ZFIN ID: ZDB-PUB-190314-6
Homozygous frameshift mutations in FAT1 cause a syndrome characterized by colobomatous-microphthalmia, ptosis, nephropathy and syndactyly
Lahrouchi, N., George, A., Ratbi, I., Schneider, R., Elalaoui, S.C., Moosa, S., Bharti, S., Sharma, R., Abu-Asab, M., Onojafe, F., Adadi, N., Lodder, E.M., Laarabi, F.Z., Lamsyah, Y., Elorch, H., Chebbar, I., Postma, A.V., Lougaris, V., Plebani, A., Altmueller, J., Kyrieleis, H., Meiner, V., McNeill, H., Bharti, K., Lyonnet, S., Wollnik, B., Henrion-Caude, A., Berraho, A., Hildebrandt, F., Bezzina, C.R., Brooks, B.P., Sefiani, A.
Date: 2019
Source: Nature communications   10: 1180 (Journal)
Registered Authors: Brooks, Brian P., Hildebrandt, Friedhelm, Lyonnet, Stanislas, Schneider, Ronen
Keywords: none
MeSH Terms:
  • Adolescent
  • Adult
  • Animals
  • Blepharoptosis/genetics*
  • Cadherins/genetics*
  • Cells, Cultured
  • Child
  • Child, Preschool
  • Coloboma/genetics*
  • DNA Mutational Analysis
  • Embryo, Mammalian
  • Eye/embryology
  • Facial Bones/abnormalities
  • Female
  • Frameshift Mutation
  • Humans
  • Intercellular Junctions/metabolism
  • Kidney Diseases/genetics*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microphthalmos/genetics*
  • Organogenesis/genetics*
  • Primary Cell Culture
  • Retinal Pigment Epithelium/cytology
  • Syndactyly/genetics*
  • Syndrome
  • Whole Exome Sequencing
  • Young Adult
  • Zebrafish
  • Zebrafish Proteins/genetics
PubMed: 30862798 Full text @ Nat. Commun.
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.