Homozygous frameshift mutations in FAT1 cause a syndrome characterized by colobomatous-microphthalmia, ptosis, nephropathy and syndactyly

• Published in: Nature communications Vol. 10; no. 1; p. 1180
• Main Authors: Lahrouchi, Najim, George, Aman, Ratbi, Ilham, Schneider, Ronen, Elalaoui, Siham C., Moosa, Shahida, Bharti, Sanita, Sharma, Ruchi, Abu-Asab, Mones, Onojafe, Felix, Adadi, Najlae, Lodder, Elisabeth M., Laarabi, Fatima-Zahra, Lamsyah, Yassine, Elorch, Hamza, Chebbar, Imane, Postma, Alex V., Lougaris, Vassilios, Plebani, Alessandro, Altmueller, Janine, Kyrieleis, Henriette, Meiner, Vardiella, McNeill, Helen, Bharti, Kapil, Lyonnet, Stanislas, Wollnik, Bernd, Henrion-Caude, Alexandra, Berraho, Amina, Hildebrandt, Friedhelm, Bezzina, Connie R., Brooks, Brian P., Sefiani, Abdelaziz
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12.03.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/106; 13/51; 14; 14/1; 14/19; 14/28; 42; 42/41; 42/70; 45; 45/22; 45/23; 45/41; 59; 631/208/1516; 631/208/2489/144; 631/378/2583; 64; 64/116; 64/60; 692/699/3161; 96; Adolescent; Adult; Animals; Blepharoptosis - genetics; Cadherins - genetics; Cell junctions; Cells, Cultured; Child; Child, Preschool; Coloboma - genetics; DNA Mutational Analysis; Embryo, Mammalian; Embryos; Epithelium; Eye; Eye - embryology; Facial Bones - abnormalities; Female; Frameshift Mutation; Hereditary diseases; Humanities and Social Sciences; Humans; Intercellular Junctions - metabolism; Kidney Diseases - genetics; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Microphthalmia; Microphthalmos - genetics; Missense mutation; multidisciplinary; Mutation; Nephropathy; Organogenesis - genetics; Primary Cell Culture; Retina; Retinal pigment epithelium; Retinal Pigment Epithelium - cytology; Rodents; Science; Science (multidisciplinary); Syndactyly; Syndactyly - genetics; Syndrome; Vertebrates; Whole Exome Sequencing; Young Adult; Zebrafish; Zebrafish Proteins - genetics
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-08547-w

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. Loss of the cadherin FAT1 has been associated with nephropathy and epithelial cell adhesion defects. Here, the authors report five families with a syndromic form of coloboma associated with homozygous frameshift variants in FAT1 and recapitulate the phenotype in mutant mice and zebrafish.