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

Najim Lahrouchi, Aman George, Ilham Ratbi, Ronen Schneider, Siham C. Elalaoui, Shahida Moosa, Sanita Bharti, Ruchi Sharma, Mones Abu-Asab, Felix Onojafe, Najlae Adadi, Elisabeth M. Lodder, Fatima-Zahra Laarabi, Yassine Lamsyah, Hamza Elorch, Imane Chebbar, Alex V. Postma, Vassilios Lougaris, Alessandro Plebani, Janine Altmueller, Henriette Kyrieleis, Vardiella Meiner, Helen McNeill, Kapil Bharti, Stanislas Lyonnet, Bernd Wollnik, Alexandra Henrion-Caude, Amina Berraho, Friedhelm Hildebrandt, Connie R. Bezzina (), Brian P. Brooks () and Abdelaziz Sefiani ()
Additional contact information
Najim Lahrouchi: Amsterdam Cardiovascular Sciences
Aman George: NIH
Ilham Ratbi: Mohammed V University of Rabat
Ronen Schneider: Harvard Medical School
Siham C. Elalaoui: Mohammed V University of Rabat
Shahida Moosa: University Medical Center Goettingen
Sanita Bharti: NIH
Ruchi Sharma: NIH
Mones Abu-Asab: Section of Histopathology, National Eye Institute, NIH
Felix Onojafe: NIH
Najlae Adadi: Mohammed V University of Rabat
Elisabeth M. Lodder: Amsterdam Cardiovascular Sciences
Fatima-Zahra Laarabi: Institut National d’Hygiène
Yassine Lamsyah: Mohammed V University of Rabat
Hamza Elorch: Mohammed V University of Rabat
Imane Chebbar: Mohammed V University of Rabat
Alex V. Postma: Amsterdam Cardiovascular Sciences
Vassilios Lougaris: University of Brescia and ASST-Spedali Civili of Brescia
Alessandro Plebani: University of Brescia and ASST-Spedali Civili of Brescia
Janine Altmueller: Cologne Center for Genomics University of Cologne
Henriette Kyrieleis: Bethanien Hospital
Vardiella Meiner: Hadassah-Hebrew University Medical Center
Helen McNeill: Washington University School of Medicine
Kapil Bharti: NIH
Stanislas Lyonnet: Institut Imagine
Bernd Wollnik: University Medical Center Goettingen
Alexandra Henrion-Caude: Assistance Publique Hôpitaux de Paris (APHP)
Amina Berraho: Mohammed V University of Rabat
Friedhelm Hildebrandt: Harvard Medical School
Connie R. Bezzina: Amsterdam Cardiovascular Sciences
Brian P. Brooks: NIH
Abdelaziz Sefiani: Mohammed V University of Rabat

Nature Communications, 2019, vol. 10, issue 1, 1-11

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-08547-w

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