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1.
Science ; 366(6472): 1486-1492, 2019 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-31857479

RESUMO

Disruptions in the ubiquitin protein ligase E3A (UBE3A) gene cause Angelman syndrome (AS). Whereas AS model mice have associated synaptic dysfunction and altered plasticity with abnormal behavior, whether similar or other mechanisms contribute to network hyperactivity and epilepsy susceptibility in AS patients remains unclear. Using human neurons and brain organoids, we demonstrate that UBE3A suppresses neuronal hyperexcitability via ubiquitin-mediated degradation of calcium- and voltage-dependent big potassium (BK) channels. We provide evidence that augmented BK channel activity manifests as increased intrinsic excitability in individual neurons and subsequent network synchronization. BK antagonists normalized neuronal excitability in both human and mouse neurons and ameliorated seizure susceptibility in an AS mouse model. Our findings suggest that BK channelopathy underlies epilepsy in AS and support the use of human cells to model human developmental diseases.


Assuntos
Síndrome de Angelman/metabolismo , Canais de Cálcio Tipo N/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Síndrome de Angelman/fisiopatologia , Animais , Epilepsia/metabolismo , Humanos , Camundongos , Modelos Neurológicos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Organoides , Bloqueadores dos Canais de Potássio/farmacologia , Bloqueadores dos Canais de Potássio/uso terapêutico , Convulsões/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitinação
2.
Medicine (Baltimore) ; 98(51): e18077, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31860958

RESUMO

RATIONALE: Angelman syndrome (AS) is an uncommon genetic disease characterized as serious retarded mental development and ocular abnormality. PATIENT CONCERNS: This report aims to present the ophthalmological features, and identify the diagnosis and outcomes of strabismus surgery in AS patients. DIAGNOSIS: Three children with exotropia were diagnosed with AS based on their typical clinical features. INTERVENTIONS: All patients underwent multiplex ligation-dependent probe amplification (MLPA) analysis and accepted lateral rectus recession surgery with the assistance of intravenous combined inhalation anesthesia. OUTCOMES: The maternal heritage deletion of chromosome 15q11.2-q13 was verified in all patients by MLPA. All patients with strabismus could not cooperate during the vision test, and had astigmatism. The strabismus type of AS patients was horizontal exotropia, and no vertical strabismus was found. One of these patients was combined with high myopia. The hypopigmentation on the hair and iris was ubiquitous. However, retina pigmentation was normal. After different degrees of lateral rectus recession, the exotropia was significantly relieved, and the surgical effects were stable postoperatively. LESSONS: Horizontal exotropia is the major strabismus type. Severe intellectual disability, hyperactivity, and speech impairment are the common characteristics of AS children. Its examination and operation design remains challenging. Thus, repeated examinations and intelligence rehabilitation are essential.


Assuntos
Síndrome de Angelman/diagnóstico , Exotropia/diagnóstico , Exotropia/cirurgia , Movimentos Oculares/fisiologia , Músculos Oculomotores/cirurgia , Procedimentos Cirúrgicos Oftalmológicos/métodos , Síndrome de Angelman/complicações , Criança , Pré-Escolar , China , Exotropia/complicações , Feminino , Humanos , Masculino , Músculos Oculomotores/fisiopatologia , Prognóstico , Doenças Raras , Recuperação de Função Fisiológica , Estrabismo/complicações , Estrabismo/diagnóstico , Estrabismo/cirurgia , Resultado do Tratamento , Testes Visuais
3.
Am J Med Genet A ; 179(11): 2317-2318, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31498953
4.
Codas ; 31(4): e20180177, 2019 Aug 22.
Artigo em Português, Inglês | MEDLINE | ID: mdl-31460569

RESUMO

PURPOSE: This study aimed to present findings on language, behavior, and neurodevelopment in a girl diagnosed with Angelman Syndrome, evaluated when she was three and eight years old. METHODS: The following evaluation instruments were used: Observation of Communication Behavior, Early Language Milestone (ELM) Scale, and Denver Developmental Screening Test, 2nd edition (DDST-II). RESULTS: In this case report, presence of AS phenotype signals such as wide mouth and wide-spaced teeth, tongue thrusting, strabismus, up slanting palpebral fissures, and sialorrhea are verified. Expressive and receptive deficits were verified in the language assessment, with the absence of orality and loss of comprehension with very similar performances in both evaluations. The ELM and DDST-II tests indicated severe impairment of all abilities evaluated at both three and eight years of age. Performance was quite similar in both evaluations in all areas of child development. Little progress was observed over time despite the great therapeutic and educational investment. CONCLUSION: The presence of a complex scenario such as AS demands high complexity clinical needs, a situation that is worsened due to scarcity of therapeutic resources that could minimize the harmful impacts of AS and culminate in increased quality of life for the AS population and their families.


