scholarly journals Identification of disease-linked hyperactivating mutations in UBE3A through large-scale functional variant analysis

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Kellan P. Weston ◽  
Xiaoyi Gao ◽  
Jinghan Zhao ◽  
Kwang-Soo Kim ◽  
Susan E. Maloney ◽  
...  
Keyword(s):  
Angelman Syndrome ◽  
Large Scale ◽  
Phenotypic Diversity ◽  
Function Analysis ◽  
Genetic Disorders ◽  
Neurodevelopmental Disorder ◽  
Loss Of Function ◽  
Monogenic Disorders ◽  
Functional Variant ◽  
Variant Analysis

AbstractThe mechanisms that underlie the extensive phenotypic diversity in genetic disorders are poorly understood. Here, we develop a large-scale assay to characterize the functional valence (gain or loss-of-function) of missense variants identified in UBE3A, the gene whose loss-of-function causes the neurodevelopmental disorder Angelman syndrome. We identify numerous gain-of-function variants including a hyperactivating Q588E mutation that strikingly increases UBE3A activity above wild-type UBE3A levels. Mice carrying the Q588E mutation exhibit aberrant early-life motor and communication deficits, and individuals possessing hyperactivating UBE3A variants exhibit affected phenotypes that are distinguishable from Angelman syndrome. Additional structure-function analysis reveals that Q588 forms a regulatory site in UBE3A that is conserved among HECT domain ubiquitin ligases and perturbed in various neurodevelopmental disorders. Together, our study indicates that excessive UBE3A activity increases the risk for neurodevelopmental pathology and suggests that functional variant analysis can help delineate mechanistic subtypes in monogenic disorders.

scholarly journals BIOLOGICAL SCIENCES: Genetics

2018 ◽  
Author(s):  
Jack S. Hsiao ◽  
Noelle D. Germain ◽  
Andrea Wilderman ◽  
Christopher Stoddard ◽  
Luke A. Wojenski ◽  
...  
Keyword(s):  
Boundary Element ◽  
Angelman Syndrome ◽  
Antisense Transcript ◽  
Neurodevelopmental Disorder ◽  
Boundary Function ◽  
Paternal Allele ◽  
Loss Of Function ◽  
Maternal Allele ◽  
Specific Expression ◽  
Human Neurons

ABSTRACTAngelman syndrome (AS) is a severe neurodevelopmental disorder caused by the loss of function from the maternal allele of UBE3A, a gene encoding an E3 ubiquitin ligase. UBE3A is only expressed from the maternally-inherited allele in mature human neurons due to tissue-specific genomic imprinting. Imprinted expression of UBE3A is restricted to neurons by expression of UBE3A antisense transcript (UBE3A-ATS) from the paternally-inherited allele, which silences the paternal allele of UBE3A in cis. However, the mechanism restricting UBE3A-ATS expression and UBE3A imprinting to neurons is not understood. We used CRISPR/Cas9-mediated genome editing to functionally define a bipartite boundary element critical for neuron-specific expression of UBE3A-ATS in humans. Removal of this element led to upregulation of UBE3A-ATS without repressing paternal UBE3A. However, increasing expression of UBE3A-ATS in the absence of the boundary element resulted in full repression of paternal UBE3A, demonstrating that UBE3A imprinting requires both the loss of function from the boundary element as well as upregulation of UBE3A-ATS. These results suggest that manipulation of the competition between UBE3A-ATS and UBE3A may provide a potential therapeutic approach for AS.SIGNIFICANCE STATEMENTAngelman syndrome is a neurodevelopmental disorder caused by loss of function from the maternal allele of UBE3A, an imprinted gene. The paternal allele of UBE3A is silenced by a long, non-coding antisense transcript in mature neurons. We have identified a boundary element that stops the transcription of the antisense transcript in human pluripotent stem cells, and thus restricts UBE3A imprinted expression to neurons. We further determined that UBE3A imprinting requires both the loss of the boundary function and sufficient expression of the antisense transcript to silence paternal UBE3A. These findings provide essential details about the mechanisms of UBE3A imprinting that may suggest additional therapeutic approaches for Angelman syndrome.

