Missense Variants in RHOBTB2 Cause a Developmental and Epileptic Encephalopathy in Humans, and Altered Levels Cause Neurological Defects in Drosophila

Journal article


Publication Details

Author(s): Straub J, Konrad E, Grüner J, Toutain A, Bok LA, Cho MT, Crawford HP, Dubbs H, Douglas G, Jobling R, Johnson D, Krock B, Mikati MA, Nesbitt A, Nicolai J, Phillips M, Poduri A, Ortiz-Gonzalez XR, Powis Z, Santani A, Smith L, Stegmann APA, Stumpel C, Vreeburg M, Fliedner A, Gregor A, Sticht H, Zweier C
Journal: American Journal of Human Genetics
Publication year: 2018
Volume: 102
Journal issue: 1
Pages range: 44-57
ISSN: 0002-9297


Abstract

Although the role of typical Rho GTPases and other Rho-linked proteins in synaptic plasticity and cognitive function and dysfunction is widely acknowledged, the role of atypical Rho GTPases (such as RHOBTB2) in neurodevelopment has barely been characterized. We have now identified de novo missense variants clustering in the BTB-domain-encoding region of RHOBTB2 in ten individuals with a similar phenotype, including early-onset epilepsy, severe intellectual disability, postnatal microcephaly, and movement disorders. Three of the variants were recurrent. Upon transfection of HEK293 cells, we found that mutant RHOBTB2 was more abundant than the wild-type, most likely because of impaired degradation in the proteasome. Similarly, elevated amounts of the Drosophila ortholog RhoBTB in vivo were associated with seizure susceptibility and severe locomotor defects. Knockdown of RhoBTB in the Drosophila dendritic arborization neurons resulted in a decreased number of dendrites, thus suggesting a role of RhoBTB in dendritic development. We have established missense variants in the BTB-domain-encoding region of RHOBTB2 as causative for a developmental and epileptic encephalopathy and have elucidated the role of atypical Rho GTPase RhoBTB in Drosophila neurological function and possibly dendrite development.


FAU Authors / FAU Editors

Fliedner, Anna
Lehrstuhl für Humangenetik
Gregor, Anne Dr. rer. nat.
Humangenetisches Institut
Grüner, Johanna
Medizinische Fakultät
Konrad, Enrico
Humangenetisches Institut
Sticht, Heinrich Prof. Dr.
Professur für Bioinformatik
Straub, Jonas
Humangenetisches Institut
Zweier, Christiane Prof. Dr.
Medizinische Fakultät


External institutions with authors

Ambry Genetics
Boston Children's Hospital
Centre Hospitalier Régional Universitaire de TOURS
Children's Hospital of Philadelphia
Cook Children's Health Care System
Duke University
GeneDX
Maastricht University
Maxima Medisch Centrum MMC Veldhoven
Sheffield Children's NHS Foundation Trust
University of Toronto


How to cite

APA:
Straub, J., Konrad, E., Grüner, J., Toutain, A., Bok, L.A., Cho, M.T.,... Zweier, C. (2018). Missense Variants in RHOBTB2 Cause a Developmental and Epileptic Encephalopathy in Humans, and Altered Levels Cause Neurological Defects in Drosophila. American Journal of Human Genetics, 102(1), 44-57. https://dx.doi.org/10.1016/j.ajhg.2017.11.008

MLA:
Straub, Jonas, et al. "Missense Variants in RHOBTB2 Cause a Developmental and Epileptic Encephalopathy in Humans, and Altered Levels Cause Neurological Defects in Drosophila." American Journal of Human Genetics 102.1 (2018): 44-57.

BibTeX: 

Last updated on 2019-16-01 at 06:02