In this review we summarize the clinical and genetic aspects of Angelman syndrome (AS), its molecular and cellular underpinnings, and current treatment strategies. AS is a neurodevelopmental disorder characterized by severe cognitive disability, motor dysfunction, speech impairment, hyperactivity, and frequent seizures. AS is caused by disruption of the maternally expressed and paternally imprinted UBE3A, which encodes an E3 ubiquitin ligase. Four mechanisms that render the maternally inherited UBE3A nonfunctional are recognized, the most common of which is deletion of the maternal chromosomal region 15q11-q13. Remarkably, duplication of the same chromosomal region is one of the few characterized persistent genetic abnormalities associated with autistic spectrum disorder, occurring in >1–2 % of all cases of autism spectrum disorder. While the overall morphology of the brain and connectivity of neural projections appear largely normal in AS mouse models, major functional defects are detected at the level of context-dependent learning, as well as impaired maturation of hippocampal and neocortical circuits. While these findings demonstrate a crucial role for ubiquitin protein ligase E3A in synaptic development, the mechanisms by which deficiency of ubiquitin protein ligase E3A leads to AS pathophysiology in humans remain poorly understood. However, recent efforts have shown promise in restoring functions disrupted in AS mice, renewing hope that an effective treatment strategy can be found.
In 1965, the English physician Harry Angelman described 3 patients who presented with a stiff, jerky gait, absence of speech, excessive laughter, and seizures. The disorder that came to bear his name [Angelman syndrome (AS)] is now recognized to affect approximately 1 in 15,000 individuals and is characterized by motor dysfunction, severe intellectual disability, speech impairment, seizures, hyperactivity, and autism spectrum disorder (ASD) as a common comorbidity .
Developmental delay in individuals with AS is usually observed within the first year of life. Though most individuals lack speech entirely, some who are mildly affected can acquire a few words. Receptive language is less impaired. Seizures occur in >80 % of patients, and onset is usually before the age of 3 years. Movement disorders include tremors, jerkiness, and ataxia. The characteristic behaviors of AS include mouthing of objects, happy demeanor with easily provoked laughter, attraction to water, hyperactivity, short attention span, and decreased sleeping (see recent reviews for more detailed description of the clinical phenotype [2–4]). These features of AS can be seen in other neurodevelopmental disorders, leading to a broad differential diagnosis , which has recently been reviewed (Table 1) . Overlapping clinical features may indicate common neurophysiological pathways, most of which remain to be elucidated. The diagnosis of AS should be confirmed molecularly, as discussed below, in order to provide accurate information regarding prognosis, complications, and risk of recurrence. Precision in diagnosis helps to inform future research endeavors by establishing the genotype–phenotype relationship more clearly and providing a foundation upon which the success of new therapies can be gauged.
Genetic Etiology and Diagnosis
Human genetic studies revealed that AS is caused by 4 molecular mechanisms: de novo maternal deletions of chromosome 15q11-q13 (70–80 %); intragenic mutations in the maternally inherited UBE3A within chromosome15q11-q13 (10–20 %); paternal uniparental disomy (UPD) for chromosome 15q11-q13 (3–5 %); or imprinting defects within chromosome 15q11-q13 that alter the expression of maternally inherited UBE3A (3–5 %) (Fig. 1) . While there is variability with each molecular class of AS, in general those with deletion have a more severe phenotype, and those with UPD and imprinting defects a less severe phenotype [2, 8–11].
The diagnostic algorithm described in Fig. 2 begins with testing to determine the DNA methylation status of chromosome 15q11-q13, not specifically UBE3A. A methylation pattern showing only the paternal imprinting pattern secures the diagnosis of AS, and further testing is needed to distinguish between deletion, UPD or an imprinting defect as the etiology. Fluorescent in situ hybridization determines if a deletion has occurred. Chromosomal microarray can further refine the deletion size, which has been shown to correlate with severity of clinical features [8, 11, 12]. For those whom deletion is excluded by fluorescent in situ hybridization, DNA marker analysis of the proband’s and parents’ chromosome 15q11-q13 region will confirm or exclude UPD. When both UPD and 15q11-q13 deletion have been excluded in an individual with abnormal DNA methylation, AS is therefore due to an imprinting defect, most of which are epigenetic phenomena, and a minority of which are caused by small imprinting center deletions or point mutations (testing for the latter is available on research basis). Abnormal DNA methylation is observed in 80–90 % of cases of AS. The remaining cases, which show a normal pattern of DNA methylation, are due to UBE3A point mutations or small intragenic rearrangements. UBE3A sequencing that returns normal excludes point mutations, but small deletions within UBE3A require multiplex ligation-dependent probe amplification for detection . While it was formerly believed that 10–15 % of cases of AS were due to an as-yet-unrecognized molecular etiology, it is more likely that these patients represent phenocopies and actually have other diagnoses, such as those listed in Table 1 [2, 6].
