RARE DISEASE
15q11q13 microduplication syndrome
15q11q13 microduplication syndrome
15q11q13 microduplication syndrome
Synonyms: 15q11q13 duplication syndrome, Dup(15)(q11q13), Trisomy 15q11q13
Synonyms: 15q11q13 duplication syndrome, Dup(15)(q11q13), Trisomy 15q11q13
Synonyms: 15q11q13 duplication syndrome, Dup(15)(q11q13), Trisomy 15q11q13
Drug discovery
1
drug
With orphan designation
Overview
15q11q13 Microduplication Syndrome is a neurodevelopmental disorder caused by maternal-origin duplications in the imprinted 15q11-q13 chromosomal region, spanning the Prader-Willi/Angelman critical region. Key features include hypotonia, intellectual disability, language delay, autism spectrum disorder (ASD), and treatment-resistant epilepsy. Variability in severity is linked to duplication type (interstitial vs. isodicentric) and parent of origin. Diagnosis involves cytogenetic testing, FISH, and methylation analysis. Multidisciplinary management focuses on symptom relief and developmental support [1][2][9].
Burden
High morbidity: Severe intellectual disability (70%), refractory epilepsy (50–70%), and ASD (60–80%) necessitate lifelong care [1][6][9].
Economic impact: Costs from multidisciplinary care, special education, and caregiver support [5][6].
Psychosocial strain: Increased familial stress due to behavioral challenges and variable prognosis [9][12].
Therapies
Symptomatic care: Antiseizure medications (e.g., valproate, lamotrigine), guided by video-EEG monitoring [1][6].
Developmental interventions: Early speech, physical, and occupational therapy; behavioral therapies for ASD [5][9].
Supportive care: Genetic counseling, psychiatric support for mood/psychosis, and cardiac surveillance [1][5].
Categories: rare developmental anomalies during embryogenesis, rare genetic diseases
Research Papers
42 drug discovery papers about 15q11q13 microduplication syndrome, with 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
42 drug discovery papers about 15q11q13 microduplication syndrome, with 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-04-17 | Real-world effectiveness of highly purified cannabidiol in epilepsy associated with 15q11.2-q13.1 duplication and deletion syndromes: A multicenter study.
This multicenter retrospective study evaluated the effectiveness and safety of highly purified cannabidiol (CBD) in 22 patients with 15q11.2-q13.1 duplication or deletion syndromes (15q-DDS), including 12 with 15q duplication syndrome (dup15q) and 10 with Angelman syndrome (AS). Median (interquartile range [IQR]) age at CBD initiation was 14.5 (10-22.5) years, with a median (IQR) follow-up of 21 (14-33) months. All dup15q and two AS patients presented with a Lennox-Gastaut phenotype. At last observation, mean seizure reduction was 55.7% (95% confidence interval 38.7-72.7), with 63.6% patients achieving ≥50% reduction, 40.9% achieving ≥75% reduction, and 18.2% achieving seizure freedom. Tonic seizures in dup15q and myoclonic seizures in AS showed the most notable reductions. EEG improvement was observed in 7/16 patients, with marked improvement observed in two dup15q patients. Clinical improvement on the Clinical Global Impression-Improvement scale was reported in 72.7%, alongside nonseizure benefits such as improved sleep, behavior, and attention in a subset of patients. CBD was well tolerated; no patient discontinued CBD due to side effects alone, and retention at last visit was 81.8%. These findings suggest that CBD may provide clinically meaningful benefit in patients with 15q-DDS, including seizure reduction and improvements in sleep, behavior, and attention in selected cases. PLAIN LANGUAGE SUMMARY: Epilepsy secondary to 15q11.2-q13.1 duplication or deletion syndromes (15q-DDS) is often severe, making daily life difficult for patients and their families. In this study, treatment with highly purified cannabidiol (CBD) reduced seizures in many patients with 15q-DDS. CBD was generally well tolerated, and caregivers also reported improvements in sleep, behavior, and attention in a number of cases. Overall, these findings suggest that CBD may be a helpful treatment option for people with 15q-DDS.
2026-01-06 | RO4938581, a GABAA-α5 negative allosteric modulator rescued behavioral and EEG phenotypes of a mouse model of Dup15q syndrome.
We investigated the correlation between increased gene copy number of gamma aminobutyric acid type A (GABAA) receptor α5-containing subunits and electrophysiological and behavioral phenotypes in a mouse model of Dup15q syndrome (15q dup) and tested the hypothesis that selectively inhibiting the activity of GABAA-α5 receptors may have therapeutic effects. Dup15q syndrome is a rare neurodevelopmental disorder caused by copy number gains of the 15q11.2-q13.1 chromosomal region, which includes UBE3A and a cluster of three genes (GABRA5, GABRB3, and GABRG3) encoding GABAA receptor subunits, all of which are critical for neural development and function. Most affected children display hypotonia, motor delays, intellectual disability, and epilepsy, as well as a characteristic electroencephalography (EEG) beta-band phenotype. There is no disease-modifying therapy available. Autoradiography showed increased density of GABAA-α5 receptors in the brains of 15q dup mice, while electrophysiology revealed enhanced GABAergic transmission in hippocampal slices from these mice. A GABAA-α5 negative allosteric modulator, RO4938581, decreased inhibitory synaptic charge transfer in 15q dup hippocampal slices. The behavioral analyses confirmed inflexibility in learning and abnormal social behaviors in 15q dup mice, and both phenotypes were normalized following chronic treatment with RO4938581. EEG recordings showed increased beta-power in 15q dup mice - which resembled the spectral signature of subjects with Dup15q - and was partially normalized following RO4938581 treatment. Our results suggest that excessive expression and function of the GABAA-α5 receptor subtype plays a key role in the pathophysiology of Dup15q and GABAA-α5 NAMs may represent a potential precision medicine therapeutic option.