scholarly journals Deleting a UBE3A substrate rescues impaired hippocampal physiology and learning in Angelman syndrome mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Gabrielle L. Sell ◽  
Wendy Xin ◽  
Emily K. Cook ◽  
Mark A. Zbinden ◽  
Thomas B. Schaffer ◽  
...  
Keyword(s):  
Angelman Syndrome ◽  
Developmental Disorders ◽  
Motor Coordination ◽  
Synapse Formation ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Loss Of Function ◽  
Behavioral Deficits ◽  
Altered Expression ◽  
Exciting Potential

AbstractIn humans, loss-of-function mutations in the UBE3A gene lead to the neurodevelopmental disorder Angelman syndrome (AS). AS patients have severe impairments in speech, learning and memory, and motor coordination, for which there is currently no treatment. In addition, UBE3A is duplicated in > 1–2% of patients with autism spectrum disorders—a further indication of the significant role it plays in brain development. Altered expression of UBE3A, an E3 ubiquitin ligase, is hypothesized to lead to impaired levels of its target proteins, but identifying the contribution of individual UBE3A targets to UBE3A-dependent deficits remains of critical importance. Ephexin5 is a putative UBE3A substrate that has restricted expression early in development, regulates synapse formation during hippocampal development, and is abnormally elevated in AS mice, modeled by maternally-derived Ube3a gene deletion. Here, we report that Ephexin5 can be directly ubiquitylated by UBE3A. Furthermore, removing Ephexin5 from AS mice specifically rescued hippocampus-dependent behaviors, CA1 physiology, and deficits in dendritic spine number. Our findings identify Ephexin5 as a key driver of hippocampal dysfunction and related behavioral deficits in AS mouse models. These results demonstrate the exciting potential of targeting Ephexin5, and possibly other UBE3A substrates, to improve symptoms of AS and other UBE3A-related developmental disorders.

scholarly journals Seizure-like activity in a juvenile Angelman syndrome mouse model is attenuated by reducing Arc expression

2015 ◽  
Vol 112 (16) ◽  
pp. 5129-5134 ◽  
Author(s):  
Caleigh Mandel-Brehm ◽  
John Salogiannis ◽  
Sameer C. Dhamne ◽  
Alexander Rotenberg ◽  
Michael E. Greenberg
Keyword(s):  
Angelman Syndrome ◽  
Motor Coordination ◽  
Neural Circuit ◽  
Brain Activity ◽  
Neurodevelopmental Disorder ◽  
Ultrasonic Vocalizations ◽  
Therapeutic Interventions ◽  
Motor Deficits ◽  
Loss Of Function ◽  
Circuit Defects

Angelman syndrome (AS) is a neurodevelopmental disorder arising from loss-of-function mutations in the maternally inherited copy of the UBE3A gene, and is characterized by an absence of speech, excessive laughter, cognitive delay, motor deficits, and seizures. Despite the fact that the symptoms of AS occur in early childhood, behavioral characterization of AS mouse models has focused primarily on adult phenotypes. In this report we describe juvenile behaviors in AS mice that are strain-independent and clinically relevant. We find that young AS mice, compared with their wild-type littermates, produce an increased number of ultrasonic vocalizations. In addition, young AS mice have defects in motor coordination, as well as abnormal brain activity that results in an enhanced seizure-like response to an audiogenic challenge. The enhanced seizure-like activity, but not the increased ultrasonic vocalizations or motor deficits, is rescued in juvenile AS mice by genetically reducing the expression level of the activity-regulated cytoskeleton-associated protein, Arc. These findings suggest that therapeutic interventions that reduce the level of Arc expression have the potential to reverse the seizures associated with AS. In addition, the identification of aberrant behaviors in young AS mice may provide clues regarding the neural circuit defects that occur in AS and ultimately allow new approaches for treating this disorder.

scholarly journals Predicting functional effect of missense variants using graph attention neural networks

2021 ◽  
Author(s):  
Haicang Zhang ◽  
Michelle S. Xu ◽  
Wendy K. Chung ◽  
Yufeng Shen
Keyword(s):  
Neural Networks ◽  
Large Scale ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Loss Of Function ◽  
Sequencing Data ◽  
Missense Variants ◽  
Scale Population ◽  
Scan Data ◽  
Main Component