Within human chromosomal region 15q11-q13 there are maternally imprinted (i.e., paternally expressed) genes, paternally imprinted (i.e., maternally expressed) genes, and biallelically expressed genes (Fig. 1A). Mouse studies have shown Ube3a to be paternally imprinted in the brain and biallelically expressed in all other tissues that have been examined . This brain-specific imprinting of UBE3A is presumably found in humans as well [15, 16]. Moreover, within the brain there appears to be some regional or tissue-specific developmental control of Ube3a imprinting in neurons and restriction of imprinting to neurons (and not glia) in the central nervous system . The mechanism of this brain region-specific imprinting of Ube3a has just begun to be explored (as reviewed in [18, 19]). Recent evidence indicates that an antisense RNA transcript (ATS), Ube3a-ATS, is necessary for this brain-specific imprinting of Ube3a [20, 21]. Greater understanding of this imprinting mechanism is likely to provide important insight into new approaches for treating AS (see below).
Patients with AS harboring a deletion of the maternal copy of chromosome 15q11-q13 presumably display normal expression of the maternally imprinted genes from the normal paternal chromosome, very little UBE3A expression (in the brain), and hemizygous expression of genes that are typically expressed from both chromosomes. Patients with AS with UPD and imprinting defects are predicted to have elevated expression of the maternally imprinted genes and very little expression of UBE3A. Those harboring loss-of-function mutations in UBE3A presumably have normal expression of all other genes in the region and very little or defective ubiquitin protein ligase E3A (UBE3A) protein in the brain. While the commonality between these genetic etiologies is a loss of UBE3A activity, patients with AS due to a chromosomal deletion present with more severe phenotypes than those with AS due to other molecular etiologies [9, 10, 22, 23]. One possibility is that the other genes located within 15q11-q13 play significant roles in brain development. Insight into this comes from studies associating this chromosomal region, and possibly UBE3A, with ASD [24, 25].
AS and Autism
ASD is a complex neurological disorder characterized by impairment in social interactions and language/communication skills in combination with rigid, repetitive behaviors. Despite the high prevalence of ASD (recent reports indicate that as many as 1 in 68 children are born with ASD), a specific etiology is identified in <20 % of patients (as reviewed in ). Notwithstanding, there is a significant genetic component to ASD, as illustrated by the observation that 1) risk of recurrence is approximately 20 % for siblings, and 2) concordance for autism in monozygotic twins is 8 times higher than in dizygotic twins [27–31]. For this reason, considerable effort has been invested into identifying human genetic causes of ASD. Genetic abnormalities within chromosomal region 15q11-q13 are among the most prevalent of all mutations identified in ASD, accounting for approximately 1–2 % of all cases [32, 33]. Furthermore, recent reports indicate that copy number variants of 15q11-q13 are associated with autism . These data, together with the observation that individuals with AS often have a comorbid diagnosis of autism, suggest that mutation of UBE3A may play a role in the etiology of ASD. However, it remains to be determined whether changes in UBE3A expression itself are sufficient to cause autism.
AS Mouse Models
Mouse models generated by targeted inactivation of Ube3a provide additional support to the causative role of UBE3A mutations in AS [35, 36]. Upon inheritance of Ube3a deletion through the maternal but not the paternal germline, mice recapitulate many features of the human disorder, displaying impaired motor function, seizures, and deficits in context-dependent and spatial learning (summarized in Table 2 and discussed below). The observation that paternal imprinting of Ube3a occurs in mature neurons, but not in immature neurons, glia or non-nervous system tissues, reinforces the idea that the loss of UBE3A function in the central nervous system underlies AS pathology [14, 17, 35, 36, 45].