2024-07-17 | Sleep EEG signatures in mouse models of 15q11.2-13.1 duplication (Dup15q) syndrome.
Sleep disturbances are a prevalent and complex comorbidity in neurodevelopmental disorders (NDDs). Dup15q syndrome (duplications of 15q11.2-13.1) is a genetic disorder highly penetrant for NDDs such as autism and intellectual disability and it is frequently accompanied by significant disruptions in sleep patterns. The 15q critical region harbors genes crucial for brain development, notably UBE3A and a cluster of gamma-aminobutyric acid type A receptor (GABAAR) genes. We previously described an electrophysiological biomarker of the syndrome, marked by heightened beta oscillations (12-30 Hz) in individuals with Dup15q syndrome, akin to electroencephalogram (EEG) alterations induced by allosteric modulation of GABAARs. Those with Dup15q syndrome exhibited increased beta oscillations during the awake resting state and during sleep, and they showed profoundly abnormal NREM sleep. This study aims to assess the translational validity of these EEG signatures and to delve into their neurobiological underpinnings by quantifying sleep physiology in chromosome-engineered mice with maternal (matDp/ + mice) or paternal (patDp/ + mice) inheritance of the full 15q11.2-13.1-equivalent duplication, and mice with duplication of just the UBE3A gene (Ube3a overexpression mice; Ube3a OE mice) and comparing the sleep metrics with their respective wildtype (WT) littermate controls. We collected 48-h EEG/EMG recordings from 35 (23 male, 12 female) 12-24-week-old matDp/ + , patDp/ + , Ube3a OE mice, and their WT littermate controls. We quantified baseline sleep, sleep fragmentation, spectral power dynamics during sleep states, and recovery following sleep deprivation. Within each group, distinctions between Dup15q mutant mice and WT littermate controls were evaluated using analysis of variance (ANOVA) and student's t-test. The impact of genotype and time was discerned through repeated measures ANOVA, and significance was established at p < 0.05. Our study revealed that across brain states, matDp/ + mice mirrored the elevated beta oscillation phenotype observed in clinical EEGs from individuals with Dup15q syndrome. Time to sleep onset after light onset was significantly reduced in matDp/ + and Ube3a OE mice. However, NREM sleep between Dup15q mutant and WT littermate mice remained unaltered, suggesting a divergence from the clinical presentation in humans. Additionally, while increased beta oscillations persisted in matDp/ + mice after 6-h of sleep deprivation, recovery NREM sleep remained unaltered in all groups, thus suggesting that these mice exhibit resilience in the fundamental processes governing sleep-wake regulation. Quantification of mechanistic and translatable EEG biomarkers is essential for advancing our understanding of NDDs and their underlying pathophysiology. Our study of sleep physiology in the Dup15q mice underscores that the beta EEG biomarker has strong translational validity, thus opening the door for pre-clinical studies of putative drug targets, using the biomarker as a translational measure of drug-target engagement. The unaltered NREM sleep may be due to inherent differences in neurobiology between mice and humans. These nuanced distinctions highlight the complexity of sleep disruptions in Dup15q syndrome and emphasize the need for a comprehensive understanding that encompasses both shared and distinct features between murine models and clinical populations.
2024-03-29 | Integration of CTCF Loops, Methylome, and Transcriptome in Differentiating LUHMES as a Model for Imprinting Dynamics of the 15q11-q13 Locus in Human Neurons
Human cell line models, including the neuronal precursor line LUHMES, are important for investigating developmental transcriptional dynamics within imprinted regions, particularly the 15q11-q13 Angelman (AS) and Prader-Willi (PWS) syndrome locus. AS results from loss of maternal UBE3A in neurons, where the paternal allele is silenced by a convergent antisense transcript UBE3A-ATS, a lncRNA that normally terminates at PWAR1 in non-neurons. qRTPCR analysis confirmed the exclusive and progressive increase in UBE3A-ATS in differentiating LUHMES neurons, validating their use for studying UBE3A silencing. Genome-wide transcriptome analyses revealed changes to 11,834 genes during neuronal differentiation, including the upregulation of most genes within the 15q11-q13 locus. To identify dynamic changes in chromatin loops linked to transcriptional activity, we performed a HiChIP validated by 4C, which identified two neuron-specific CTCF loops between MAGEL2-SNRPN and PWAR1-UBE3A. To determine if allele-specific differentially methylated regions (DMR) may be associated with CTCF loop anchors, whole genome long-read nanopore sequencing was performed. We identified a paternally hypomethylated DMR near the SNRPN upstream loop anchor exclusive to neurons and a paternally hypermethylated DMR near the PWAR1 CTCF anchor exclusive to undifferentiated cells, consistent with increases in neuronal transcription. Additionally, DMRs near CTCF loop anchors were observed in both cell types, indicative of allele-specific differences in chromatin loops regulating imprinted transcription. These results provide an integrated view of the 15q11-q13 epigenetic landscape during LUHMES neuronal differentiation, underscoring the complex interplay of transcription, chromatin looping, and DNA methylation. They also provide insights for future therapeutic approaches for AS and PWS.