AbstractAccurate prediction of damaging missense variants is critically important for interpretating genome sequence. While many methods have been developed, their performance has been limited. Recent progress in machine learning and availability of large-scale population genomic sequencing data provide new opportunities to significantly improve computational predictions. Here we describe gMVP, a new method based on graph attention neural networks. Its main component is a graph with nodes capturing predictive features of amino acids and edges weighted by coevolution strength, which enables effective pooling of information from local protein sequence context and functionally correlated distal positions. Evaluated by deep mutational scan data, gMVP outperforms published methods in identifying damaging variants in TP53, PTEN, BRCA1, and MSH2. Additionally, it achieves the best separation of de novo missense variants in neurodevelopmental disorder cases from the ones in controls. Finally, the model supports transfer learning to optimize gain- and loss-of-function predictions in sodium and calcium channels. In summary, we demonstrate that gMVP can improve interpretation of missense variants in clinical testing and genetic studies.

scholarly journals Emerging Gene and Small Molecule Therapies for the Neurodevelopmental Disorder Angelman Syndrome

2021 ◽  
Author(s):  
Nycole A. Copping ◽  
Stephanie M. McTighe ◽  
Kyle D. Fink ◽  
Jill L. Silverman
Keyword(s):  
Small Molecule ◽  
Angelman Syndrome ◽  
Sleep Disturbances ◽  
Single Gene ◽  
Neurodevelopmental Disorder ◽  
The Body ◽  
Motor Deficits ◽  
Loss Of Function ◽  
Gene Therapies ◽  
High Prevalence

AbstractAngelman syndrome (AS) is a rare (~1:15,000) neurodevelopmental disorder characterized by severe developmental delay and intellectual disability, impaired communication skills, and a high prevalence of seizures, sleep disturbances, ataxia, motor deficits, and microcephaly. AS is caused by loss-of-function of the maternally inherited UBE3A gene. UBE3A is located on chromosome 15q11–13 and is biallelically expressed throughout the body but only maternally expressed in the brain due to an RNA antisense transcript that silences the paternal copy. There is currently no cure for AS, but advancements in small molecule drugs and gene therapies offer a promising approach for the treatment of the disorder. Here, we review AS and how loss-of-function of the maternal UBE3A contributes to the disorder. We also discuss the strengths and limitations of current animal models of AS. Furthermore, we examine potential small molecule drug and gene therapies for the treatment of AS and associated challenges faced by the therapeutic design. Finally, gene therapy offers the opportunity for precision medicine in AS and advancements in the treatment of this disorder can serve as a foundation for other single-gene neurodevelopmental disorders.

scholarly journals Deleting a UBE3A substrate rescues impaired hippocampal physiology and learning in Angelman syndrome mice

2019 ◽  
Author(s):  
Gabrielle L. Sell ◽  
Wendy Xin ◽  
Emily K. Cook ◽  
Mark A. Zbinden ◽  
Thomas B. Schaffer ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Angelman Syndrome ◽  
Developmental Disorders ◽  
Motor Coordination ◽  
Synapse Formation ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Loss Of Function ◽  
Altered Expression ◽  
Exciting Potential

ABSTRACTIn humans, loss-of-function mutations in the UBE3A gene lead to the neurodevelopmental disorder Angelman syndrome (AS). AS patients have severe impairments in speech, learning and memory, and motor coordination, for which there is currently no treatment. In addition, UBE3A is duplicated in >1-2% of patients with autism spectrum disorders – a further indication of the significant role it plays in brain development. Altered expression of UBE3A, an E3 ubiquitin ligase, is hypothesized to lead to impaired levels of its target proteins, but identifying the contribution of individual UBE3A targets to UBE3A-dependent deficits remains of critical importance. Ephexin5 is a putative UBE3A substrate that has restricted expression early in development, regulates synapse formation during hippocampal development, and is abnormally elevated in AS mice, modeled by maternally-derived Ube3a gene deletion. Here, we report that Ephexin5 is a direct substrate of UBE3A ubiquitin ligase activity. Furthermore, removing Ephexin5 from AS mice specifically rescued hippocampus-dependent behaviors, CA1 physiology, and deficits in dendritic spine number. Our findings identify Ephexin5 as a key driver of hippocampal dysfunction and related behavioral deficits in AS mouse models. These results demonstrate the exciting potential of targeting Ephexin5, and possibly other UBE3A substrates, to improve symptoms of AS and other UBE3A-related developmental disorders.