Maternal (and not paternal) deletion of Ube3a (referred to as Ube3a m–/p+) mediates the behavioral phenotypes. For the mouse models of AS caused by Ube3a maternal deletions, there is some phenotypic inconsistency, after accounting for genotype and background strain . Motor deficits on rotarod and beam balance tests have been seen consistently [25, 35, 36, 38, 39]. Differences in gait analysis, clasping, pole test, and tape removal are less consistently reported . Hypoactivity has been shown in the Ube3a m–/p+ animals both in an open field type of environment, reflected in slower speed and less distance travelled, and in water-maze testing, where slower swim speed is observed . Generally, Ube3a m–/p+ mice show decreased freezing in contextual fear conditioning and no deficit in cued fear conditioning, although the opposite has also been reported [35, 36, 38]. Depending on the strain and reporting laboratory, Ube3a m–/p+ mice may show a deficit in water-maze acquisition, testing, or reversal training [35, 36, 38, 42]. Anxiety phenotypes are reported, as shown by dark preferences in light–dark tests and lack of novel object preference, as well as preference for edges and increased freezing in open field-testing [38, 43]. Mice with AS bury fewer marbles than their wild-type controls . This robust and reproducible decrease in marble burying exhibited by mice with AS may indicate abnormal repetitive, compulsive, anxiety-driven behaviors, or motor dysfunction . Socially, Ube3a m–/p+ mice show reduced activity in social testing but not substantial social preference deficit [25, 38]. Finally, Ube3a m–/p+ animals show pathway-specific misregulation of dopaminergic release, potentially contributing to both reward and motor phenotypes in these animals, and informing clinical trials for levodopa and the use of stimulants in patients with AS . These animals are also prone to seizures depending on the background strain .
While many studies have focused on AS mouse models that only remove the maternal Ube3a, one group also worked toward generating a mouse model with a larger maternal deletion of mouse chromosome 7 that mirrors the human maternal deletion of chromosome 15q11-q13. Many of the phenotypes observed in this AS mouse model are the same as maternal deletion of Ube3a only: impaired rotarod performance, contextual fear conditioning deficit, water-maze deficits, communication deficits as measured by abnormal newborn isolation-induced ultrasonic vocalizations, seizures, and light–dark activity alterations . These data are consistent with the loss of UBE3A playing a significant role in AS etiology.
Several studies using mouse models duplicated for a portion of mouse chromosome 7 syntenic to the human chromosomal region 15q11-q13 indicate that an increase in Ube3a expression leads to mild but significant changes in neuronal function. Duplication of this chromosomal region specifically on the maternal allele leads to increased Ube3a expression with little effect on animal behavior , whereas the corresponding paternal duplication leads to alterations in behavior consistent with autism [24, 41]. An inconsistency between these 2 studies is that while relative levels of Ube3a mRNA are unchanged in the paternal duplication of this chromosomal region as expected, Ube3a protein level is unexpectedly elevated, suggesting that elevated Ube3a levels contribute to the observed phenotypes in these studies. Consistent with this, using a bacterial artificial chromosome recombination approach, mice harboring extra copies of only Ube3a exhibit impaired social behavior, decreased communication as measured by interaction-induced adult ultrasonic vocalizations (number and duration during males response to female urine and same sex pairs), and increased repetitive behavior as measured by increased grooming time . These animals do not exhibit anxiety, motor, memory, or sensory behavioral deficits. These studies imply that elevated UBE3A alone in patients with autism may be sufficient to give rise to several core autism-related behaviors. Continued efforts to understand the mechanistic pathways downstream of Ube3a will provide new insights into our understanding of how alterations in the cellular abundance of Ube3a protein may lead to neurological disorders related to autism.
Cellular and Molecular Underpinnings of AS
Despite the critical role that UBE3A plays in human cognitive function, relatively little is known about UBE3A’s role in human nervous system development or how the perturbation of UBE3A expression leads to the cognitive and language impairment underlying AS and ASD. The development of Ube3a-deficient mice has been especially useful for investigating the molecular and cellular events contributing to the pathophysiology of AS. As detailed above, Ube3a-deficient mice display phenotypes that correlate well with the human disorder, including impaired learning and memory, motor deficits, and seizures . While the overall morphology of the brain and connectivity of neural projections appears largely normal in Ube3a-deficient mice, defects are detected at the level of synapses. Ube3a-deficient mouse brains exhibit reduced density of dendritic spines (the location of >95 % of excitatory synapses) in both hippocampal and neocortical neurons [47, 48]. Consistent with Ube3a playing an important role in synaptic function, electrophysiological experiments have demonstrated that long-term potentiation and long-term depression are impaired in the hippocampus and neocortex of mice with AS [35, 42, 47, 49, 50]. Additionally, studies implicate Ube3a in experience-dependent visual cortical plasticity . Other studies have found that deletion of Ube3a also leads to changes in inhibitory synapse function . These findings suggest the intriguing hypothesis that AS may result from a fundamental defect in excitatory synapse development leading to lower numbers of functional excitatory and inhibitory synapses in the brain. While these experiments demonstrate a crucial role for Ube3a in synaptic transmission and suggest that the fundamental defect may be in synaptic function, the mechanisms by which Ube3a regulates synaptic function remain to be elucidated.
