UBE3A/E6-AP mutations cause Angelman syndrome

Kishino, Tatsuya; Lalande, Marc; Wagstaff, Joseph

doi:10.1007/bf01876326

Cited by 398 publications

(512 citation statements)

References 4 publications

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“…1) [7]. 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][9][10][11].…”

Section: Genetic Etiology and Diagnosismentioning

confidence: 99%

Angelman Syndrome

et al. 2015

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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.Key Words Angelman syndrome . neurodevelopmental disorders . autism . ubiquitin ligase . Ube3a . Imprinting. Clinical OverviewIn 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 [1].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][3][4]). These features of AS can be seen in other neurodevelopmental disorders, leading to a broad differential diagnosis [5], which has recently been reviewed (Table 1) [6]. Overlapping clinical features may indicate common neurophysiological pathways,

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Section: Genetic Etiology and Diagnosismentioning

confidence: 99%

Angelman Syndrome

et al. 2015

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“…64,65 AS is usually associated with genetic abnormalities at an imprinted cluster containing UBE3A within 15q11-q13, and approximately 2-4% of the patients show epigenetic defects at this region, which include loss of methylation at the ICR at an imprinted bicistronic transcript encoding small nuclear ribonucleoprotein N (SNRPN) and SNRPN upstream reading frame (SNURF) (referred to as SNRPN) (Figure 2 and Table 1). [66][67][68] Among those, 92% are thought to have epigenetic mutations occurring in either oocytes or early embryos.…”

Section: Childhood Diseases Associated With Imprint Establishment or mentioning

confidence: 99%

Genomic imprinting and its relevance to congenital disease, infertility, molar pregnancy and induced pluripotent stem cell

Tomizawa

Sasaki

2012

J Hum Genet

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Genomic imprinting is an epigenetic gene-marking phenomenon that occurs in the germline, whereby genes are expressed from only one of the two parental copies in embryos and adults. Imprinting is essential for normal mammalian development and its disruption can cause various developmental defects and diseases. The process of imprinting in the germline involves DNA methylation of the imprint control regions (ICRs), and resulting parental-specific methylation imprints are maintained in the zygote and act as the marks controlling imprinted gene expression. Recent studies in mice have revealed new factors involved in imprint establishment during gametogenesis and maintenance during early development. Clinical studies have identified cases of imprinting disorders where involvement of factors shared by multiple ICRs for establishment or maintenance is suspected. These include Beckwith-Wiedemann syndrome, transient neonatal diabetes, Silver-Russell syndrome and others. More severe disruptions can lead to recurrent molar pregnancy, miscarriage or infertility. Imprinting defects may also occur during assisted reproductive technology or cell reprogramming. In this review, we summarize our current knowledge on the mechanisms of imprint establishment and maintenance, and discuss the relationship with various human disorders.

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“…Phenotypic presentation includes abnormal gait, frequent laughter, seizures, microcephaly, and craniofacial abnormalities. Despite the range of symptoms, individuals with AS are often recognized by a generally happy disposition [18,19]. AS affects between 1 in 15,000 and 1 in 40,000 individuals [20,21].…”

Section: Angelman Syndromementioning

confidence: 99%

“…UBE3A is involved in the ubiquitination of other proteins within the cell, thereby targeting them for degradation. Evidence suggests that UBE3A has 2 roles within the process of ubiquitination-the first in catalyzing complex formation and the second in recognizing substrate specificity [19,23,24].…”

Section: Angelman Syndromementioning

confidence: 99%

Discovery of Rare Mutations in Autism: Elucidating Neurodevelopmental Mechanisms

et al. 2015

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Autism spectrum disorder (ASD) is a group of highly genetic neurodevelopmental disorders characterized by language, social, cognitive, and behavioral abnormalities. ASD is a complex disorder with a heterogeneous etiology. The genetic architecture of autism is such that a variety of different rare mutations have been discovered, including rare monogenic conditions that involve autistic symptoms. Also, de novo copy number variants and single nucleotide variants contribute to disease susceptibility. Finally, autosomal recessive loci are contributing to our understanding of inherited factors. We will review the progress that the field has made in the discovery of these rare genetic variants in autism. We argue that mutation discovery of this sort offers an important opportunity to identify neurodevelopmental mechanisms in disease. The hope is that these mechanisms will show some degree of convergence that may be amenable to treatment intervention.

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UBE3A/E6-AP mutations cause Angelman syndrome

Cited by 398 publications

References 4 publications

Angelman Syndrome

Angelman Syndrome

Genomic imprinting and its relevance to congenital disease, infertility, molar pregnancy and induced pluripotent stem cell

Discovery of Rare Mutations in Autism: Elucidating Neurodevelopmental Mechanisms

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