scholarly journals Understanding the Pathogenesis of Angelman Syndrome through Animal Models

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Nihar Ranjan Jana
Keyword(s):  
Animal Models ◽  
Angelman Syndrome ◽  
Neurodevelopmental Disorder ◽  
Synaptic Function ◽  
Loss Of Function ◽  
Disease Biology ◽  
Regulation Of Activity ◽  
Fundamental Insight ◽  
Motor Abnormalities ◽  
Activity Dependent

Angelman syndrome (AS) is a neurodevelopmental disorder characterized by severe mental retardation, lack of speech, ataxia, susceptibility to seizures, and unique behavioral features such as easily provoked smiling and laughter and autistic features. The disease is primarily caused by deletion or loss-of-function mutations of the maternally inheritedUBE3Agene located within chromosome 15q11-q13. TheUBE3Agene encodes a 100 kDa protein that functions as ubiquitin ligase and transcriptional coactivator. Emerging evidence now indicates that UBE3A plays a very important role in synaptic function and in regulation of activity-dependent synaptic plasticity. A number of animal models for AS have been generated to understand the disease pathogenesis. The most widely used model is theUBE3A-maternal-deficient mouse that recapitulates most of the essential features of AS including cognitive and motor abnormalities. This paper mainly discusses various animal models of AS and how these models provide fundamental insight into understanding the disease biology for potential therapeutic intervention.

scholarly journals An optical observational cluster mass function at z ∼ 1 with the ORELSE survey

2021 ◽  
Vol 502 (3) ◽  
pp. 3942-3954
Author(s):  
D Hung ◽  
B C Lemaux ◽  
R R Gal ◽  
A R Tomczak ◽  
L M Lubin ◽  
...  
Keyword(s):  
Monte Carlo ◽  
Large Scale ◽  
Near Infrared ◽  
Function Analysis ◽  
Voronoi Tessellation ◽  
Cosmological Parameters ◽  
Mass Range ◽  
Mass Function ◽  
Cluster Mass ◽  
Theoretical Mass

ABSTRACT We present a new mass function of galaxy clusters and groups using optical/near-infrared (NIR) wavelength spectroscopic and photometric data from the Observations of Redshift Evolution in Large-Scale Environments (ORELSE) survey. At z ∼ 1, cluster mass function studies are rare regardless of wavelength and have never been attempted from an optical/NIR perspective. This work serves as a proof of concept that z ∼ 1 cluster mass functions are achievable without supplemental X-ray or Sunyaev-Zel’dovich data. Measurements of the cluster mass function provide important contraints on cosmological parameters and are complementary to other probes. With ORELSE, a new cluster finding technique based on Voronoi tessellation Monte Carlo (VMC) mapping, and rigorous purity and completeness testing, we have obtained ∼240 galaxy overdensity candidates in the redshift range 0.55 < z < 1.37 at a mass range of 13.6 < log (M/M⊙) < 14.8. This mass range is comparable to existing optical cluster mass function studies for the local universe. Our candidate numbers vary based on the choice of multiple input parameters related to detection and characterization in our cluster finding algorithm, which we incorporated into the mass function analysis through a Monte Carlo scheme. We find cosmological constraints on the matter density, Ωm, and the amplitude of fluctuations, σ8, of $\Omega _{m} = 0.250^{+0.104}_{-0.099}$ and $\sigma _{8} = 1.150^{+0.260}_{-0.163}$. While our Ωm value is close to concordance, our σ8 value is ∼2σ higher because of the inflated observed number densities compared to theoretical mass function models owing to how our survey targeted overdense regions. With Euclid and several other large, unbiased optical surveys on the horizon, VMC mapping will enable optical/NIR cluster cosmology at redshifts much higher than what has been possible before.