UBE3A encodes a HECT (homologous to the E6-AP carboxyl terminus) domain E3 ubiquitin ligase that catalyzes the addition of ubiquitin to lysine residues on substrate proteins, leading to the degradation of the ubiquitinated substrate protein [52–59]. Human genetic studies have identified several mutations that specifically disrupt the ubiquitin ligase activity of UBE3A while having no effect on protein expression or substrate interactions (Fig. 1) . Given that the ligase activity is important for the ubiquitination and degradation of target proteins, these observations suggest that disruption of UBE3A activity leads to inappropriately high levels of these target proteins and consequent neuronal dysfunction. While several candidate substrates have been discovered, AS-relevant targets leading to neural defects after UBE3A loss have yet to be identified [61, 62]. In addition, because UBE3A lies within a region of chromosome 15 that is duplicated in a subset of heterogeneous ASDs, it remains possible that altered levels of UBE3A substrates might be a mechanism relevant to the etiology of autism [34, 63].
Although the causative role for UBE3A mutations in AS has been appreciated since 1997, to date, no approach has been effective in significantly advancing our understanding of the molecular substrates of UBE3A relevant to synaptic dysfunction and disease etiology. Recent studies using Drosophila melanogaster have identified potential fly Dube3a substrates . In an attempt to take an unbiased approach to identify AS-relevant substrates of Ube3a, several laboratories have tried to compare the complement of ubiquitinated proteins in AS mouse brains with wild-type brains using quantitative mass spectrometry [52, 62, 65]. It is unclear from the results of these studies which substrates are affected directly or indirectly by Ube3a. More importantly, these studies have yet to evaluate the relevance of the identified substrates to the development of AS phenotypes. Such molecular studies are vital to our understanding of the mechanisms by which UBE3A functions. Future studies investigating the relevance of the discovered UBE3A substrates to the development of AS may shed light on the molecular pathogenesis of other neurodevelopmental disorders, such as ASDs.
At present, there is no specific treatment for AS. Treatment is supportive and includes 1) therapies to mitigate gross and fine motor delays; 2) augmentative communication strategies such as the use of communication devices, picture exchange cards, and modified sign language; and 3) intervention for comorbid ASD when present [2–4, 8–10]. The remainder of treatment is limited to managing the problems associated with AS . Gastrointestinal problems such as gastroesophageal reflux disease and constipation are managed with pharmacological agents when dietary modifications are insufficient. Sleep problems are treated with a combination of pharmacologic and behavioral interventions. Seizures are treated with anticonvulsants (valproic acid, clonazepam, lamotrigine and levetiracetam have greatest efficacy) and, rarely, ketogenic diet and vagal nerve stimulation are needed for seizures refractory to pharmacological intervention . Those with substantial hypopigmentation require skin and eye protection. Disruptive behaviors can usually be managed with a behavior modification program but the occasional patient with AS will require medications for aggressive behavior. Longitudinal care includes monitoring for scoliosis and anticipatory guidance regarding obesity (more common in the nondeletion group) [see also [2–4] (and the other citations in the second paragraph of “Clinical Overview”) for more detailed descriptions of clinical features and management].
Research and Development
Several clinical trials conducted thus far have produced negative results. Attempts to alter methylation of UBE3A using promethylation vitamin supplements to increase transcription from the paternal allele did not alter the phenotype of AS [68, 69]. Data analysis is in progress for a randomized, placebo-controlled trial using levodopa/carbidopa to treat AS (ClinicalTrials.gov identifier: NCT01281475). The rationale for this trial was based on the observations that levodopa influenced phosphorylation of calcium/calmodulin-dependent protein kinase II threonine residues in a rat model of Parkinson’s disease [70, 71]; the finding of dopaminergic neuronal loss in AS mouse models ; and a report of 2 adults with AS and Parkinsonian symptoms who responded to levodopa . Results of a short open-label trial of minocycline treatment (ClinicalTrials.gov identifier: NCT01531582) were recently published and suggest that small benefits could be possible .
