{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T23:30:32Z","timestamp":1790811032587,"version":"4.1.0"},"reference-count":36,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2023,7,21]],"date-time":"2023-07-21T00:00:00Z","timestamp":1689897600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["20K09818"],"award-info":[{"award-number":["20K09818"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>The human fovea is a specialized pit structure in the central retina. Foveal hypoplasia is a condition where the foveal pit does not fully develop, and it is associated with poor vision. Autosomal dominant isolated foveal hypoplasia (FVH1) is a rare condition of foveal hypoplasia (FH) that lacks any other ocular manifestations. FVH1 is associated with hypomorphic mutations in the PAX6 gene that encodes a sequence-specific DNA-binding transcription factor for morphogenesis and evolution of the eye. We report our findings in 17 patients with PAX6 mutations associated with FVH1 or FH with aniridia and corneal opacities. Patients with three mutations, p.V78E, p.V83F and p.R128H, in the C-terminal subdomain of the paired domain (CTS) consistently have severe FH. Luciferase assays for a single reporter containing a representative PAX6 binding site indicated that the transcriptional activities of these mutations were significantly reduced, comparable to that of the truncation mutation of p.G65Rfs*5. Patients with p.P20S in the N-terminal subdomain of the paired domain, and a patient with p.N365K in the proline-serine-threonine-rich domain (PSTD) had mild FH. A patient with p.Q255L in the homeodomain had severe FH. The P20S and Q255L mutants did not affect the transcriptional activity. Mutant N365K has a retained DNA-binding activity but a reduced transcriptional activity, due to a low PSTD transactivation. These findings demonstrated that mutations associated with FVH1 underlie a functional divergence between DNA-binding ability and transcriptional activity. We conclude that a wide range of mutations in the PAX6 gene is not limited to the CST region and are responsible for FVH1.<\/jats:p>","DOI":"10.3390\/genes14071483","type":"journal-article","created":{"date-parts":[[2023,7,21]],"date-time":"2023-07-21T01:52:35Z","timestamp":1689904355000},"page":"1483","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Functional Characteristics of Diverse PAX6 Mutations Associated with Isolated Foveal Hypoplasia"],"prefix":"10.3390","volume":"14","author":[{"given":"Itsuka","family":"Matsushita","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, University of Occupational and Environmental Health, Kitakyushu 807-8555, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0327-582X","authenticated-orcid":false,"given":"Hiroto","family":"Izumi","sequence":"additional","affiliation":[{"name":"Department of Occupational Pneumology, University of Occupational and Environmental Health, Kitakyushu 807-8555, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinji","family":"Ueno","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan"},{"name":"Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1535-0279","authenticated-orcid":false,"given":"Takaaki","family":"Hayashi","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, The Jikei University School of Medicine, Tokyo 105-8461, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaoru","family":"Fujinami","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, National Hospital Organization Tokyo Medical Center, Tokyo 152-8902, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-4913-1277","authenticated-orcid":false,"given":"Kazushige","family":"Tsunoda","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, National Hospital Organization Tokyo Medical Center, Tokyo 152-8902, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeshi","family":"Iwata","sequence":"additional","affiliation":[{"name":"Division of Molecular and Cellular Biology, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Tokyo 152-8902, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1915-1864","authenticated-orcid":false,"given":"Yoshiaki","family":"Kiuchi","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Science, Graduate School of Biomedical and Health Sciences, Hiroshima 734-8551, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3194-152X","authenticated-orcid":false,"given":"Hiroyuki","family":"Kondo","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University of Occupational and Environmental Health, Kitakyushu 807-8555, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,7,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.preteyeres.2013.01.005","article-title":"Adaptation of the central retina for high acuity vision: Cones, the fovea and the avascular zone","volume":"35","author":"Provis","year":"2013","journal-title":"Prog. 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