2024-01-22 | UBE3A: The Role in Autism Spectrum Disorders (ASDs) and a Potential Candidate for Biomarker Studies and Designing Therapeutic Strategies.
Published reports from the CDC's Autism and Development Disabilities Monitoring Networks have shown that an average of 1 in every 44 (2.3%) 8-year-old children were estimated to have ASD in 2018. Many of the ASDs exhibiting varying degrees of autism-like phenotypes have chromosomal anomalies in the Chr15q11-q13 region. Numerous potential candidate genes linked with ASD reside in this chromosomal segment. However, several clinical, in vivo, and in vitro studies selected one gene more frequently than others randomly and unbiasedly. This gene codes for UBE3A or Ubiquitin protein ligase E3A [also known as E6AP ubiquitin-protein ligase (E6AP)], an enzyme involved in the cellular degradation of proteins. This gene has been listed as one of the several genes with a high potential of causing ASD in the Autism Database. The gain of function mutations, triplication, or duplication in the UBE3A gene is also associated with ASDs like Angelman Syndrome (AS) and Dup15q Syndrome. The genetic imprinting of UBE3A in the brain and a preference for neuronal maternal-specific expression are the key features of various ASDs. Since the UBE3A gene is involved in two main important diseases associated with autism-like symptoms, there has been widespread research going on in understanding the link between this gene and autism. Additionally, since no universal methodology or mechanism exists for identifying UBE3A-mediated ASD, it continues to be challenging for neurobiologists, neuroscientists, and clinicians to design therapies or diagnostic tools. In this review, we focus on the structure and functional aspects of the UBE3A protein, discuss the primary relevance of the 15q11-q13 region in the cause of ASDs, and highlight the link between UBE3A and ASD. We try to broaden the knowledge of our readers by elaborating on the possible mechanisms underlying UBE3A-mediated ASDs, emphasizing the usage of UBE3A as a prospective biomarker in the preclinical diagnosis of ASDs and discuss the positive outcomes, advanced developments, and the hurdles in the field of therapeutic strategies against UBE3A-mediated ASDs. This review is novel as it lays a very detailed and comprehensive platform for one of the most important genes associated with diseases showing autistic-like symptoms. Additionally, this review also attempts to lay optimistic feedback on the possible steps for the diagnosis, prevention, and therapy of these UBE3A-mediated ASDs in the upcoming years.
gene therapies
2024-08-15 | Elimination of the extra chromosome of Dup15q syndrome iPSCs for cellular and molecular investigation.
Chromosome 15q11.2-13.1 duplication (Dup15q) syndrome is one of the most common autism spectrum disorders (ASDs) associated with copy number variants (CNVs). For the analysis of CNV-relevant pathological cellular phenotypes, a CNV-corrected isogenic cell line is useful for excluding the influence of genetic background. Here, we devised a strategy to remove the isodicentric chromosome 15 by inserting a puro-ΔTK selection cassette into the extra chromosome using the CRISPR-Cas9 system, followed by a subsequent two-step drug selection. A series of assays, including qPCR-based copy number analysis and karyotype analysis, confirmed the elimination of the extra chromosome. Furthermore, cerebral organoids were generated from the parental Dup15q iPSCs and their isogenic iPSCs. scRNA-seq analysis revealed the alteration of expression levels in ion-channel-related genes and synapse-related genes in glutamatergic and GABAergic neurons in Dup15q organoids, respectively. The established isogenic cell line is a valuable resource for unraveling cellular and molecular alterations associated with Dup15q syndrome.
2021-08-03 | Genetic dissection identifies Necdin as a driver gene in a mouse model of paternal 15q duplications.
Maternally inherited duplication of chromosome 15q11-q13 (Dup15q) is a pathogenic copy number variation (CNV) associated with autism spectrum disorder (ASD). Recently, paternally derived duplication has also been shown to contribute to the development of ASD. The molecular mechanism underlying paternal Dup15q remains unclear. Here, we conduct genetic and overexpression-based screening and identify Necdin (Ndn) as a driver gene for paternal Dup15q resulting in the development of ASD-like phenotypes in mice. An excess amount of Ndn results in enhanced spine formation and density as well as hyperexcitability of cortical pyramidal neurons. We generate 15q dupΔNdn mice with a normalized copy number of Ndn by excising its one copy from Dup15q mice using a CRISPR-Cas9 system. 15q dupΔNdn mice do not show ASD-like phenotypes and show dendritic spine dynamics and cortical excitatory-inhibitory balance similar to wild type animals. Our study provides an insight into the role of Ndn in paternal 15q duplication and a mouse model of paternal Dup15q syndrome.
2020-09-18 | Specific ZNF274 binding interference at SNORD116 activates the maternal transcripts in Prader-Willi syndrome neurons.
Prader-Willi syndrome (PWS) is characterized by neonatal hypotonia, developmental delay and hyperphagia/obesity. This disorder is caused by the absence of paternally expressed gene products from chromosome 15q11-q13. We previously demonstrated that knocking out ZNF274, a Kruppel-associated box-A-domain zinc finger protein capable of recruiting epigenetic machinery to deposit the H3K9me3 repressive histone modification, can activate expression from the normally silent maternal allele of SNORD116 in neurons derived from PWS induced pluripotent stem cells (iPSCs). However, ZNF274 has many other targets in the genome in addition to SNORD116. Depleting ZNF274 will surely affect the expression of other important genes and disrupt other pathways. Here, we used CRISPR/Cas9 to delete ZNF274 binding sites at the SNORD116 locus to determine whether activation of the maternal copy of SNORD116 could be achieved without altering ZNF274 protein levels. We obtained similar activation of gene expression from the normally silenced maternal allele in neurons derived from PWS iPSCs, compared with ZNF274 knockout, demonstrating that ZNF274 is directly involved in the repression of SNORD116. These results suggest that interfering with ZNF274 binding at the maternal SNORD116 locus is a potential therapeutic strategy for PWS.