Encouraging preclinical studies suggest that new avenues for treatment could open up in the near future. Several groups have attempted to reactivate the silenced paternal copy of Ube3a [74–76]. Large-scale small compound screening led to identification of the topoisomerase inhibitor topotecan as having the potential to activate Ube3a from the paternal allele [74, 76, 77]. While details of topotecan’s action remain to be elucidated, recent studies suggest that topotecan works by reducing the levels of Ube3a-ATS, thereby unsilencing the paternal allele of Ube3a. This may be accomplished through inhibition of topoisomerases, which relieves the torsional stress that results from the transcription of large transcripts thus blocking the production of the Ube3a-ATS or by stabilizing R-loops, or RNA–DNA hybrids, resulting in chromatin decondensation and Ube3a-ATS silencing [76, 77]. Another approach used antisense oligonucleotides to interfere with the Ube3a-ATS transcript, which mediates the silencing of the paternal allele . While some phenotypes were rescued by this approach in adulthood, including contextual fear testing, many were not, indicating that this restoration of Ube3A protein is insufficient for full rescue, owing to the developmental timing, protein level, or some other factor. However, this approach was effective in adult mice, suggesting that reactivation of Ube3a can reverse some behavioral deficits, even after several months of development with a defective copy of Ube3a. Whether the specificity of the antisense oligonucleotides for the target transcript limits systemic toxicity in humans remains to be tested. Drug delivery and blood–brain barrier considerations will be additional challenges to overcome. Alternative efforts to target key disrupted pathways in these AS mice, such as those mediated by calcium/calmodulin-dependent protein kinase II, Na/K-adenosine triphosphatase, activity-regulated cytoskeleton-associated protein and neuregulin-ErB4, for example, have met with some success in rescuing various phenotypes observed in mice with AS [42, 49, 50, 78]. Rescuing AS phenotypes through manipulation of Ube3a substrates have not yet been tested rigorously.
Loss of maternal Ube3a is a known cause of AS. While many deficits in neurons are known from the mouse model of AS the molecular pathophysiology in humans is poorly understood. An improved understanding will be vital to developing effective treatment approaches for AS. Given the apparent symptomatic overlap of AS with other neurodevelopmental disorders, including ASD, efforts towards understanding and treating AS are anticipated to be broadly applicable.
Williams CA, Beaudet AL, Clayton-Smith J, et al. Angelman syndrome 2005: updated consensus for diagnostic criteria. Am J Med Genet A 2006;140:413-418.
Bird LM. Angelman syndrome: review of clinical and molecular aspects. Appl Clin Genet 2014;7:93-104.
Dagli A, Buiting K, Williams CA. Molecular and clinical aspects of Angelman syndrome. Mol Syndromol 2012;2:100-112.
Williams CA, Driscoll DJ, Dagli AI. Clinical and genetic aspects of Angelman syndrome. Genet Med 2010;12:385-395.
Williams CA. Looks like Angelman syndrome but isn’t—What is in the differential? RCPU Newsl 2011;22.
Tan WH, Bird LM, Thibert RL, Williams CA. If not Angelman, what is it? A review of Angelman-like syndromes. Am J Med Genet A 2014;164A:975-992.
Kishino T, Lalande M, Wagstaff J. UBE3A/E6-AP mutations cause Angelman syndrome. Nat Genet 1997;15:70-73.
Peters SU, Horowitz L, Barbieri-Welge R, Taylor JL, Hundley RJ. Longitudinal follow-up of autism spectrum features and sensory behaviors in Angelman syndrome by deletion class. J Child Psychol Psychiatry 2012;53:152-159.
Gentile JK, Tan WH, Horowitz LT, et al. A neurodevelopmental survey of Angelman syndrome with genotype-phenotype correlations. J Dev Behav Pediatr 2010;31:592-601.
Tan WH, Bacino CA, Skinner SA, et al. Angelman syndrome: Mutations influence features in early childhood. Am J Med Genet A 2011;155A:81-90.
Valente KD, Varela MC, Koiffmann CP, et al. Angelman syndrome caused by deletion: a genotype-phenotype correlation determined by breakpoint. Epilepsy Res 2013;105:234-239.
Sahoo T, Peters SU, Madduri NS, et al. Microarray based comparative genomic hybridization testing in deletion bearing patients with Angelman syndrome: genotype–phenotype correlations. J Med Genet 2006;43:512-516.
Procter M, Chou LS, Tang W, Jama M, Mao R. Molecular diagnosis of Prader-Willi and Angelman syndromes by methylation-specific melting analysis and methylation-specific multiplex ligation-dependent probe amplification. Clin Chem 2006;52:1276-1283.
Albrecht U, Sutcliffe JS, Cattanach BM, et al. Imprinted expression of the murine Angelman syndrome gene, Ube3a, in hippocampal and Purkinje neurons. Nat Genet 1997;17:75-78.
