Dworschak, GC;
Punetha, J;
Kalanithy, JC;
Mingardo, E;
Erdem, HB;
Akdemir, ZC;
Karaca, E;
Mitani, T;
Marafi, D;
Fatih, JM;
et al.
Dworschak, GC; Punetha, J; Kalanithy, JC; Mingardo, E; Erdem, HB; Akdemir, ZC; Karaca, E; Mitani, T; Marafi, D; Fatih, JM; Jhangiani, SN; Hunter, JV; Dakal, TC; Dhabhai, B; Dabbagh, O; Alsaif, HS; Alkuraya, FS; Maroofian, R; Houlden, H; Efthymiou, S; Dominik, N; Salpietro, V; Sultan, T; Haider, S; Bibi, F; Thiele, H; Hoefele, J; Riedhammer, KM; Wagner, M; Guella, I; Demos, M; Keren, B; Buratti, J; Charles, P; Nava, C; Héron, D; Heide, S; Valkanas, E; Waddell, LB; Jones, KJ; Oates, EC; Cooper, ST; MacArthur, D; Syrbe, S; Ziegler, A; Platzer, K; Okur, V; Chung, WK; O'Shea, SA; Alcalay, R; Fahn, S; Mark, PR; Guerrini, R; Vetro, A; Hudson, B; Schnur, RE; Hoganson, GE; Burton, JE; McEntagart, M; Lindenberg, T; Yilmaz, Ö; Odermatt, B; Pehlivan, D; Posey, JE; Lupski, JR; Reutter, H
(2021)
Biallelic and monoallelic variants in PLXNA1 are implicated in a novel neurodevelopmental disorder with variable cerebral and eye anomalies.
Genet Med, 23 (9).
pp. 1715-1725.
ISSN 1530-0366
https://doi.org/10.1038/s41436-021-01196-9
SGUL Authors: Maroofian, Reza
Abstract
PURPOSE: To investigate the effect of PLXNA1 variants on the phenotype of patients with autosomal dominant and recessive inheritance patterns and to functionally characterize the zebrafish homologs plxna1a and plxna1b during development. METHODS: We assembled ten patients from seven families with biallelic or de novo PLXNA1 variants. We describe genotype-phenotype correlations, investigated the variants by structural modeling, and used Morpholino knockdown experiments in zebrafish to characterize the embryonic role of plxna1a and plxna1b. RESULTS: Shared phenotypic features among patients include global developmental delay (9/10), brain anomalies (6/10), and eye anomalies (7/10). Notably, seizures were predominantly reported in patients with monoallelic variants. Structural modeling of missense variants in PLXNA1 suggests distortion in the native protein. Our zebrafish studies enforce an embryonic role of plxna1a and plxna1b in the development of the central nervous system and the eye. CONCLUSION: We propose that different biallelic and monoallelic variants in PLXNA1 result in a novel neurodevelopmental syndrome mainly comprising developmental delay, brain, and eye anomalies. We hypothesize that biallelic variants in the extracellular Plexin-A1 domains lead to impaired dimerization or lack of receptor molecules, whereas monoallelic variants in the intracellular Plexin-A1 domains might impair downstream signaling through a dominant-negative effect.
Item Type: |
Article
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Additional Information: |
Open Access This article is licensed under a Creative CommonsAttribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the CreativeCommons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
© The Author(s) 2021 |
Keywords: |
0604 Genetics, 1103 Clinical Sciences, Genetics & Heredity |
SGUL Research Institute / Research Centre: |
Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) |
Journal or Publication Title: |
Genet Med |
ISSN: |
1530-0366 |
Language: |
eng |
Dates: |
Date | Event |
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23 September 2021 | Published | 30 May 2021 | Published Online | 16 April 2021 | Accepted |
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Publisher License: |
Creative Commons: Attribution 4.0 |
Projects: |
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PubMed ID: |
34054129 |
Web of Science ID: |
WOS:000656114000001 |
![](http://static.pubmed.gov/portal/portal3rc.fcgi/2745237/img/27842) |
Go to PubMed abstract |
URI: |
https://openaccess.sgul.ac.uk/id/eprint/113364 |
Publisher's version: |
https://doi.org/10.1038/s41436-021-01196-9 |
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