2020-06-14 | Specific ZNF274 binding interference at SNORD116 activates the maternal transcripts in Prader-Willi syndrome neurons
Abstract Prader-Willi syndrome (PWS) is characterized by neonatal hypotonia, developmental delay, and hyperphagia/obesity. This disorder is caused by the absence of paternally-expressed gene products from chromosome 15q11-q13. We previously demonstrated that knocking out ZNF274, a KRAB-domain zinc finger protein capable of recruiting epigenetic machinery to deposit the H3K9me3 repressive histone modification, can activate expression from the normally silent maternal allele of SNORD116 in neurons derived from PWS iPSCs. However, ZNF274 has many other targets in the genome in addition to SNORD116 . Depleting ZNF274 will surely affect the expression of other important genes and disrupt other pathways. Here we used CRISPR/Cas9 to delete ZNF274 binding sites at the SNORD116 locus to determine whether activation of the maternal copy of SNORD116 could be achieved without altering ZNF274 protein levels. We obtained similar activation of gene expression from the normally silenced maternal allele in neurons derived from PWS iPSCs, compared to ZNF274 knockout, demonstrating that ZNF274 is directly involved in the repression of SNORD116 . These results suggest that interfering with ZNF274 binding at the maternal SNORD116 locus is a potential therapeutic strategy for PWS.
oligonucleotides
2024-08-09 | Cell-type-specific effects of autism-associated 15q duplication syndrome in the human brain.
Recurrent copy-number variation represents one of the most well-established genetic drivers in neurodevelopmental disorders, including autism spectrum disorder. Duplication of 15q11-q13 (dup15q) is a well-described neurodevelopmental syndrome that increases the risk of autism more than 40-fold. However, the effects of this duplication on gene expression and chromatin accessibility in specific cell types in the human brain remain unknown. To identify the cell-type-specific transcriptional and epigenetic effects of dup15q in the human frontal cortex, we conducted single-nucleus RNA sequencing and multi-omic sequencing on dup15q-affected individuals (n = 6) as well as individuals with non-dup15q autism (n = 7) and neurotypical control individuals (n = 7). Cell-type-specific differential expression analysis identified significantly regulated genes, critical biological pathways, and differentially accessible genomic regions. Although there was overall increased gene expression across the duplicated genomic region, cellular identity represented an important factor mediating gene-expression changes. As compared to other cell types, neuronal subtypes showed greater upregulation of gene expression across a critical region within the duplication. Genes that fell within the duplicated region and had high baseline expression in control individuals showed only modest changes in dup15q, regardless of cell type. Of note, dup15q and autism had largely distinct signatures of chromatin accessibility but shared the majority of transcriptional regulatory motifs, suggesting convergent biological pathways. However, the transcriptional binding-factor motifs implicated in each condition implicated distinct biological mechanisms: neuronal JUN and FOS networks in autism vs. an inflammatory transcriptional network in dup15q microglia. This work provides a cell-type-specific analysis of how dup15q changes gene expression and chromatin accessibility in the human brain, and it finds evidence of marked cell-type-specific effects of this genetic driver. These findings have implications for guiding therapeutic development in dup15q syndrome, as well as understanding the functional effects of copy-number variants more broadly in neurodevelopmental disorders.
2023-04-18 | The role of UBE3A in the autism and epilepsy-related Dup15q syndrome using patient-derived, CRISPR-corrected neurons.
Chromosome 15q11-q13 duplication syndrome (Dup15q) is a neurodevelopmental disorder caused by maternal duplications of this region. Autism and epilepsy are key features of Dup15q. UBE3A, which encodes an E3 ubiquitin ligase, is likely a major driver of Dup15q because UBE3A is the only imprinted gene expressed solely from the maternal allele. Nevertheless, the exact role of UBE3A has not been determined. To establish whether UBE3A overexpression is required for Dup15q neuronal deficits, we generated an isogenic control line for a Dup15q patient-derived induced pluripotent stem cell line. Dup15q neurons exhibited hyperexcitability compared with control neurons, and this phenotype was generally prevented by normalizing UBE3A levels using antisense oligonucleotides. Overexpression of UBE3A resulted in a profile similar to that of Dup15q neurons except for synaptic phenotypes. These results indicate that UBE3A overexpression is necessary for most Dup15q cellular phenotypes but also suggest a role for other genes in the duplicated region.