Nakao M, Sutcliffe JS, Durtschi B, Mutirangura A, Ledbetter DH, Beaudet AL. Imprinting analysis of three genes in the Prader-Willi/Angelman region: SNRPN, E6-associated protein, and PAR-2 (D15S225E). Hum Mol Genet 1994;3:309-315.
Rougeulle C, Glatt H, Lalande M. The Angelman syndrome candidate gene, UBE3A/E6-AP, is imprinted in brain. Nat Genet 1997;17:14-15.
Judson MC, Sosa-Pagan JO, Del Cid WA, Han JE, Philpot BD. Allelic specificity of Ube3a expression in the mouse brain during postnatal development. J Comp Neurol 2014;522:1874-1896.
Chamberlain SJ. RNAs of the human chromosome 15q11-q13 imprinted region. Wiley Interdiscip Rev RNA 2013;4:155-166.
Mabb AM, Judson MC, Zylka MJ, Philpot BD. Angelman syndrome: insights into genomic imprinting and neurodevelopmental phenotypes. Trends Neurosci 2011;34:293-303.
Martins-Taylor K, Hsiao JS, Chen PF, et al. Imprinted expression of UBE3A in non-neuronal cells from a Prader-Willi syndrome patient with an atypical deletion. Hum Mol Genet 2014;23:2364-2373.
Meng L, Person RE, Huang W, Zhu PJ, Costa-Mattioli M, Beaudet AL. Truncation of Ube3a-ATS unsilences paternal Ube3a and ameliorates behavioral defects in the Angelman syndrome mouse model. PLoS Genet 2013;9:e1004039.
Mertz LG, Thaulov P, Trillingsgaard A, et al. Neurodevelopmental outcome in Angelman syndrome: genotype-phenotype correlations. Res Dev Disabil 2014;35:1742-1747.
Valente KD, Fridman C, Varela MC, et al. Angelman syndrome: uniparental paternal disomy 15 determines mild epilepsy, but has no influence on EEG patterns. Epilepsy Res 2005;67:163-168.
Nakatani J, Tamada K, Hatanaka F, et al. Abnormal behavior in a chromosome-engineered mouse model for human 15q11-13 duplication seen in autism. Cell 2009;137:1235-1246.
Smith SE, Zhou YD, Zhang G, Jin Z, Stoppel DC, Anderson MP. Increased gene dosage of Ube3a results in autism traits and decreased glutamate synaptic transmission in mice. Sci Transl Med 2011;3:103ra97.
Bhat S, Acharya UR, Adeli H, Bairy GM, Adeli A. Autism: cause factors, early diagnosis and therapies. Rev Neurosci 2014;25:841-850.
Folstein SE, Rosen-Sheidley B. Genetics of autism: complex aetiology for a heterogeneous disorder. Nat Rev Genet 2001;2:943-955.
Ozonoff S, Young GS, Carter A, et al. Recurrence risk for autism spectrum disorders: a Baby Siblings Research Consortium study. Pediatrics 2011;128:e488-e495.
Risch N, Hoffmann TJ, Anderson M, Croen LA, Grether JK, Windham GC. Familial recurrence of autism spectrum disorder: evaluating genetic and environmental contributions. Am J Psychiatry 2014;171:1206-1213.
Sandin S, Lichtenstein P, Kuja-Halkola R, Larsson H, Hultman CM, Reichenberg A. The familial risk of autism. JAMA 2014;311:1770-1777.
Wood CL, Warnell F, Johnson M, et al. Evidence for ASD recurrence rates and reproductive stoppage from large UK ASD research family databases. Autism Res 2015;8:73-81.
Sutcliffe JS, Jiang YH, Galijaard RJ, et al. The E6-Ap ubiquitin-protein ligase (UBE3A) gene is localized within a narrowed Angelman syndrome critical region. Genome Res 1997;7:368-377.
Cook EH, Jr., Lindgren V, Leventhal BL, et al. Autism or atypical autism in maternally but not paternally derived proximal 15q duplication. Am J Hum Genet 1997;60:928-934.
Glessner JT, Wang K, Cai G, et al. Autism genome-wide copy number variation reveals ubiquitin and neuronal genes. Nature 2009;459:569-573.
Jiang YH, Armstrong D, Albrecht U, et al. Mutation of the Angelman ubiquitin ligase in mice causes increased cytoplasmic p53 and deficits of contextual learning and long-term potentiation. Neuron 1998;21:799-811.
Miura K, Kishino T, Li E, et al. Neurobehavioral and electroencephalographic abnormalities in Ube3a maternal-deficient mice. Neurobiol Dis 2002;9:149-159.
