TY - JOUR
T1 - Missense Variants in RHOBTB2 Cause a Developmental and Epileptic Encephalopathy in Humans, and Altered Levels Cause Neurological Defects in Drosophila
AU - Straub, Jonas
AU - Konrad, Enrico D. H.
AU - Gruner, Johanna
AU - Toutain, Annick
AU - Bok, Levinus A.
AU - Cho, Megan T.
AU - Crawford, Heather P.
AU - Dubbs, Holly
AU - Douglas, Ganka
AU - Jobling, Rebekah
AU - Johnson, Diana
AU - Krock, Bryan
AU - Mikati, Mohamad A.
AU - Nesbitt, Addie
AU - Nicolai, Joost
AU - Phillips, Meredith
AU - Poduri, Annapurna
AU - Ortiz-Gonzalez, Xilma R.
AU - Powis, Zoe
AU - Santani, Avni
AU - Smith, Lacey
AU - Stegmann, Alexander P. A.
AU - Stumpel, Constance
AU - Vreeburg, Maaike
AU - Fliedner, Anna
AU - Gregor, Anne
AU - Sticht, Heinrich
AU - Zweier, Christiane
AU - Deciphering Dev Disorders Study
PY - 2018/1/4
Y1 - 2018/1/4
N2 - 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 wildtype, 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.
AB - 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 wildtype, 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.
KW - SENSITIVE PARALYTIC MUTANTS
KW - AUTISM SPECTRUM DISORDERS
KW - UBIQUITIN LIGASE COMPLEX
KW - DE-NOVO MUTATIONS
KW - INTELLECTUAL DISABILITY
KW - MENTAL-RETARDATION
KW - SPINE MORPHOGENESIS
KW - TUMOR-SUPPRESSOR
KW - BREAST-CANCER
KW - RHO-GTPASES
U2 - 10.1016/j.ajhg.2017.11.008
DO - 10.1016/j.ajhg.2017.11.008
M3 - Article
SN - 0002-9297
VL - 102
SP - 44
EP - 57
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 1
ER -