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

Straub, Jonas; Konrad, Enrico D.H.; Grüner, Johanna; Toutain, Annick; Bok, Levinus A.; Cho, Megan T.; Crawford, Heather P.; Dubbs, Holly; Douglas, Ganka; Jobling, Rebekah; Johnson, Diana; Krock, Bryan L.; Mikati, Mohamad A.; Nesbitt, Addie I.; Nicolai, Joost; Phillips, Meredith; Poduri, Annapurna; Ortiz-González, Xilma R.; Powis, Zöe; Santani, Avni; Smith, Lacey; Stegmann, Alexander P.A.; Stumpel, Constance T. R. M.; Vreeburg, Maaike; Fliedner, Anna; Gregor, Anne; Sticht, Heinrich; Zweier, Christiane

doi:10.1016/j.ajhg.2017.11.008

Cited by 54 publications

(66 citation statements)

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“…RHOBTB2 mRNA levels are relatively high in mouse and human neuronal tissues, indicating possible roles in the nervous system (Ramos, Khademi, Somesh, & Rivero, ; St‐Pierre, Jiang, Egan, & Zacksenhaus, ). Consistent with this hypothesis, de novo missense variants in RHOBTB2 were very recently reported in 10 patients with EE (Straub et al., ). Transiently expressed mutant RHOBTB2 was more abundant than wild‐type RHOBTB2, probably because of impaired degradation in the proteasome, indicating that precise regulation of RHOBTB2 levels is essential for normal brain function (Straub et al., ).…”

Section: Clinical Features Of Individuals With De Novo Rhobtb2 Variantssupporting

confidence: 63%

“…Consistent with this hypothesis, de novo missense variants in RHOBTB2 were very recently reported in 10 patients with EE (Straub et al., ). Transiently expressed mutant RHOBTB2 was more abundant than wild‐type RHOBTB2, probably because of impaired degradation in the proteasome, indicating that precise regulation of RHOBTB2 levels is essential for normal brain function (Straub et al., ).…”

Section: Clinical Features Of Individuals With De Novo Rhobtb2 Variantssupporting

confidence: 63%

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De novo variants in RHOBTB2 , an atypical Rho GTPase gene, cause epileptic encephalopathy

et al. 2018

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By whole exome sequencing, we identified three de novo RHOBTB2 variants in three patients with epileptic encephalopathies (EEs). Interestingly, all three patients showed acute encephalopathy (febrile status epilepticus), with magnetic resonance imaging revealing hemisphere swelling or reduced diffusion in various brain regions. RHOBTB2 encodes Rho-related BTB domain-containing protein 2, an atypical Rho GTPase that is a substrate-specific adaptor or itself is a substrate for the Cullin-3 (CUL3)-based ubiquitin ligase complex. Transient expression experiments in Neuro-2a cells revealed that mutant RHOBTB2 was more abundant than wild-type RHOBTB2. Coexpression of CUL3 with RHOBTB2 decreased the level of wild-type RHOBTB2 but not the level of any of the three mutants, indicating impaired CUL3 complex-dependent degradation of the three mutants. These data indicate that RHOBTB2 variants are a rare genetic cause of EEs, in which acute encephalopathy might be a characteristic feature, and that precise regulation of RHOBTB2 levels is essential for normal brain function.

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Section: Clinical Features Of Individuals With De Novo Rhobtb2 Variantssupporting

confidence: 63%

Section: Clinical Features Of Individuals With De Novo Rhobtb2 Variantssupporting

confidence: 63%

De novo variants in RHOBTB2 , an atypical Rho GTPase gene, cause epileptic encephalopathy

et al. 2018

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“…Most patients presented with neonatal onset encephalopathies and most frequently had variants in KCNQ2 (n = 8) and SCN2A (n = 4). In nine patients, we identified variants in recently described genes such as GNAO1 , NPRL3 , NR2F1, and RHOBTB2 . These variants were not identified or reported clinically because of the time lag between research discovery and clinical testing incorporating new genes.…”

Section: Discussionmentioning

confidence: 99%

“…In nine patients, we identified variants in recently described genes such as GNAO1, 29 NPRL3, [30][31][32] NR2F1, 33 and RHOBTB2. 34 These variants were not identified or reported clinically because of the time lag between research discovery and clinical testing incorporating new genes. Recently, we have observed that some testing laboratories report candidate gene findings, which would make such findings available for assessment and correlation with the clinical phenotype.…”

