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ALX1-related Frontonasal Dysplasia Results From Defective Neural Crest Cell Development and Migration

Jonathan Pini, Janina Kueper, Yiyuan David Hu, Kenta Kawasaki, Pan Yeung, Casey Tsimbal, Baul Yoon, Nikkola Carmichael, Richard L. Maas, Justin Cotney, Yevgenya Grinblat, Eric C. Liao
doi: https://doi.org/10.1101/2020.06.12.148262
Jonathan Pini
1Center for Regenerative Medicine, Department of Surgery, Massachusetts General Hospital
2Shriners Hospital for Children, Boston
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Janina Kueper
1Center for Regenerative Medicine, Department of Surgery, Massachusetts General Hospital
2Shriners Hospital for Children, Boston
3Life & Brain Center, University of Bonn
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Yiyuan David Hu
1Center for Regenerative Medicine, Department of Surgery, Massachusetts General Hospital
2Shriners Hospital for Children, Boston
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Kenta Kawasaki
1Center for Regenerative Medicine, Department of Surgery, Massachusetts General Hospital
2Shriners Hospital for Children, Boston
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Pan Yeung
1Center for Regenerative Medicine, Department of Surgery, Massachusetts General Hospital
2Shriners Hospital for Children, Boston
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Casey Tsimbal
1Center for Regenerative Medicine, Department of Surgery, Massachusetts General Hospital
2Shriners Hospital for Children, Boston
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Baul Yoon
4Departments of Integrative Biology, Neuroscience, and Genetics Ph.D. Training Program University of Wisconsin-Madison
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Nikkola Carmichael
5Department of Genetics, Brigham and Women’s Hospital, Harvard Medical School
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Richard L. Maas
5Department of Genetics, Brigham and Women’s Hospital, Harvard Medical School
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Justin Cotney
6Genetics & Genome Sciences, UConn Health
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Yevgenya Grinblat
4Departments of Integrative Biology, Neuroscience, and Genetics Ph.D. Training Program University of Wisconsin-Madison
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Eric C. Liao
1Center for Regenerative Medicine, Department of Surgery, Massachusetts General Hospital
2Shriners Hospital for Children, Boston
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  • For correspondence: cliao@partners.org
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ABSTRACT

A pedigree of subjects with frontonasal dysplasia (FND) presented with bilateral oblique facial clefts and ocular phenotypes. Genome sequencing and analysis identified a L165F missense variant in the homeodomain of the transcription factor ALX1 which was imputed to be pathogenic. Induced pluripotent stem cells (iPSC) were derived from the subjects and differentiated to neural crest cells (NCC). NCC derived from ALX1L165F/L165F iPSC were more sensitive to apoptosis, showed an elevated expression of several neural crest progenitor state markers, and exhibited impaired migration compared to wild type controls. NCC migration was also evaluated in vivo using lineage tracing in a zebrafish model, which revealed defective migration of the anterior NCC stream that contributes to the median portion of the anterior neurocranium, phenocopying the clinical presentation. Analysis of human NCC culture media revealed a change in the level of bone morphogenic proteins (BMP), with a low-level of BMP2 and a high level of BMP9. Soluble BMP2 and BMP9 antagonist treatments were able to rescue the defective migration phenotype. Taken together, these results demonstrate a mechanistic requirement of ALX1 in NCC development and migration.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted June 13, 2020.
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ALX1-related Frontonasal Dysplasia Results From Defective Neural Crest Cell Development and Migration
Jonathan Pini, Janina Kueper, Yiyuan David Hu, Kenta Kawasaki, Pan Yeung, Casey Tsimbal, Baul Yoon, Nikkola Carmichael, Richard L. Maas, Justin Cotney, Yevgenya Grinblat, Eric C. Liao
bioRxiv 2020.06.12.148262; doi: https://doi.org/10.1101/2020.06.12.148262
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ALX1-related Frontonasal Dysplasia Results From Defective Neural Crest Cell Development and Migration
Jonathan Pini, Janina Kueper, Yiyuan David Hu, Kenta Kawasaki, Pan Yeung, Casey Tsimbal, Baul Yoon, Nikkola Carmichael, Richard L. Maas, Justin Cotney, Yevgenya Grinblat, Eric C. Liao
bioRxiv 2020.06.12.148262; doi: https://doi.org/10.1101/2020.06.12.148262

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