<i>NBEA</i>: Developmental disease gene with early generalized epilepsy phenotypes

Mulhern, Maureen; Stumpel, Constance T. R. M.; Stong, Nicholas; Brunner, Han G.; Bier, Louise; Lippa, Natalie; Riviello, James J.; Rouhl, Rob P.W.; Kempers, Marlies; Pfundt, Rolph; Stegmann, Alexander P.A.; Kukolich, Mary K.; Telegrafi, Aida; Lehman, Anna; Lopez-Rangel, Elena; Houcinat, Nada; Barth, Magalie; Hollander, Nicolette den; Hoffer, Mariëtte J.V.; Weckhuysen, Sarah; Roovers, Jolien; Djémié, Tania; Barca, Diana; Ceulemans, Berten; Craiu, Dana; Lemke, Johannes R.; Korff, Christian; Mefford, Heather C; Meyers, Candace T.; Siegler, Zsuzsanna; Hiatt, Susan M.; Cooper, Gregory M.; Bebin, E. Martina; Blok, Lot Snijders; Veenstra‐Knol, Hermine E.; Baugh, Evan H.; Brilstra, Eva H.; Volker‐Touw, Catharina M.L.; Binsbergen, Ellen van; Revah‐Politi, Anya; Pereira, Elaine M.; McBrian, Danielle; Pacault, Mathilde; Isidor, Bertrand; Caignec, Cédric Le; Gilbert‐Dussardier, Brigitte; Bilan, Frédéric; Heinzen, Erin L.; Goldstein, David B.; Stevens, Servi J.C.; Sands, Tristan T.

doi:10.1002/ana.25350

Cited by 41 publications

(34 citation statements)

References 36 publications

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“…These CNVs included a large number of genes, but the phenotype of affected individuals was complex and we were unable to identify an association with known genetic syndromes or with candidate epilepsy genes. However, for one individual with EE and a large de novo 13q13.1‐q13.3 deletion, we can suggest that a key gene is NBEA , which was reported as a possible EE gene through an in silico prioritization approach and was recently associated with neurodevelopmental disease with epilepsy …”

Section: Discussionmentioning

confidence: 91%

“…However, for one individual with EE and a large de novo 13q13.1-q13.3 deletion, we can suggest that a key gene is NBEA, which was reported as a possible EE gene through an in silico prioritization approach 35 and was recently associated with neurodevelopmental disease with epilepsy. 36 Four of the CNVs we classified as large and pathogenic were inherited. Interestingly, a duplication on 12q21.31 was inherited from a mother with a family history of autism.…”

Section: Discussionmentioning

confidence: 99%

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Diagnostic implications of genetic copy number variation in epilepsy plus

et al. 2019

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Summary Objective Copy number variations ( CNV s) represent a significant genetic risk for several neurodevelopmental disorders including epilepsy. As knowledge increases, reanalysis of existing data is essential. Reliable estimates of the contribution of CNV s to epilepsies from sizeable populations are not available. Methods We assembled a cohort of 1255 patients with preexisting array comparative genomic hybridization or single nucleotide polymorphism array based CNV data. All patients had “epilepsy plus,” defined as epilepsy with comorbid features, including intellectual disability, psychiatric symptoms, and other neurological and nonneurological features. CNV classification was conducted using a systematic filtering workflow adapted to epilepsy. Results Of 1097 patients remaining after genetic data quality control, 120 individuals (10.9%) carried at least one autosomal CNV classified as pathogenic; 19 individuals (1.7%) carried at least one autosomal CNV classified as possibly pathogenic. Eleven patients (1%) carried more than one (possibly) pathogenic CNV . We identified CNV s covering recently reported ( HNRNPU ) or emerging ( RORB ) epilepsy genes, and further delineated the phenotype associated with mutations of these genes. Additional novel epilepsy candidate genes emerge from our study. Comparing phenotypic features of pathogenic CNV carriers to those of noncarriers of pathogenic CNV s, we show that patients with nonneurological comorbidities, especially dysmorphism, were more likely to carry pathogenic CNV s (odds ratio = 4.09, confidence interval = 2.51‐6.68; P = 2.34 × 10 −9 ). Meta‐analysis including data from published control groups showed that the presence or absence of epilepsy did not affect the detected frequency of CNV s. Significance The use of a specifically adapted workflow enabled identification of pathogenic autosomal CNV s in 10.9% of patients with epilepsy plus, which rose to 12.7% when we also considered possibly pathogenic CNV s. Our data indicate that epilepsy with comorbid features should be considered an indication for patients to be selected for a diagnostic algorithm including CNV detection. Collaborative large‐scale CNV reanalysis leads to novel declaration of pathogenicity in unexplained cases and can promote discovery of promising candidate epilepsy genes.