Section: The Dynamic Landscape Of the Genetic Epilepsiesmentioning

confidence: 99%

Genetic diagnoses in epilepsy: The impact of dynamic exome analysis in a pediatric cohort

et al. 2020

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Objective We evaluated the yield of systematic analysis and/or reanalysis of whole exome sequencing (WES) data from a cohort of well‐phenotyped pediatric patients with epilepsy and suspected but previously undetermined genetic etiology. Methods We identified and phenotyped 125 participants with pediatric epilepsy. Etiology was unexplained at the time of enrollment despite clinical testing, which included chromosomal microarray (57 patients), epilepsy gene panel (n = 48), both (n = 28), or WES (n = 8). Clinical epilepsy diagnoses included developmental and epileptic encephalopathy (DEE), febrile infection‐related epilepsy syndrome, Rasmussen encephalitis, and other focal and generalized epilepsies. We analyzed WES data and compared the yield in participants with and without prior clinical genetic testing. Results Overall, we identified pathogenic or likely pathogenic variants in 40% (50/125) of our study participants. Nine patients with DEE had genetic variants in recently published genes that had not been recognized as epilepsy‐related at the time of clinical testing (FGF12, GABBR1, GABBR2, ITPA, KAT6A, PTPN23, RHOBTB2, SATB2), and eight patients had genetic variants in candidate epilepsy genes (CAMTA1, FAT3, GABRA6, HUWE1, PTCHD1). Ninety participants had concomitant or subsequent clinical genetic testing, which was ultimately explanatory for 26% (23/90). Of the 67 participants whose molecular diagnoses were "unsolved" through clinical genetic testing, we identified pathogenic or likely pathogenic variants in 17 (25%). Significance Our data argue for early consideration of WES with iterative reanalysis for patients with epilepsy, particularly those with DEE or epilepsy with intellectual disability. Rigorous analysis of WES data of well‐phenotyped patients with epilepsy leads to a broader understanding of gene‐specific phenotypic spectra as well as candidate disease gene identification. We illustrate the dynamic nature of genetic diagnosis over time, with analysis and in some cases reanalysis of exome data leading to the identification of disease‐associated variants among participants with previously nondiagnostic results from a variety of clinical testing strategies.

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“…Analysis of type 1b neuromuscular junctions (NMJs) of muscle 4 was performed as previously described 60 . Male L3 non-GFP larvae upon pan-neuronal manipulation (elav-GAL4/CyO-GFP;elav-GAL4) were dissected in PBST, fixated in 4% paraformaldehyde and stained with nc82 and anti-discs large antibodies (both from the Developmental Studies Hybridoma Bank, Iowa City, IA).…”

Section: Analysis Of Neuromuscular Junctions (Nmjs) From L3 Larvaementioning

confidence: 99%

Genetic interaction screen for severe neurodevelopmental disorders reveals a functional link between Ube3a and Mef2 in Drosophila melanogaster

Straub

Gregor

Sauerer

et al. 2020

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neurodevelopmental disorders (nDDs) are clinically and genetically extremely heterogeneous with shared phenotypes often associated with genes from the same networks. Mutations in TCF4, MEF2C, UBE3A, ZEB2 or ATRX cause phenotypically overlapping, syndromic forms of NDDs with severe intellectual disability, epilepsy and microcephaly. To characterize potential functional links between these genes/proteins, we screened for genetic interactions in Drosophila melanogaster. We induced ubiquitous or tissue specific knockdown or overexpression of each single orthologous gene (Da, Mef2, Ube3a, Zfh1, XNP) and in pairwise combinations. Subsequently, we assessed parameters such as lethality, wing and eye morphology, neuromuscular junction morphology, bang sensitivity and climbing behaviour in comparison between single and pairwise dosage manipulations. We found most stringent evidence for genetic interaction between Ube3a and Mef2 as simultaneous dosage manipulation in different tissues including glia, wing and eye resulted in multiple phenotype modifications. We subsequently found evidence for physical interaction between UBE3A and MEF2C also in human cells. Systematic pairwise assessment of the Drosophila orthologues of five genes implicated in clinically overlapping, severe NDDs and subsequent confirmation in a human cell line revealed interactions between UBE3A/Ube3a and MEF2C/Mef2, thus contributing to the characterization of the underlying molecular commonalities.

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

Cited by 54 publications

References 61 publications

De novo variants in RHOBTB2 , an atypical Rho GTPase gene, cause epileptic encephalopathy

De novo variants in RHOBTB2 , an atypical Rho GTPase gene, cause epileptic encephalopathy

Genetic diagnoses in epilepsy: The impact of dynamic exome analysis in a pediatric cohort

Genetic interaction screen for severe neurodevelopmental disorders reveals a functional link between Ube3a and Mef2 in Drosophila melanogaster

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