Dworschak, Gabriel C., Punetha, Jaya ORCID: 0000-0002-6774-4464, Kalanithy, Jeshurun C., Mingardo, Enrico, Erdem, Haktan B., Akdemir, Zeynep C., Karaca, Ender, Mitani, Tadahiro, Marafi, Dana, Fatih, Jawid M., Jhangiani, Shalini N., Hunter, Jill V., Dakal, Tikam Chand, Dhabhai, Bhanupriya, Dabbagh, Omar, Alsaif, Hessa S., Alkuraya, Fowzan S., Maroofian, Reza, Houlden, Henry, Efthymiou, Stephanie ORCID: 0000-0003-4900-9877, Dominik, Natalia, Salpietro, Vincenzo, Sultan, Tipu, Haider, Shahzad, Bibi, Farah, Thiele, Holger, Hoefele, Julia ORCID: 0000-0002-7917-7129, Riedhammer, Korbinian M., Wagner, Matias, Guella, Ilaria, Demos, Michelle, Keren, Boris, Buratti, Julien, Charles, Perrine, Nava, Caroline, Heron, Delphine, Heide, Solveig, Valkanas, Elise, Waddell, Leigh B., Jones, Kristi J., Oates, Emily C., Cooper, Sandra T., MacArthur, Daniel, Syrbe, Steffen, Ziegler, Andreas, Platzer, Konrad, Okur, Volkan ORCID: 0000-0001-6461-0957, Chung, Wendy K., O'Shea, Sarah A., Alcalay, Roy, Fahn, Stanley, Mark, Paul R., Guerrini, Renzo ORCID: 0000-0002-7272-7079, Vetro, Annalisa, Hudson, Beth, Schnur, Rhonda E., Hoganson, George E., Burton, Jennifer E., McEntagart, Meriel, Lindenberg, Tobias, Yilmaz, Oeznur, Odermatt, Benjamin, Pehlivan, Davut, Posey, Jennifer E., Lupski, James R. and Reutter, Heiko (2021). Biallelic and monoallelic variants in PLXNA1 are implicated in a novel neurodevelopmental disorder with variable cerebral and eye anomalies. Genet. Med., 23 (9). S. 1715 - 1726. NEW YORK: ELSEVIER SCIENCE INC. ISSN 1530-0366

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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: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Dworschak, Gabriel C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Punetha, JayaUNSPECIFIEDorcid.org/0000-0002-6774-4464UNSPECIFIED
Kalanithy, Jeshurun C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mingardo, EnricoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Erdem, Haktan B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Akdemir, Zeynep C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Karaca, EnderUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mitani, TadahiroUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Marafi, DanaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fatih, Jawid M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jhangiani, Shalini N.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hunter, Jill V.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dakal, Tikam ChandUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dhabhai, BhanupriyaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dabbagh, OmarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Alsaif, Hessa S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Alkuraya, Fowzan S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Maroofian, RezaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Houlden, HenryUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Efthymiou, StephanieUNSPECIFIEDorcid.org/0000-0003-4900-9877UNSPECIFIED
Dominik, NataliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Salpietro, VincenzoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sultan, TipuUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Haider, ShahzadUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bibi, FarahUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thiele, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoefele, JuliaUNSPECIFIEDorcid.org/0000-0002-7917-7129UNSPECIFIED
Riedhammer, Korbinian M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wagner, MatiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Guella, IlariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Demos, MichelleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Keren, BorisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buratti, JulienUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Charles, PerrineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nava, CarolineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heron, DelphineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heide, SolveigUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Valkanas, EliseUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Waddell, Leigh B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jones, Kristi J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Oates, Emily C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cooper, Sandra T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
MacArthur, DanielUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Syrbe, SteffenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ziegler, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Platzer, KonradUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Okur, VolkanUNSPECIFIEDorcid.org/0000-0001-6461-0957UNSPECIFIED
Chung, Wendy K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
O'Shea, Sarah A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Alcalay, RoyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fahn, StanleyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mark, Paul R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Guerrini, RenzoUNSPECIFIEDorcid.org/0000-0002-7272-7079UNSPECIFIED
Vetro, AnnalisaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hudson, BethUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schnur, Rhonda E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoganson, George E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Burton, Jennifer E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
McEntagart, MerielUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lindenberg, TobiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yilmaz, OeznurUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Odermatt, BenjaminUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pehlivan, DavutUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Posey, Jennifer E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lupski, James R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reutter, HeikoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-607807
DOI: 10.1038/s41436-021-01196-9
Journal or Publication Title: Genet. Med.
Volume: 23
Number: 9
Page Range: S. 1715 - 1726
Date: 2021
Publisher: ELSEVIER SCIENCE INC
Place of Publication: NEW YORK
ISSN: 1530-0366
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
DE-NOVO MUTATIONS; PLEXINA1; EXPRESSION; PROTEINS; RECEPTOR; FAMILYMultiple languages
Genetics & HeredityMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/60780

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