changes in intraocular pressure or retinal morphology. Overall, the data provide important in vivo validation that subtle PMEL mutations can cause a dominantly inherited pigment pathology that aligns with the inheritance of pigmentary glaucoma patient pedigrees. These in vivo observations help to resolve controversy regarding the necessity of PMEL\u2019s repeat domain in pigmentation. The data foster an ongoing interest in an antithetical dysamyloidosis mechanism that, akin to the amyloidosis of devastating dementias, manifests as a slow progressive neurodegenerative disease.<\/jats:p>","DOI":"10.3390\/ijms241914423","type":"journal-article","created":{"date-parts":[[2023,9,22]],"date-time":"2023-09-22T03:44:42Z","timestamp":1695354282000},"page":"14423","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Disrupting the Repeat Domain of Premelanosome Protein (PMEL) Produces Dysamyloidosis and Dystrophic Ocular Pigment Reflective of Pigmentary Glaucoma"],"prefix":"10.3390","volume":"24","author":[{"given":"Elizabeth D.","family":"Hodges","sequence":"first","affiliation":[{"name":"Department of Biological Sciences, University of Alberta, Edmonton, AB T6G 2E9, Canada"},{"name":"Faculty of Science, University of Alberta, Edmonton, AB T6G 2E9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5371-1178","authenticated-orcid":false,"given":"Paul W.","family":"Chrystal","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Alberta, Edmonton, AB T6G 2E9, Canada"},{"name":"Department of Cell & Systems Biology, University of Toronto, Toronto, ON M5S 3G5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim","family":"Footz","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, University of Alberta, Edmonton, AB T6G 2R3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lance P.","family":"Doucette","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Alberta, Edmonton, AB T6G 2E9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9094-6745","authenticated-orcid":false,"given":"Nicole C. L.","family":"Noel","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Alberta, Edmonton, AB T6G 2E9, Canada"},{"name":"Department of Medical Genetics, University of Alberta, Edmonton, AB T6G 2R3, Canada"},{"name":"Institute of Ophthalmology, University College London, London EC1V 9EL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zixuan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Alberta, Edmonton, AB T6G 2E9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0567-0113","authenticated-orcid":false,"given":"Michael A.","family":"Walter","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, University of Alberta, Edmonton, AB T6G 2R3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8461-4864","authenticated-orcid":false,"given":"W. Ted","family":"Allison","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Alberta, Edmonton, AB T6G 2E9, Canada"},{"name":"Department of Medical Genetics, University of Alberta, Edmonton, AB T6G 2R3, Canada"},{"name":"Centre for Prions & Protein Folding Disease, University of Alberta, Edmonton, AB T6G 2M8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,9,22]]},"reference":[{"key":"ref_1","first-page":"1298","article-title":"Non-Synonymous variants in premelanosome protein (PMEL) cause ocular pigment dispersion and pigmentary glaucoma","volume":"28","author":"Footz","year":"2018","journal-title":"Hum. Mol. Genet."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3451","DOI":"10.1091\/mbc.12.11.3451","article-title":"Pmel17 Initiates Premelanosome Morphogenesis within Multivesicular Bodies","volume":"12","author":"Berson","year":"2001","journal-title":"Mol. 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