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Dworschak, G.C.* ; Punetha, J.* ; Kalanithy, J.C.* ; Mingardo, E.* ; Erdem, H.B.* ; Akdemir, Z.C.* ; Karaca, E.* ; Mitani, T.* ; Marafi, D.* ; Fatih, J.M.* ; Jhangiani, S.N.* ; Hunter, J.V.* ; Dakal, T.C.* ; Dhabhai, B.* ; Dabbagh, O.* ; Alsaif, H.S.* ; Alkuraya, F.S.* ; Maroofian, R.* ; Houlden, H.* ; Efthymiou, S.* ; Dominik, N.* ; Salpietro,V.* ; Sultan, T.* ; Haider, S.* ; Bibi, F.* ; Thiele, H.* ; Hoefele, J.* ; Riedhammer, K.M.* ; Wagner, M. ; Guella, I.* ; Demos, M.* ; Keren, B.* ; Buratti, J.* ; Charles, P.* ; Nava, C.* ; Heron, D.* ; Heide, S.* ; Valkanas, E.* ; Waddell, L.B.* ; Jones, K.J.* ; Oates, E.C.* ; Cooper, S.T.* ; MacArthur, D.* ; Syrbe, S.* ; Ziegler, A.* ; Platzer, K.* ; Okur, V.* ; Chung, W.K.* ; O'Shea, S.A.* ; Alcalay, R.* ; Fahn, S.* ; Mark, P.R.* ; Guerrini, R.* ; Vetro, A.* ; Hudson, B.* ; Schnur, R.E.* ; Hoganson, G.E.* ; Burton, J.E.* ; McEntagart, M.* ; Lindenberg, T.* ; Yilmaz, Ö.* ; Odermatt, B.* ; Pehlivan, D.* ; Posey, J.E.* ; Lupski, J.R.* ; Reutter, H.*

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

Genet. Med. 23, 1715–1725 (2021)
Postprint Forschungsdaten DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter De-novo Mutations; Plexina1; Expression; Proteins; Receptor; Family
Sprache englisch
Veröffentlichungsjahr 2021
HGF-Berichtsjahr 2021
ISSN (print) / ISBN 1530-0366
e-ISSN 1098-3600
Zeitschrift Genetics in Medicine
Quellenangaben Band: 23, Heft: , Seiten: 1715–1725 Artikelnummer: , Supplement: ,
Verlag Lippincott Williams & Wilkins
Verlagsort Baltimore, Md.
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Neurogenomics (ING)
POF Topic(s) 30205 - Bioengineering and Digital Health
Forschungsfeld(er) Genetics and Epidemiology
PSP-Element(e) G-503200-001
Förderungen Deutsche Forschungsgemeinschaft
DOI 10.1038/s41436-021-01196-9
WOS ID WOS:000656114000001
Scopus ID 85107328325
PubMed ID 34054129
Erfassungsdatum 2021-07-07
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