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Biallelic and monoallelic variants in PLXNA1 are implicated in a novel neurodevelopmental disorder with variable cerebral and eye anomalies.

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

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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
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:
DateEvent
23 September 2021Published
30 May 2021Published Online
16 April 2021Accepted
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
RE 1723/5-1Deutsche Forschungsgemeinschafthttp://dx.doi.org/10.13039/501100001659
BO102/1–3Deutsche Forschungsgemeinschafthttp://dx.doi.org/10.13039/501100001659
TH 1327/2–1Deutsche Forschungsgemeinschafthttp://dx.doi.org/10.13039/501100001659
INST 1172/37–1 FUGGDeutsche Forschungsgemeinschafthttp://dx.doi.org/10.13039/501100001659
O-120.0001BONFORUNSPECIFIED
2019Herbert-Reeck FoundationUNSPECIFIED
Q614.0754BonnNiUNSPECIFIED
R35 NS105078National Institute of Neurological Disorders and Strokehttp://dx.doi.org/10.13039/100000065
512848Muscular Dystrophy Associationhttp://dx.doi.org/10.13039/100005202
UM1 HG006542National Heart, Lung, and Blood Institutehttp://dx.doi.org/10.13039/100000050
K08 HG008986National Human Genome Research Institutehttp://dx.doi.org/10.13039/100000051
3701–1International Rett Syndrome Foundationhttp://dx.doi.org/10.13039/100001819
WT093205 MAWellcome Trusthttp://dx.doi.org/10.13039/100004440
WT104033AIAWellcome Trusthttp://dx.doi.org/10.13039/100004440
MR/S01165X/1Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
MR/S005021/1Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
G0601943Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
UM1 HG008900National Heart, Lung, and Blood Institutehttp://dx.doi.org/10.13039/100000050
R01 HG009141National Human Genome Research Institutehttp://dx.doi.org/10.13039/100000051
602531Seventh Framework Programmehttp://dx.doi.org/10.13039/501100004963
APP1048816National Health and Medical Research Councilhttp://dx.doi.org/10.13039/501100000925
APP1136197National Health and Medical Research Councilhttp://dx.doi.org/10.13039/501100000925
APP1136197National Health and Medical Research Councilhttp://dx.doi.org/10.13039/501100000925
GNT1090428National Health and Medical Research Councilhttp://dx.doi.org/10.13039/501100000925
PubMed ID: 34054129
Web of Science ID: WOS:000656114000001
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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