2022-03-12 | The role ofUBE3Ain the autism and epilepsy-related Dup15q syndrome using patient-derived, CRISPR-corrected neurons
Abstract Chromosome 15q11-q13 duplication syndrome (Dup15q) is a neurodevelopmental disorder caused by maternal duplications of this region. Autism and epilepsy are key features of Dup15q, but affected individuals also exhibit intellectual disability and developmental delay. UBE3A , the gene encoding the ubiquitin protein ligase E3A, is likely a major driver of Dup15q because individuals with maternal, but not paternal 15q duplications have the disorder, and UBE3A is the only imprinted gene expressed solely from the maternal allele in mature neurons. Nevertheless, the exact role of UBE3A is yet to be determined. To establish whether UBE3A overexpression is required for Dup15q neuronal deficits, UBE3A expression was manipulated in patient-derived induced pluripotent stem cell (iPSC) lines using antisense oligonucleotides. Dup15q neurons exhibited hyperexcitability features compared to genome-edited isogenic control neurons, and this phenotype was generally prevented by normalizing UBE3A levels throughout in vitro development. Overexpression of UBE3A in an iPSC line with a paternal duplication resulted in a profile similar to that of Dup15q neurons except for synaptic phenotypes. These results indicate that UBE3A overexpression is necessary for most Dup15q cellular phenotypes. However, the inability of UBE3A overexpression to recapitulate synaptic phenotypes suggests an important role for non-imprinted genes in the disorder.
small molecules
2026-04-17 | Real-world effectiveness of highly purified cannabidiol in epilepsy associated with 15q11.2-q13.1 duplication and deletion syndromes: A multicenter study.
This multicenter retrospective study evaluated the effectiveness and safety of highly purified cannabidiol (CBD) in 22 patients with 15q11.2-q13.1 duplication or deletion syndromes (15q-DDS), including 12 with 15q duplication syndrome (dup15q) and 10 with Angelman syndrome (AS). Median (interquartile range [IQR]) age at CBD initiation was 14.5 (10-22.5) years, with a median (IQR) follow-up of 21 (14-33) months. All dup15q and two AS patients presented with a Lennox-Gastaut phenotype. At last observation, mean seizure reduction was 55.7% (95% confidence interval 38.7-72.7), with 63.6% patients achieving ≥50% reduction, 40.9% achieving ≥75% reduction, and 18.2% achieving seizure freedom. Tonic seizures in dup15q and myoclonic seizures in AS showed the most notable reductions. EEG improvement was observed in 7/16 patients, with marked improvement observed in two dup15q patients. Clinical improvement on the Clinical Global Impression-Improvement scale was reported in 72.7%, alongside nonseizure benefits such as improved sleep, behavior, and attention in a subset of patients. CBD was well tolerated; no patient discontinued CBD due to side effects alone, and retention at last visit was 81.8%. These findings suggest that CBD may provide clinically meaningful benefit in patients with 15q-DDS, including seizure reduction and improvements in sleep, behavior, and attention in selected cases. PLAIN LANGUAGE SUMMARY: Epilepsy secondary to 15q11.2-q13.1 duplication or deletion syndromes (15q-DDS) is often severe, making daily life difficult for patients and their families. In this study, treatment with highly purified cannabidiol (CBD) reduced seizures in many patients with 15q-DDS. CBD was generally well tolerated, and caregivers also reported improvements in sleep, behavior, and attention in a number of cases. Overall, these findings suggest that CBD may be a helpful treatment option for people with 15q-DDS.
2026-01-06 | RO4938581, a GABAA-α5 negative allosteric modulator rescued behavioral and EEG phenotypes of a mouse model of Dup15q syndrome.
We investigated the correlation between increased gene copy number of gamma aminobutyric acid type A (GABAA) receptor α5-containing subunits and electrophysiological and behavioral phenotypes in a mouse model of Dup15q syndrome (15q dup) and tested the hypothesis that selectively inhibiting the activity of GABAA-α5 receptors may have therapeutic effects. Dup15q syndrome is a rare neurodevelopmental disorder caused by copy number gains of the 15q11.2-q13.1 chromosomal region, which includes UBE3A and a cluster of three genes (GABRA5, GABRB3, and GABRG3) encoding GABAA receptor subunits, all of which are critical for neural development and function. Most affected children display hypotonia, motor delays, intellectual disability, and epilepsy, as well as a characteristic electroencephalography (EEG) beta-band phenotype. There is no disease-modifying therapy available. Autoradiography showed increased density of GABAA-α5 receptors in the brains of 15q dup mice, while electrophysiology revealed enhanced GABAergic transmission in hippocampal slices from these mice. A GABAA-α5 negative allosteric modulator, RO4938581, decreased inhibitory synaptic charge transfer in 15q dup hippocampal slices. The behavioral analyses confirmed inflexibility in learning and abnormal social behaviors in 15q dup mice, and both phenotypes were normalized following chronic treatment with RO4938581. EEG recordings showed increased beta-power in 15q dup mice - which resembled the spectral signature of subjects with Dup15q - and was partially normalized following RO4938581 treatment. Our results suggest that excessive expression and function of the GABAA-α5 receptor subtype plays a key role in the pathophysiology of Dup15q and GABAA-α5 NAMs may represent a potential precision medicine therapeutic option.
2024-07-17 | Sleep EEG signatures in mouse models of 15q11.2-13.1 duplication (Dup15q) syndrome.
