Lahrouchi, Najim, George, Aman, Ratbi, Ilham, Schneider, Ronen, Elalaoui, Siham C., Moosa, Shahida ORCID: 0000-0002-4463-3067, 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. and Sefiani, Abdelaziz (2019). Homozygous frameshift mutations in FAT1 cause a syndrome characterized by colobomatous-microphthalmia, ptosis, nephropathy and syndactyly. Nat. Commun., 10. LONDON: NATURE PUBLISHING GROUP. ISSN 2041-1723

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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 fatla 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Lahrouchi, NajimUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
George, AmanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ratbi, IlhamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schneider, RonenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Elalaoui, Siham C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moosa, ShahidaUNSPECIFIEDorcid.org/0000-0002-4463-3067UNSPECIFIED
Bharti, SanitaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sharma, RuchiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Abu-Asab, MonesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Onojafe, FelixUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Adadi, NajlaeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lodder, Elisabeth M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Laarabi, Fatima-ZahraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lamsyah, YassineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Elorch, HamzaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chebbar, ImaneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Postma, Alex, VUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lougaris, VassiliosUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Plebani, AlessandroUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Altmueller, JanineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kyrieleis, HenrietteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Meiner, VardiellaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
McNeill, HelenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bharti, KapilUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lyonnet, StanislasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wollnik, BerndUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Henrion-Caude, AlexandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Berraho, AminaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hildebrandt, FriedhelmUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bezzina, Connie R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brooks, Brian P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sefiani, AbdelazizUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-153917
DOI: 10.1038/s41467-019-08547-w
Journal or Publication Title: Nat. Commun.
Volume: 10
Date: 2019
Publisher: NATURE PUBLISHING GROUP
Place of Publication: LONDON
ISSN: 2041-1723
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
RETINAL-PIGMENT EPITHELIUM; OPTIC FISSURE CLOSURE; GENETIC-VARIATION; ACTIN DYNAMICS; MOUSE; PROLIFERATION; PROTEINS; DEFECTSMultiple languages
Multidisciplinary SciencesMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/15391

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