Abstract
A failure in optic fissure fusion during development can lead to blinding malformations of the eye. Here, we report a syndrome characterized by facial dysmorphism, colobomatous microphthalmia, ptosis and syndactyly with or without nephropathy, associated with homozygous frameshift mutations in FAT1. We show that Fat1 knockout mice and zebrafish embryos homozygous for truncating fat1a mutations exhibit completely penetrant coloboma, recapitulating the most consistent developmental defect observed in affected individuals. In human retinal pigment epithelium (RPE) cells, the primary site for the fusion of optic fissure margins, FAT1 is localized at earliest cell-cell junctions, consistent with a role in facilitating optic fissure fusion during vertebrate eye development. Our findings establish FAT1 as a gene with pleiotropic effects in human, in that frameshift mutations cause a severe multi-system disorder whereas recessive missense mutations had been previously associated with isolated glomerulotubular nephropathy.
Highlights
A failure in optic fissure fusion during development can lead to blinding malformations of the eye
We here identified five unrelated families presenting with a new syndrome consisting of colobomatous microphthalmia, ptosis, and cutaneous syndactyly with or without glomerulotubular nephropathy, associated with homozygous frame-shift mutations in the FAT1 gene
The causal relation between loss of function mutations in FAT1 and coloboma was established through studies in mice and fish loss-of-function models, underscoring a highly conserved role of FAT1 during vertebrate eye development
Summary
A failure in optic fissure fusion during development can lead to blinding malformations of the eye. Fat1−/− mice display partially penetrant anterior neural tube closure defects due to reduced actin accumulation, leading to apical constriction defects in the neural epithelium[9] These developmental observations in epithelial cell types suggest that FAT1 plays an important role in epithelial cell–cell adhesion and/or sheet fusion. We demonstrate that Fat[1] knockout mice and zebrafish homozygous for truncating fat1a mutations exhibit coloboma, supporting the causality of these mutations and pointing to an evolutionary conserved role of Fat[1] in eye development and optic fissure closure. Studies conducted in human primary retinal pigment epithelium (RPE) cells point to a defect in optic fissure margin fusion likely caused by loss of FAT1 at the earliest cell–cell contacts that mediate optic fissure fusion
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
