Abnormal Behavior in a Chromosome- Engineered Mouse Model for Human 15q11-13 Duplication Seen in Autism

Nakatani, Jin; Tamada, Kota; Hatanaka, Fumiyuki; Ise, Satoko; Ohta, Hisashi; Inoue, Kiyoshi; Tomonaga, Shozo; Watanabe, Yasumasa; Chung, Yeun Jun; Banerjee, Ruby; Iwamoto, Kazuya; Kato, Takeshi; Okazawa, Makoto; Yamauchi, Kenta; Tanda, Koichi; Takao, Keizo; Miyakawa, Tsuyoshi; Bradley, Allan; Takumi, Toru

doi:10.1016/j.cell.2009.04.024

Cited by 442 publications

(467 citation statements)

References 59 publications

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“…Duplication of this chromosomal region specifically on the maternal allele leads to increased Ube3a expression with little effect on animal behavior [24], 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.…”

Section: As Mouse Modelsmentioning

confidence: 75%

“…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].…”

Section: Genetic Etiology and Diagnosismentioning

confidence: 99%

“…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 USV = ultrasonic vocalization *Maternal deletion described in [37] † Ube3a triplication described in [25] ‡ Maternal duplication described in [24] § Paternal duplication described in [24] and [41] 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.…”

Section: Cellular and Molecular Underpinnings Of Asmentioning

confidence: 99%

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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: As Mouse Modelsmentioning

confidence: 75%

Section: Genetic Etiology and Diagnosismentioning

confidence: 99%

Section: Cellular and Molecular Underpinnings Of Asmentioning

confidence: 99%

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Angelman Syndrome

et al. 2015

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“…These experimental approaches have yielded a number of important mouse models of human deletion disorders such as DiGeorge (Lindsay et al ., 1999) and Smith–Magenis syndrome (Walz et al ., 2003). Duplication disorders have also been modeled such as a 6‐Mb duplication on Chr 15q11‐13 seen in autism (Nakatani et al ., 2009). The very large Down's syndrome trisomy Chr21 was modeled by generating in ES cells duplications on three different mouse chromosomes corresponding to human chromosome 21 conserved linkage groups and crossing them into a single mouse line (Yu et al ., 2010).…”

Section: Introductionmentioning

confidence: 99%

Chromosome engineering in zygotes with CRISPR/Cas9

Boroviak

Doe

Banerjee

et al. 2016

Genesis

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SUMMARYDeletions, duplications, and inversions of large genomic regions covering several genes are an important class of disease causing variants in humans. Modeling these structural variants in mice requires multistep processes in ES cells, which has limited their availability. Mutant mice containing small insertions, deletions, and single nucleotide polymorphisms can be reliably generated using CRISPR/Cas9 directly in mouse zygotes. Large structural variants can be generated using CRISPR/Cas9 in ES cells, but it has not been possible to generate these directly in zygotes. We now demonstrate the direct generation of deletions, duplications and inversions of up to one million base pairs by zygote injection. genesis 54:78–85, 2016. © 2016 The Authors. genesis Published by Wiley Periodicals, Inc.

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“…We and others have previously used chromosome engineering (19) to model genetic alterations found in complex human diseases including cancer (20) and genomic disorders (21)(22)(23)(24), allowing identification of the causative gene and elucidation of the mechanism involved (20,(25)(26)(27). Here we used a similar approach to generate mouse models with deletion and duplication corresponding to those found in patients with 16p11.2 CNVs.…”

mentioning

confidence: 99%

Dosage-dependent phenotypes in models of 16p11.2 lesions found in autism

Horev

Ellegood²,

Lerch³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

313

342

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Recurrent copy number variations (CNVs) of human 16p11.2 have been associated with a variety of developmental/neurocognitive syndromes. In particular, deletion of 16p11.2 is found in patients with autism, developmental delay, and obesity. Patients with deletions or duplications have a wide range of clinical features, and siblings carrying the same deletion often have diverse symptoms. To study the consequence of 16p11.2 CNVs in a systematic manner, we used chromosome engineering to generate mice harboring deletion of the chromosomal region corresponding to 16p11.2, as well as mice harboring the reciprocal duplication. These 16p11.2 CNV models have dosage-dependent changes in gene expression, viability, brain architecture, and behavior. For each phenotype, the consequence of the deletion is more severe than that of the duplication. Of particular note is that half of the 16p11.2 deletion mice die postnatally; those that survive to adulthood are healthy and fertile, but have alterations in the hypothalamus and exhibit a "behavior trap" phenotype-a specific behavior characteristic of rodents with lateral hypothalamic and nigrostriatal lesions. These findings indicate that 16p11.2 CNVs cause brain and behavioral anomalies, providing insight into human neurodevelopmental disorders.Home-cage | stereotypic behavior | structural variation | brain MRI A ccumulating evidence suggests the importance of copy number variations (CNVs) in the etiology of neuropsychiatric disorders, including autism (1), schizophrenia (2-4), developmental delay (5), and other complex traits (6). The 16p11.2 region is particularly intriguing. Whereas deletion of 16p11.2 has been associated with autism (7-9), duplication of 16p11.2 has been associated with autism (9, 10) as well as schizophrenia (11). 16p11.2 CNVs have also been reported in patients with developmental delay, mental retardation, repetitive behaviors (12-16), and a highly penetrant form of obesity (17). A reciprocal effect of 16p11.2 dosage on head size has been noted, as deletions are associated with large head size or macrocephaly, whereas duplications are associated with microcephaly (16). These studies reveal the variability of symptoms in patients carrying the same 16p11.2 CNV, an extreme example being a family with three affected members with symptoms so heterogeneous that they were barely overlapping (18).Mouse models allow direct assessment of CNVs while reducing variability caused by genetic and environmental factors. We and others have previously used chromosome engineering (19) to model genetic alterations found in complex human diseases including cancer (20) and genomic disorders (21-24), allowing identification of the causative gene and elucidation of the mechanism involved (20,(25)(26)(27)). Here we used a similar approach to generate mouse models with deletion and duplication corresponding to those found in patients with 16p11.2 CNVs. Because of the evidence for clinical heterogeneity, we screened these models for multiple changes in brain anatomy and behavior by usin...

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Abnormal Behavior in a Chromosome- Engineered Mouse Model for Human 15q11-13 Duplication Seen in Autism

Cited by 442 publications

References 59 publications

Angelman Syndrome

Angelman Syndrome

Chromosome engineering in zygotes with CRISPR/Cas9

Dosage-dependent phenotypes in models of 16p11.2 lesions found in autism

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