@article{294d962558534f899aa92817bc541736,
title = "Functional analysis of a de novo variant in the neurodevelopment and generalized epilepsy disease gene NBEA",
abstract = "Neurobeachin (NBEA) was initially identified as a candidate gene for autism. Recently, variants in NBEA have been associated with neurodevelopmental delay and childhood epilepsy. Here, we report on a novel NBEA missense variant (c.5899G > A, p.Gly1967Arg) in the Domain of Unknown Function 1088 (DUF1088) identified in a child enrolled in the Undiagnosed Diseases Network (UDN), who presented with neurodevelopmental delay and seizures. Modeling of this variant in the Caenorhabditis elegans NBEA ortholog, sel-2, indicated that the variant was damaging to in vivo function as evidenced by altered cell fate determination and trafficking of potassium channels in neurons. The variant effect was indistinguishable from that of the reference null mutation suggesting that the variant is a strong hypomorph or a complete loss-of-function. Our experimental data provide strong support for the molecular diagnosis and pathogenicity of the NBEA p.Gly1967Arg variant and the importance of the DUF1088 for NBEA function.",
keywords = "C. elegans, Epilepsy, Neurobeachin, Neurodevelopmental delay, SEL-2",
author = "{Undiagnosed Diseases Network} and Thomas Boulin and Omar Itani and {El Mouridi}, Sonia and Alice Leclercq-Blondel and Marie Gendrel and Ellen Macnamara and Ariane Soldatos and Murphy, {Jennifer L.} and Gorman, {Mark P.} and Anika Lindsey and Shino Shimada and Darian Turner and Silverman, {Gary A.} and Dustin Baldridge and Malicdan, {May C.} and Tim Schedl and Pak, {Stephen C.}",
note = "Funding Information: We thank Kyuhyung Kim for sharing unpublished data for the IL1DV-specific flp-3 promoter sequence. Research reported in this manuscript was supported by the NIH Common Fund, through the Office of Strategic Coordination / Office of the NIH Director under Award Number U54 NS108251 (TS and Lila Solnica-Krezel). The NIH Undiagnosed Diseases Program (UDP) is partly supported by the NIH Common Fund from the NIH Office of the Director , and the NHGRI Intramural Research Program. Funding was also provided by the Children's Discovery Institute, St Louis Children's Hospital Foundation (GAS and SCP), the European Research Council (TB, MG& SEM, ERC Starting Grant Kelegans), and AFM T{\'e}l{\'e}thon (TB & ALB, Alliance MyoNeurALP). Some strains were provided by the CGC, which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440). The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Funding Information: We thank Kyuhyung Kim for sharing unpublished data for the IL1DV-specific flp-3 promoter sequence. Research reported in this manuscript was supported by the NIH Common Fund, through the Office of Strategic Coordination/Office of the NIH Director under Award Number U54 NS108251 (TS and Lila Solnica-Krezel). The NIH Undiagnosed Diseases Program (UDP) is partly supported by the NIH Common Fund from the NIH Office of the Director, and the NHGRI Intramural Research Program. Funding was also provided by the Children's Discovery Institute, St Louis Children's Hospital Foundation (GAS and SCP), the European Research Council (TB, MG& SEM, ERC Starting Grant Kelegans), and AFM T?l?thon (TB & ALB, Alliance MyoNeurALP). Some strains were provided by the CGC, which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440). The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Publisher Copyright: {\textcopyright} 2021 The Authors",
year = "2021",
month = sep,
day = "1",
doi = "10.1016/j.ymgme.2021.07.013",
language = "English",
volume = "134",
pages = "195--202",
journal = "Molecular Genetics and Metabolism",
issn = "1096-7192",
number = "1-2",
}