Suppressors of a Cold-Sensitive Mutation in Yeast U4 RNA Define Five Domains in the Splicing Factor Prp8 That Influence Spliceosome Activation

Genetics ◽  
2000 ◽  
Vol 155 (4) ◽  
pp. 1667-1682 ◽  
Author(s):  
Andreas N Kuhn ◽  
David A Brow
Keyword(s):  
Large Scale ◽  
Splicing Factor ◽  
Cold Sensitivity ◽  
Splicing Factors ◽  
Loss Of Function ◽  
U1 Snrnp ◽  
Snrnp Protein ◽  
Cold Sensitive ◽  
Spliceosome Activation ◽  
U4 Rna

AbstractThe highly conserved splicing factor Prp8 has been implicated in multiple stages of the splicing reaction. However, assignment of a specific function to any part of the 280-kD U5 snRNP protein has been difficult, in part because Prp8 lacks recognizable functional or structural motifs. We have used a large-scale screen for Saccharomyces cerevisiae PRP8 alleles that suppress the cold sensitivity caused by U4-cs1, a mutant U4 RNA that blocks U4/U6 unwinding, to identify with high resolution five distinct regions of PRP8 involved in the control of spliceosome activation. Genetic interactions between two of these regions reveal a potential long-range intramolecular fold. Identification of a yeast two-hybrid interaction, together with previously reported results, implicates two other regions in direct and indirect contacts to the U1 snRNP. In contrast to the suppressor mutations in PRP8, loss-of-function mutations in the genes for two other splicing factors implicated in U4/U6 unwinding, Prp44 (Brr2/Rss1/Slt22/Snu246) and Prp24, show synthetic enhancement with U4-cs1. On the basis of these results we propose a model in which allosteric changes in Prp8 initiate spliceosome activation by (1) disrupting contacts between the U1 snRNP and the U4/U6-U5 tri-snRNP and (2) orchestrating the activities of Prp44 and Prp24.

scholarly journals Emerging Role of ODC1 in Neurodevelopmental Disorders and Brain Development

Genes ◽  
2021 ◽  
Vol 12 (4) ◽  
pp. 470
Author(s):  
Jeremy W. Prokop ◽  
Caleb P. Bupp ◽  
Austin Frisch ◽  
Stephanie M. Bilinovich ◽  
Daniel B. Campbell ◽  
...  
Keyword(s):  
Brain Development ◽  
Neural Progenitor Cells ◽  
Neurodevelopmental Disorder ◽  
Fetal Brain ◽  
Missense Variant ◽  
Neural Progenitor ◽  
Loss Of Function ◽  
Gain Of Function ◽  
Systematic Analysis ◽  
Function Expression

Ornithine decarboxylase 1 (ODC1 gene) has been linked through gain-of-function variants to a rare disease featuring developmental delay, alopecia, macrocephaly, and structural brain anomalies. ODC1 has been linked to additional diseases like cancer, with growing evidence for neurological contributions to schizophrenia, mood disorders, anxiety, epilepsy, learning, and suicidal behavior. The evidence of ODC1 connection to neural disorders highlights the need for a systematic analysis of ODC1 genotype-to-phenotype associations. An analysis of variants from ClinVar, Geno2MP, TOPMed, gnomAD, and COSMIC revealed an intellectual disability and seizure connected loss-of-function variant, ODC G84R (rs138359527, NC_000002.12:g.10444500C > T). The missense variant is found in ~1% of South Asian individuals and results in 2.5-fold decrease in enzyme function. Expression quantitative trait loci (eQTLs) reveal multiple functionally annotated, non-coding variants regulating ODC1 that associate with psychiatric/neurological phenotypes. Further dissection of RNA-Seq during fetal brain development and within cerebral organoids showed an association of ODC1 expression with cell proliferation of neural progenitor cells, suggesting gain-of-function variants with neural over-proliferation and loss-of-function variants with neural depletion. The linkage from the expression data of ODC1 in early neural progenitor proliferation to phenotypes of neurodevelopmental delay and to the connection of polyamine metabolites in brain function establish ODC1 as a bona fide neurodevelopmental disorder gene.

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