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Genet."],"published-print":{"date-parts":[[2024,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Ocular coloboma (OC) is a congenital disorder caused by the incomplete closure of the embryonic ocular fissure. OC can present as a simple anomaly or, in more complex forms, be associated with additional ocular abnormalities. It can occur in isolation or as part of a broader syndrome, exhibiting considerable genetic heterogeneity. Diagnostic yield for OC remains below 30%, indicating the need for further genetic exploration. Mutations in the Wnt receptor <jats:italic>FZD5<\/jats:italic>, which is expressed throughout eye development, have been linked to both isolated and complex forms of coloboma. These mutations often result in a dominant-negative effect, where the mutated FZD5 protein disrupts WNT signaling by sequestering WNT ligands. Here, we describe a case of syndromic bilateral OC with additional features such as microcornea, bone developmental anomalies, and mild intellectual disability. Whole exome sequencing revealed a homozygous rare missense variant in <jats:italic>FZD5<\/jats:italic>. Consistent with a loss-of-function effect, overexpressing of <jats:italic>fzd5<\/jats:italic> mRNA harboring the missense variant in zebrafish embryos does not influence embryonic development, whereas overexpression of wild-type <jats:italic>fzd5<\/jats:italic> mRNA results in body axis duplications. However, in vitro TOPFlash assays revealed that the missense variant only caused partial loss-of-function, behaving as a hypomorphic mutation. We further showed that the mutant protein still localized to the cell membrane and maintained proper conformation when modeled in silico, suggesting that the impairment lies in signal transduction. This hypothesis is further supported by the fact that the variant affects a highly conserved amino acid known to be crucial for protein-protein interactions.<\/jats:p>","DOI":"10.1007\/s00439-024-02712-y","type":"journal-article","created":{"date-parts":[[2024,11,6]],"date-time":"2024-11-06T08:07:11Z","timestamp":1730880431000},"page":"1509-1521","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Homozygosity for a hypomorphic mutation in frizzled class receptor 5 causes syndromic ocular coloboma with microcornea in humans"],"prefix":"10.1007","volume":"143","author":[{"given":"Vianney","family":"Cort\u00e9s-Gonz\u00e1lez","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miguel","family":"Rodriguez-Morales","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paris","family":"Ataliotis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claudine","family":"Mayer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julie","family":"Plaisanci\u00e9","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicolas","family":"Chassaing","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hane","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jean-Michel","family":"Rozet","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Florencia","family":"Cavodeassi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lucas","family":"Fares Taie","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2024,11,6]]},"reference":[{"key":"2712_CR1","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1177\/0023677219869037","volume":"54","author":"P Alestr\u00f6m","year":"2020","unstructured":"Alestr\u00f6m P, D\u2019Angelo L, Midtlyng PJ et al (2020) Zebrafish: housing and husbandry recommendations. 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