Jiang YH, Pan Y, Zhu L, et al. Altered ultrasonic vocalization and impaired learning and memory in Angelman syndrome mouse model with a large maternal deletion from Ube3a to Gabrb3. PLoS One 2010;5:e12278.
Huang HS, Burns AJ, Nonneman RJ, et al. Behavioral deficits in an Angelman syndrome model: effects of genetic background and age. Behav Brain Res 2013;243:79-90.
Heck DH, Zhao Y, Roy S, LeDoux MS, Reiter LT. Analysis of cerebellar function in Ube3a-deficient mice reveals novel genotype-specific behaviors. Hum Mol Genet 2008;17:2181-2189.
Mulherkar SA, Jana NR. Loss of dopaminergic neurons and resulting behavioural deficits in mouse model of Angelman syndrome. Neurobiol Dis 2010;40:586-592.
Piochon C, Kloth AD, Grasselli G, et al. Cerebellar plasticity and motor learning deficits in a copy-number variation mouse model of autism. Nat Commun 2014;5:5586.
van Woerden GM, Harris KD, Hojjati MR, et al. Rescue of neurological deficits in a mouse model for Angelman syndrome by reduction of alphaCaMKII inhibitory phosphorylation. Nat Neurosci 2007;10:280-282.
Godavarthi SK, Dey P, Maheshwari M, Jana NR. Defective glucocorticoid hormone receptor signaling leads to increased stress and anxiety in a mouse model of Angelman syndrome. Hum Mol Genet 2012;21:1824-1834.
Riday TT, Dankoski EC, Krouse MC, et al. Pathway-specific dopaminergic deficits in a mouse model of Angelman syndrome. J Clin Invest 2012;122:4544-4554.
Gustin RM, Bichell TJ, Bubser M, et al. Tissue-specific variation of Ube3a protein expression in rodents and in a mouse model of Angelman syndrome. Neurobiol Dis 2010;39:283-291.
Deacon RM. Digging and marble burying in mice: simple methods for in vivo identification of biological impacts. Nat Protoc 2006;1:122-124.
Yashiro K, Riday TT, Condon KH, et al. Ube3a is required for experience-dependent maturation of the neocortex. Nat Neurosci 2009;12:777-783.
Dindot SV, Antalffy BA, Bhattacharjee MB, Beaudet AL. The Angelman syndrome ubiquitin ligase localizes to the synapse and nucleus, and maternal deficiency results in abnormal dendritic spine morphology. Hum Mol Genet 2008;17:111-118.
Kaphzan H, Hernandez P, Jung JI, et al. Reversal of impaired hippocampal long-term potentiation and contextual fear memory deficits in Angelman syndrome model mice by ErbB inhibitors. Biol Psychiatry 2012;72:182-190.
Kaphzan H, Buffington SA, Ramaraj AB, et al. Genetic reduction of the alpha1 subunit of Na/K-ATPase corrects multiple hippocampal phenotypes in Angelman syndrome. Cell Rep 2013;4:405-412.
Wallace ML, Burette AC, Weinberg RJ, Philpot BD. Maternal loss of Ube3a produces an excitatory/inhibitory imbalance through neuron type-specific synaptic defects. Neuron 2012;74:793-800.
Martinez-Noel G, Galligan JT, Sowa ME, et al. Identification and proteomic analysis of distinct UBE3A/E6AP protein complexes. Mol Cell Biol 2012;32:3095-3106.
Shirakura M, Murakami K, Ichimura T, et al. E6AP ubiquitin ligase mediates ubiquitylation and degradation of hepatitis C virus core protein. J Virol 2007;81:1174-1185.
Li L, Li Z, Howley PM, Sacks DB. E6AP and calmodulin reciprocally regulate estrogen receptor stability. J Biol Chem 2006;281:1978-1985.
Kao WH, Beaudenon SL, Talis AL, Huibregtse JM, Howley PM. Human papillomavirus type 16 E6 induces self-ubiquitination of the E6AP ubiquitin-protein ligase. J Virol 2000;74:6408-6417.
Huang L, Kinnucan E, Wang G, et al. Structure of an E6AP-UbcH7 complex: insights into ubiquitination by the E2-E3 enzyme cascade. Science 1999;286:1321-1326.
Oda H, Kumar S, Howley PM. Regulation of the Src family tyrosine kinase Blk through E6AP-mediated ubiquitination. Proc Natl Acad Sci U S A 1999;96:9557-9562.
Talis AL, Huibregtse JM, Howley PM. The role of E6AP in the regulation of p53 protein levels in human papillomavirus (HPV)-positive and HPV-negative cells. J Biol Chem 1998;273:6439-6445.