Sleep disturbances are a prevalent and complex comorbidity in neurodevelopmental disorders (NDDs). Dup15q syndrome (duplications of 15q11.2-13.1) is a genetic disorder highly penetrant for NDDs such as autism and intellectual disability and it is frequently accompanied by significant disruptions in sleep patterns. The 15q critical region harbors genes crucial for brain development, notably UBE3A and a cluster of gamma-aminobutyric acid type A receptor (GABAAR) genes. We previously described an electrophysiological biomarker of the syndrome, marked by heightened beta oscillations (12-30 Hz) in individuals with Dup15q syndrome, akin to electroencephalogram (EEG) alterations induced by allosteric modulation of GABAARs. Those with Dup15q syndrome exhibited increased beta oscillations during the awake resting state and during sleep, and they showed profoundly abnormal NREM sleep. This study aims to assess the translational validity of these EEG signatures and to delve into their neurobiological underpinnings by quantifying sleep physiology in chromosome-engineered mice with maternal (matDp/ + mice) or paternal (patDp/ + mice) inheritance of the full 15q11.2-13.1-equivalent duplication, and mice with duplication of just the UBE3A gene (Ube3a overexpression mice; Ube3a OE mice) and comparing the sleep metrics with their respective wildtype (WT) littermate controls. We collected 48-h EEG/EMG recordings from 35 (23 male, 12 female) 12-24-week-old matDp/ + , patDp/ + , Ube3a OE mice, and their WT littermate controls. We quantified baseline sleep, sleep fragmentation, spectral power dynamics during sleep states, and recovery following sleep deprivation. Within each group, distinctions between Dup15q mutant mice and WT littermate controls were evaluated using analysis of variance (ANOVA) and student's t-test. The impact of genotype and time was discerned through repeated measures ANOVA, and significance was established at p < 0.05. Our study revealed that across brain states, matDp/ + mice mirrored the elevated beta oscillation phenotype observed in clinical EEGs from individuals with Dup15q syndrome. Time to sleep onset after light onset was significantly reduced in matDp/ + and Ube3a OE mice. However, NREM sleep between Dup15q mutant and WT littermate mice remained unaltered, suggesting a divergence from the clinical presentation in humans. Additionally, while increased beta oscillations persisted in matDp/ + mice after 6-h of sleep deprivation, recovery NREM sleep remained unaltered in all groups, thus suggesting that these mice exhibit resilience in the fundamental processes governing sleep-wake regulation. Quantification of mechanistic and translatable EEG biomarkers is essential for advancing our understanding of NDDs and their underlying pathophysiology. Our study of sleep physiology in the Dup15q mice underscores that the beta EEG biomarker has strong translational validity, thus opening the door for pre-clinical studies of putative drug targets, using the biomarker as a translational measure of drug-target engagement. The unaltered NREM sleep may be due to inherent differences in neurobiology between mice and humans. These nuanced distinctions highlight the complexity of sleep disruptions in Dup15q syndrome and emphasize the need for a comprehensive understanding that encompasses both shared and distinct features between murine models and clinical populations.
2024-03-29 | Integration of CTCF Loops, Methylome, and Transcriptome in Differentiating LUHMES as a Model for Imprinting Dynamics of the 15q11-q13 Locus in Human Neurons
Human cell line models, including the neuronal precursor line LUHMES, are important for investigating developmental transcriptional dynamics within imprinted regions, particularly the 15q11-q13 Angelman (AS) and Prader-Willi (PWS) syndrome locus. AS results from loss of maternal UBE3A in neurons, where the paternal allele is silenced by a convergent antisense transcript UBE3A-ATS, a lncRNA that normally terminates at PWAR1 in non-neurons. qRTPCR analysis confirmed the exclusive and progressive increase in UBE3A-ATS in differentiating LUHMES neurons, validating their use for studying UBE3A silencing. Genome-wide transcriptome analyses revealed changes to 11,834 genes during neuronal differentiation, including the upregulation of most genes within the 15q11-q13 locus. To identify dynamic changes in chromatin loops linked to transcriptional activity, we performed a HiChIP validated by 4C, which identified two neuron-specific CTCF loops between MAGEL2-SNRPN and PWAR1-UBE3A. To determine if allele-specific differentially methylated regions (DMR) may be associated with CTCF loop anchors, whole genome long-read nanopore sequencing was performed. We identified a paternally hypomethylated DMR near the SNRPN upstream loop anchor exclusive to neurons and a paternally hypermethylated DMR near the PWAR1 CTCF anchor exclusive to undifferentiated cells, consistent with increases in neuronal transcription. Additionally, DMRs near CTCF loop anchors were observed in both cell types, indicative of allele-specific differences in chromatin loops regulating imprinted transcription. These results provide an integrated view of the 15q11-q13 epigenetic landscape during LUHMES neuronal differentiation, underscoring the complex interplay of transcription, chromatin looping, and DNA methylation. They also provide insights for future therapeutic approaches for AS and PWS.
2024-01-22 | UBE3A: The Role in Autism Spectrum Disorders (ASDs) and a Potential Candidate for Biomarker Studies and Designing Therapeutic Strategies.
