Homozygosity for a hypomorphic mutation in frizzled class receptor 5 causes syndromic ocular coloboma with microcornea in humans
Por:
Cortés-González, V, Rodriguez-Morales, M, Ataliotis, P, Mayer, C, Plaisancié, J, Chassaing, N, Lee, H, Rozet, JM, Cavodeassi, F, Taie, LF
Publicada:
1 dic 2024
Ahead of Print:
1 nov 2024
Resumen:
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 FZD5, 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 FZD5. Consistent with a loss-of-function effect, overexpressing of fzd5 mRNA harboring the missense variant in zebrafish embryos does not influence embryonic development, whereas overexpression of wild-type fzd5 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.
Filiaciones:
Cortés-González, V:
Asociac Evitar Ceguera Mexico, Dept Genet, Vicente Garcia Torres 46 Barrio San Lucas, Mexico City 04030, Mexico
Univ Nacl Autonoma Mexico, Fac Med, Mexico City, Mexico
Rodriguez-Morales, M:
Asociac Evitar Ceguera Mexico, Dept Genet, Vicente Garcia Torres 46 Barrio San Lucas, Mexico City 04030, Mexico
Univ Nacl Autonoma Mexico, Fac Med, Mexico City, Mexico
Ataliotis, P:
City St Georges Univ London, Sch Hlth & Med Sci, London SW17 0RE, England
Mayer, C:
Univ Strasbourg, ICube Lab, Complex Syst & Translat Bioinformat CSTB, UMR7357, 1 Rue Eugene Boeckel, F-67000 Strasbourg, France
Univ Paris Cite, Fac Sci, UFR Sci Vivant, F-75013 Paris, France
Plaisancié, J:
CHU Toulouse, Inst Federat Biol IFB, Lab Reference LBMR Anomalies Malformat Oeil, Toulouse, France
CHU Toulouse, CARGO, Ctr Reference Affect Rares Genet Ophtalmol, Site Constitutif, Toulouse, France
Chassaing, N:
CHU Toulouse, Inst Federat Biol IFB, Lab Reference LBMR Anomalies Malformat Oeil, Toulouse, France
CHU Toulouse, CARGO, Ctr Reference Affect Rares Genet Ophtalmol, Site Constitutif, Toulouse, France
Lee, H:
3billion Inc, Seoul, South Korea
Rozet, JM:
INSERM, Lab Genet Ophthalmol LGO, UMR1163, Imagine,Inst Genet Dis, F-75015 Paris, France
Paris Descartes Univ, F-75015 Paris, France
Cavodeassi, F:
City St Georges Univ London, Sch Hlth & Med Sci, London SW17 0RE, England
Taie, LF:
INSERM, Lab Genet Ophthalmol LGO, UMR1163, Imagine,Inst Genet Dis, F-75015 Paris, France
Paris Descartes Univ, F-75015 Paris, France
hybrid, All Open Access
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