preprints.org > biology and life sciences > biochemistry and molecular biology > doi: 10.20944/preprints202306.1772.v1

Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Version 1 : Received: 25 June 2023 / Approved: 26 June 2023 / Online: 26 June 2023 (09:44:42 CEST)

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. 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 had severe FH. Luciferase assays indicated that the transcriptional activities of these mutations were significantly reduced comparable to that with 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 had 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. Broadly distributed mutations in the PAX6 gene, not limited to the CST region, were responsible for FVH1.

foveal hypoplasia; FVH1; aniridia; corneal opacity; PAX6; DNA binding; transcriptional activity; paired domain; proline-serine-threonine-rich domain

Biology and Life Sciences, Biochemistry and Molecular Biology

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