Published reports from the CDC's Autism and Development Disabilities Monitoring Networks have shown that an average of 1 in every 44 (2.3%) 8-year-old children were estimated to have ASD in 2018. Many of the ASDs exhibiting varying degrees of autism-like phenotypes have chromosomal anomalies in the Chr15q11-q13 region. Numerous potential candidate genes linked with ASD reside in this chromosomal segment. However, several clinical, in vivo, and in vitro studies selected one gene more frequently than others randomly and unbiasedly. This gene codes for UBE3A or Ubiquitin protein ligase E3A [also known as E6AP ubiquitin-protein ligase (E6AP)], an enzyme involved in the cellular degradation of proteins. This gene has been listed as one of the several genes with a high potential of causing ASD in the Autism Database. The gain of function mutations, triplication, or duplication in the UBE3A gene is also associated with ASDs like Angelman Syndrome (AS) and Dup15q Syndrome. The genetic imprinting of UBE3A in the brain and a preference for neuronal maternal-specific expression are the key features of various ASDs. Since the UBE3A gene is involved in two main important diseases associated with autism-like symptoms, there has been widespread research going on in understanding the link between this gene and autism. Additionally, since no universal methodology or mechanism exists for identifying UBE3A-mediated ASD, it continues to be challenging for neurobiologists, neuroscientists, and clinicians to design therapies or diagnostic tools. In this review, we focus on the structure and functional aspects of the UBE3A protein, discuss the primary relevance of the 15q11-q13 region in the cause of ASDs, and highlight the link between UBE3A and ASD. We try to broaden the knowledge of our readers by elaborating on the possible mechanisms underlying UBE3A-mediated ASDs, emphasizing the usage of UBE3A as a prospective biomarker in the preclinical diagnosis of ASDs and discuss the positive outcomes, advanced developments, and the hurdles in the field of therapeutic strategies against UBE3A-mediated ASDs. This review is novel as it lays a very detailed and comprehensive platform for one of the most important genes associated with diseases showing autistic-like symptoms. Additionally, this review also attempts to lay optimistic feedback on the possible steps for the diagnosis, prevention, and therapy of these UBE3A-mediated ASDs in the upcoming years.
gene therapies
2024-08-15 | Elimination of the extra chromosome of Dup15q syndrome iPSCs for cellular and molecular investigation.
Chromosome 15q11.2-13.1 duplication (Dup15q) syndrome is one of the most common autism spectrum disorders (ASDs) associated with copy number variants (CNVs). For the analysis of CNV-relevant pathological cellular phenotypes, a CNV-corrected isogenic cell line is useful for excluding the influence of genetic background. Here, we devised a strategy to remove the isodicentric chromosome 15 by inserting a puro-ΔTK selection cassette into the extra chromosome using the CRISPR-Cas9 system, followed by a subsequent two-step drug selection. A series of assays, including qPCR-based copy number analysis and karyotype analysis, confirmed the elimination of the extra chromosome. Furthermore, cerebral organoids were generated from the parental Dup15q iPSCs and their isogenic iPSCs. scRNA-seq analysis revealed the alteration of expression levels in ion-channel-related genes and synapse-related genes in glutamatergic and GABAergic neurons in Dup15q organoids, respectively. The established isogenic cell line is a valuable resource for unraveling cellular and molecular alterations associated with Dup15q syndrome.
2021-08-03 | Genetic dissection identifies Necdin as a driver gene in a mouse model of paternal 15q duplications.
Maternally inherited duplication of chromosome 15q11-q13 (Dup15q) is a pathogenic copy number variation (CNV) associated with autism spectrum disorder (ASD). Recently, paternally derived duplication has also been shown to contribute to the development of ASD. The molecular mechanism underlying paternal Dup15q remains unclear. Here, we conduct genetic and overexpression-based screening and identify Necdin (Ndn) as a driver gene for paternal Dup15q resulting in the development of ASD-like phenotypes in mice. An excess amount of Ndn results in enhanced spine formation and density as well as hyperexcitability of cortical pyramidal neurons. We generate 15q dupΔNdn mice with a normalized copy number of Ndn by excising its one copy from Dup15q mice using a CRISPR-Cas9 system. 15q dupΔNdn mice do not show ASD-like phenotypes and show dendritic spine dynamics and cortical excitatory-inhibitory balance similar to wild type animals. Our study provides an insight into the role of Ndn in paternal 15q duplication and a mouse model of paternal Dup15q syndrome.
2020-09-18 | Specific ZNF274 binding interference at SNORD116 activates the maternal transcripts in Prader-Willi syndrome neurons.
Prader-Willi syndrome (PWS) is characterized by neonatal hypotonia, developmental delay and hyperphagia/obesity. This disorder is caused by the absence of paternally expressed gene products from chromosome 15q11-q13. We previously demonstrated that knocking out ZNF274, a Kruppel-associated box-A-domain zinc finger protein capable of recruiting epigenetic machinery to deposit the H3K9me3 repressive histone modification, can activate expression from the normally silent maternal allele of SNORD116 in neurons derived from PWS induced pluripotent stem cells (iPSCs). However, ZNF274 has many other targets in the genome in addition to SNORD116. Depleting ZNF274 will surely affect the expression of other important genes and disrupt other pathways. Here, we used CRISPR/Cas9 to delete ZNF274 binding sites at the SNORD116 locus to determine whether activation of the maternal copy of SNORD116 could be achieved without altering ZNF274 protein levels. We obtained similar activation of gene expression from the normally silenced maternal allele in neurons derived from PWS iPSCs, compared with ZNF274 knockout, demonstrating that ZNF274 is directly involved in the repression of SNORD116. These results suggest that interfering with ZNF274 binding at the maternal SNORD116 locus is a potential therapeutic strategy for PWS.
