Heterozygous loss-of-function variants in DOCK4 cause neurodevelopmental delay and microcephaly
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(Published version)
Date
2024
Authors
Herbst, C.
Bothe, V.
Wegler, M.
Axer-Schaefer, S.
Audebert-Bellanger, S.
Gecz, J.
Cogne, B.
Feldman, H.B.
Horn, A.H.C.
Hurst, A.C.E.
Editors
Merlin, T.
Tamblyn, D.
Tamblyn, D.
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Journal article
Citation
Human Genetics, 2024; 143(3):455-469
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Charlotte Herbst, Viktoria Bothe, Meret Wegler, Susanne Axer, Schaefer, Séverine Audebert, Bellanger, Jozef Gecz, Benjamin Cogne, Hagit Baris Feldman, Anselm H. C. Horn, Anna C. E. Hurst, Melissa A. Kelly, Michael C. Kruer, Alina Kurolap, Annie Laquerriere, Megan Li, Paul R. Mark, Markus Morawski, Mathilde Nizon, Tomi Pastinen, Tilman Polster, Pascale Saugier, Veber, Jang SeSong, Heinrich Sticht, Jens T. Stieler, Isabelle Thiffault, Clare L. van Eyk, Pascale Marcorelles, Myriam Vezain, Mouchard, Rami Abou Jamra, Henry Oppermann
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Abstract
Neurons form the basic anatomical and functional structure of the nervous system, and defects in neuronal differentiation or formation of neurites are associated with various psychiatric and neurodevelopmental disorders. Dynamic changes in the cytoskeleton are essential for this process, which is, inter alia, controlled by the dedicator of cytokinesis 4 (DOCK4) through the activation of RAC1. Here, we clinically describe 7 individuals (6 males and one female) with variants in DOCK4 and overlapping phenotype of mild to severe global developmental delay. Additional symptoms include coordination or gait abnormalities, microcephaly, nonspecific brain malformations, hypotonia and seizures. Four individuals carry missense variants (three of them detected de novo) and three individuals carry null variants (two of them maternally inherited). Molecular modeling of the heterozygous missense variants suggests that the majority of them affect the globular structure of DOCK4. In vitro functional expression studies in transfected Neuro-2A cells showed that all missense variants impaired neurite outgrowth. Furthermore, Dock4 knockout Neuro-2A cells also exhibited defects in promoting neurite outgrowth. Our results, including clinical, molecular and functional data, suggest that loss-of-function variants in DOCK4 probable cause a variable spectrum of a novel neurodevelopmental disorder with microcephaly.
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© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 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 Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/.