Matentzoglu K, Scheffner M. Ubiquitin ligase E6-AP and its role in human disease. Biochem Soc Trans 2008;36:797-801.
Cooper EM, Hudson AW, Amos J, Wagstaff J, Howley PM. Biochemical analysis of Angelman syndrome-associated mutations in the E3 ubiquitin ligase E6-associated protein. J Biol Chem 2004;279:41208-41217.
Margolis SS, Salogiannis J, Lipton DM, et al. EphB-mediated degradation of the RhoA GEF Ephexin5 relieves a developmental brake on excitatory synapse formation. Cell 2010;143:442-455.
Greer PL, Hanayama R, Bloodgood BL, et al. The Angelman Syndrome protein Ube3A regulates synapse development by ubiquitinating arc. Cell 2010;140:704-716.
Morrow EM, Yoo SY, Flavell SW, et al. Identifying autism loci and genes by tracing recent shared ancestry. Science 2008;321:218-223.
Jensen L, Farook MF, Reiter LT. Proteomic profiling in Drosophila reveals potential Dube3a regulation of the actin cytoskeleton and neuronal homeostasis. PLoS One 2013;8:e61952.
Low HL, Chi-Fung JC Chi-Chen KC, Tew WL, Hew CSin, Ken-Shiung C. Angelman syndrome: proteomics analysis of an UBE3A knockout mouse and its implications. Available at: http://www.intechopen.com/books/advanced-topics-in-neurological-disorders/angelman-syndrome-proteomics-analysis-of-an-ube3a-knockout-mouse-and-its-implications. Accessed May 22, 2015).
Thibert RL, Larson AM, Hsieh DT, Raby AR, Thiele EA. Neurologic manifestations of Angelman syndrome. Pediatr Neurol 2013;48:271-279.
Thibert RL, Conant KD, Braun EK, et al. Epilepsy in Angelman syndrome: a questionnaire-based assessment of the natural history and current treatment options. Epilepsia 2009;50:2369-2376.
Bird LM, Tan WH, Bacino CA, et al. A therapeutic trial of pro-methylation dietary supplements in Angelman syndrome. Am J Med Genet A 2011;155A:2956-2963.
Peters SU, Bird LM, Kimonis V, et al. Double-blind therapeutic trial in Angelman syndrome using betaine and folic acid. Am J Med Genet A 2010;152A:1994-2001.
Picconi B, Centonze D, Rossi S, Bernardi G, Calabresi P. Therapeutic doses of L-dopa reverse hypersensitivity of corticostriatal D2-dopamine receptors and glutamatergic overactivity in experimental parkinsonism. Brain 2004;127:1661-1669.
Brown AM, Deutch AY, Colbran RJ. Dopamine depletion alters phosphorylation of striatal proteins in a model of Parkinsonism. Eur J Neurosci 2005;22:247-256.
Harbord M. Levodopa responsive Parkinsonism in adults with Angelman Syndrome. J Clin Neurosci 2001;8:421-422.
Grieco JC, Ciarlone SL, Gieron-Korthals M, et al. An open-label pilot trial of minocycline in children as a treatment for Angelman syndrome. BMC Neurol 2014;14:232.
Huang HS, Allen JA, Mabb AM, et al. Topoisomerase inhibitors unsilence the dormant allele of Ube3a in neurons. Nature 2012;481:185-189.
Meng L, Ward AJ, Chun S, Bennett CF, Beaudet AL, Rigo F. Towards a therapy for Angelman syndrome by targeting a long non-coding RNA. Nature 2015;518:409-412.
King IF, Yandava CN, Mabb AM, et al. Topoisomerases facilitate transcription of long genes linked to autism. Nature 2013;501:58-62.
Powell WT, Coulson RL, Gonzales ML, et al. R-loop formation at Snord116 mediates topotecan inhibition of Ube3a-antisense and allele-specific chromatin decondensation. Proc Natl Acad Sci U S A 2013;110:13938-13943.
Mandel-Brehm C, Salogiannis J, Dhamne SC, Rotenberg A, Greenberg ME. Seizure-like activity in a juvenile Angelman syndrome mouse model is attenuated by reducing Arc expression. Proc Natl Acad Sci U S A 2015;112(16):5129-5134.
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Margolis, S.S., Sell, G.L., Zbinden, M.A. et al. Angelman Syndrome. Neurotherapeutics 12, 641–650 (2015). https://doi.org/10.1007/s13311-015-0361-y
- Angelman syndrome
- neurodevelopmental disorders
- ubiquitin ligase