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Diagnostic implications of genetic copy number variation in epilepsy plus

et al. 2019

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“…Connexins likely rely on adaptor proteins to regulate their transport to the synapse. In a forward genetic screen using zebrafish, the epilepsy-and autism-associated gene Neurobeachin was identified as necessary for both electrical and chemical synapse formation (Iossifov et al, 2014;Miller et al, 2015;Mulhern et al, 2018). Neurobeachin is localized on vesicles which are found at the trans side of the Golgi, along dendrites, and also at chemical postsynapses (Wang et al, 2000;Miller et al, 2015).…”

Section: Trafficking Of Connexins Within Neuronal Compartmentsmentioning

confidence: 99%

Understanding the Molecular and Cell Biological Mechanisms of Electrical Synapse Formation

2020

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In this review article, we will describe the recent advances made towards understanding the molecular and cell biological mechanisms of electrical synapse formation. New evidence indicates that electrical synapses, which are gap junctions between neurons, can have complex molecular compositions including protein asymmetries across joined cells, diverse morphological arrangements, and overlooked similarities with other junctions, all of which indicate new potential roles in neurodevelopmental disease. Aquatic organisms, and in particular the vertebrate zebrafish, have proven to be excellent models for elucidating the molecular mechanisms of electrical synapse formation. Zebrafish will serve as our main exemplar throughout this review and will be compared with other model organisms. We highlight the known cell biological processes that build neuronal gap junctions and compare these with the assemblies of adherens junctions, tight junctions, non-neuronal gap junctions, and chemical synapses to explore the unknown frontiers remaining in our understanding of the critical and ubiquitous electrical synapse.

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“…NBEA encodes the brain-enriched scaffolding protein neurobeachin, which is involved in membrane trafficking and synaptic functioning [33]. It has been identified as a candidate gene for neurodevelopmental diseases, including autism [34]. All selection signals associated with NBEA were inside the gene and intronic.…”

Section: Microarray Data Analysismentioning

confidence: 99%

Genomic landscape of the signals of positive natural selection in populations of Northern Eurasia: A view from Northern Russia

et al. 2020

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Natural selection of beneficial genetic variants played a critical role in human adaptation to a wide range of environmental conditions. Northern Eurasia, despite its severe climate, is home to lots of ethnically diverse populations. The genetic variants associated with the survival of these populations have hardly been analyzed. We searched for the genomic signatures of positive selection in (1) the genome-wide microarray data of 432 people from eight different northern Russian populations and (2) the whole-genome sequences of 250 people from Northern Eurasia from a public repository through testing the extended haplotype homozigosity (EHH) and direct comparison of allele frequency, respectively. The 20 loci with the strongest selection signals were characterized in detail. Among the top EHH hits were the NRG3 and NBEA genes, which are involved in the development and functioning of the neural system, the PTPRM gene, which mediates cell-cell interactions and adhesion, and a region on chromosome 4 (chr4:28.7-28.9 Mb) that contained several loci affiliated with different classes of non-coding RNAs (RN7SL101P, MIR4275, MESTP3, and LINC02364). NBEA and the region on chromosome 4 were novel selection targets that were identified for the first time in Western Siberian populations. Cross-population comparisons of EHH profiles suggested a particular role for the chr4:28.7-28.9 Mb region in the local adaptation of Western Siberians. The strongest selection signal identified in Siberian sequenced genomes was formed by six SNPs on chromosome 11 (chr11:124.9-125.2 Mb). This region included well-known genes SLC37A2 and PKNOX2. SLC37A2 is most-highly expressed in the gut. Its expression is regulated by vitamin D, which is often deficient in northern regions. The PKNOX2 gene is a transcription factor of the homeobox family that is expressed in the brain and many other tissues. This gene is associated with alcohol addiction, which is widespread in many Northern Eurasian populations.

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NBEA: Developmental disease gene with early generalized epilepsy phenotypes

Cited by 41 publications

References 36 publications

Diagnostic implications of genetic copy number variation in epilepsy plus

Diagnostic implications of genetic copy number variation in epilepsy plus

Understanding the Molecular and Cell Biological Mechanisms of Electrical Synapse Formation

Genomic landscape of the signals of positive natural selection in populations of Northern Eurasia: A view from Northern Russia

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