2020-06-14 | Specific ZNF274 binding interference at SNORD116 activates the maternal transcripts in Prader-Willi syndrome neurons
Abstract Prader-Willi syndrome (PWS) is characterized by neonatal hypotonia, developmental delay, and hyperphagia/obesity. This disorder is caused by the absence of paternally-expressed gene products from chromosome 15q11-q13. We previously demonstrated that knocking out ZNF274, a KRAB-domain zinc finger protein capable of recruiting epigenetic machinery to deposit the H3K9me3 repressive histone modification, can activate expression from the normally silent maternal allele of SNORD116 in neurons derived from PWS iPSCs. However, ZNF274 has many other targets in the genome in addition to SNORD116 . Depleting ZNF274 will surely affect the expression of other important genes and disrupt other pathways. Here we used CRISPR/Cas9 to delete ZNF274 binding sites at the SNORD116 locus to determine whether activation of the maternal copy of SNORD116 could be achieved without altering ZNF274 protein levels. We obtained similar activation of gene expression from the normally silenced maternal allele in neurons derived from PWS iPSCs, compared to ZNF274 knockout, demonstrating that ZNF274 is directly involved in the repression of SNORD116 . These results suggest that interfering with ZNF274 binding at the maternal SNORD116 locus is a potential therapeutic strategy for PWS.
oligonucleotides
2024-08-09 | Cell-type-specific effects of autism-associated 15q duplication syndrome in the human brain.
Recurrent copy-number variation represents one of the most well-established genetic drivers in neurodevelopmental disorders, including autism spectrum disorder. Duplication of 15q11-q13 (dup15q) is a well-described neurodevelopmental syndrome that increases the risk of autism more than 40-fold. However, the effects of this duplication on gene expression and chromatin accessibility in specific cell types in the human brain remain unknown. To identify the cell-type-specific transcriptional and epigenetic effects of dup15q in the human frontal cortex, we conducted single-nucleus RNA sequencing and multi-omic sequencing on dup15q-affected individuals (n = 6) as well as individuals with non-dup15q autism (n = 7) and neurotypical control individuals (n = 7). Cell-type-specific differential expression analysis identified significantly regulated genes, critical biological pathways, and differentially accessible genomic regions. Although there was overall increased gene expression across the duplicated genomic region, cellular identity represented an important factor mediating gene-expression changes. As compared to other cell types, neuronal subtypes showed greater upregulation of gene expression across a critical region within the duplication. Genes that fell within the duplicated region and had high baseline expression in control individuals showed only modest changes in dup15q, regardless of cell type. Of note, dup15q and autism had largely distinct signatures of chromatin accessibility but shared the majority of transcriptional regulatory motifs, suggesting convergent biological pathways. However, the transcriptional binding-factor motifs implicated in each condition implicated distinct biological mechanisms: neuronal JUN and FOS networks in autism vs. an inflammatory transcriptional network in dup15q microglia. This work provides a cell-type-specific analysis of how dup15q changes gene expression and chromatin accessibility in the human brain, and it finds evidence of marked cell-type-specific effects of this genetic driver. These findings have implications for guiding therapeutic development in dup15q syndrome, as well as understanding the functional effects of copy-number variants more broadly in neurodevelopmental disorders.
2023-04-18 | The role of UBE3A in the autism and epilepsy-related Dup15q syndrome using patient-derived, CRISPR-corrected neurons.
Chromosome 15q11-q13 duplication syndrome (Dup15q) is a neurodevelopmental disorder caused by maternal duplications of this region. Autism and epilepsy are key features of Dup15q. UBE3A, which encodes an E3 ubiquitin ligase, is likely a major driver of Dup15q because UBE3A is the only imprinted gene expressed solely from the maternal allele. Nevertheless, the exact role of UBE3A has not been determined. To establish whether UBE3A overexpression is required for Dup15q neuronal deficits, we generated an isogenic control line for a Dup15q patient-derived induced pluripotent stem cell line. Dup15q neurons exhibited hyperexcitability compared with control neurons, and this phenotype was generally prevented by normalizing UBE3A levels using antisense oligonucleotides. Overexpression of UBE3A resulted in a profile similar to that of Dup15q neurons except for synaptic phenotypes. These results indicate that UBE3A overexpression is necessary for most Dup15q cellular phenotypes but also suggest a role for other genes in the duplicated region.
2022-03-12 | The role ofUBE3Ain the autism and epilepsy-related Dup15q syndrome using patient-derived, CRISPR-corrected neurons
Abstract Chromosome 15q11-q13 duplication syndrome (Dup15q) is a neurodevelopmental disorder caused by maternal duplications of this region. Autism and epilepsy are key features of Dup15q, but affected individuals also exhibit intellectual disability and developmental delay. UBE3A , the gene encoding the ubiquitin protein ligase E3A, is likely a major driver of Dup15q because individuals with maternal, but not paternal 15q duplications have the disorder, and UBE3A is the only imprinted gene expressed solely from the maternal allele in mature neurons. Nevertheless, the exact role of UBE3A is yet to be determined. To establish whether UBE3A overexpression is required for Dup15q neuronal deficits, UBE3A expression was manipulated in patient-derived induced pluripotent stem cell (iPSC) lines using antisense oligonucleotides. Dup15q neurons exhibited hyperexcitability features compared to genome-edited isogenic control neurons, and this phenotype was generally prevented by normalizing UBE3A levels throughout in vitro development. Overexpression of UBE3A in an iPSC line with a paternal duplication resulted in a profile similar to that of Dup15q neurons except for synaptic phenotypes. These results indicate that UBE3A overexpression is necessary for most Dup15q cellular phenotypes. However, the inability of UBE3A overexpression to recapitulate synaptic phenotypes suggests an important role for non-imprinted genes in the disorder.
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Drug Discovery Landscape
1 orphan drug designation for 15q11q13 microduplication syndrome.
1 orphan drug designation for 15q11q13 microduplication syndrome.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Cannabidiol | small molecules | FDA | — | Benuvia Operations LLC |
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