Assuntos
Síndrome de Angelman/reabilitação , Transtornos do Neurodesenvolvimento/reabilitação , Síndrome de Angelman/diagnóstico , Síndrome de Angelman/psicologia , Criança , Desenvolvimento Infantil , Comunicação , Feminino , Humanos , Desenvolvimento da Linguagem , Testes de Linguagem , Transtornos do Neurodesenvolvimento/diagnóstico , Transtornos do Neurodesenvolvimento/psicologia , Testes Neuropsicológicos , Desempenho Psicomotor
6.
Artigo em Russo | MEDLINE | ID: mdl-31317896

RESUMO

AIM: Long continuous stretches of homozygosity (LCSH) are regularly detected in studies using molecular karyotyping (SNP array). Despite this type of variation being able to provide meaningful data on the parents' kinship, uniparental disomy and chromosome rearrangements, LCSH are rarely considered as a possible epigenetic cause of neurodevelopmental disorders. Despite their direct relationship to imprinting, LCSH in imprinted loci have not been considered in terms of pathogenicity. The present work is aimed at studying LCSH in chromosomal regions containing imprinted genes previously associated with disease in children with idiopathic intellectual disability, autism, congenital malformations and/or epilepsy. MATERIAL AND METHODS: Five hundred and four patients with autism spectrum disorders and intellectual disability were examined. RESULTS: LCSH affecting imprinted loci associated with various diseases were identified in 40 (7.9%) individuals. Chromosomal region 7q21.3 was affected in twenty three cases, 15q11.2 in twelve, 11p15.5 in five, 7q32.2 in four. Four patients had 2 LCSH affecting imprinted loci. Besides one LCSH in 7q31.33q32.3 (~4 Mbp) region, all LCSH were 1-1.6 Mbp. Clinically, these cases resembled the corresponding imprinting diseases (e.g. Silver-Russell, Beckwith-Wiedemann, Prader-Willi, Angelman syndromes). Parental kinship was identified in 8 cases (1.59%), which were not affected by LCSH at imprinted loci. CONCLUSION: The present study shows that LCSH affecting chromosomal regions 7q21.3, 7q32.2, 11p15.5 and 15p11.2 occur in about 7.9% of children with intellectual disability, autism, congenital malformations and/or epilepsy. Consequently, this type of epigenetic mutations is obviously common in a group of children with neurodevelopmental disorders. LCSH less than 2.5-10 Mbp are usually ignored in molecular karyotyping (SNP array) studies and, therefore, an important epigenetic cause of intellectual disability, autism or epilepsy with high probability remains without attention.


Assuntos
Síndrome de Angelman , Transtorno do Espectro Autista , Epigenômica , Deficiência Intelectual , Síndrome de Angelman/genética , Transtorno do Espectro Autista/genética , Criança , Humanos , Deficiência Intelectual/genética , Perda de Heterozigosidade
7.
Nat Neurosci ; 22(8): 1235-1247, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31235931

RESUMO

Mutations affecting the gene encoding the ubiquitin ligase UBE3A cause Angelman syndrome. Although most studies focus on the synaptic function of UBE3A, we show that UBE3A is highly enriched in the nucleus of mouse and human neurons. We found that the two major isoforms of UBE3A exhibit highly distinct nuclear versus cytoplasmic subcellular localization. Both isoforms undergo nuclear import through direct binding to PSMD4 (also known as S5A or RPN10), but the amino terminus of the cytoplasmic isoform prevents nuclear retention. Mice lacking the nuclear UBE3A isoform recapitulate the behavioral and electrophysiological phenotypes of Ube3am-/p+ mice, whereas mice harboring a targeted deletion of the cytosolic isoform are unaffected. Finally, we identified Angelman syndrome-associated UBE3A missense mutations that interfere with either nuclear targeting or nuclear retention of UBE3A. Taken together, our findings elucidate the mechanisms underlying the subcellular localization of UBE3A, and indicate that the nuclear UBE3A isoform is the most critical for the pathophysiology of Angelman syndrome.


Assuntos
Síndrome de Angelman/genética , Síndrome de Angelman/psicologia , Comportamento Animal , Ubiquitina-Proteína Ligases/genética , Animais , Proteínas de Transporte/metabolismo , Núcleo Celular/enzimologia , Núcleo Celular/genética , Citosol/enzimologia , Fenômenos Eletrofisiológicos/genética , Feminino , Humanos , Isoenzimas/genética , Masculino , Camundongos , Camundongos Knockout , Mutação de Sentido Incorreto/genética , Comportamento de Nidação , Neurônios/enzimologia , Desempenho Psicomotor , Natação/psicologia , Dedos de Zinco
8.
Transl Psychiatry ; 9(1): 166, 2019 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-31182707

RESUMO

Benefits of distributed learning strategies have been extensively described in the human literature, but minimally investigated in intellectual disability syndromes. We tested the hypothesis that training trials spaced apart in time could improve learning in two distinct genetic mouse models of neurodevelopmental disorders characterized by intellectual impairments. As compared to training with massed trials, spaced training significantly improved learning in both the Ts65Dn trisomy mouse model of Down syndrome and the maternally inherited Ube3a mutant mouse model of Angelman syndrome. Spacing the training trials at 1 h intervals accelerated acquisition of three cognitive tasks by Ts65Dn mice: (1) object location memory, (2) novel object recognition, (3) water maze spatial learning. Further, (4) spaced training improved water maze spatial learning by Ube3a mice. In contrast, (5) cerebellar-mediated rotarod motor learning was not improved by spaced training. Corroborations in three assays, conducted in two model systems, replicated within and across two laboratories, confirm the strength of the findings. Our results indicate strong translational relevance of a behavioral intervention strategy for improving the standard of care in treating the learning difficulties that are characteristic and clinically intractable features of many neurodevelopmental disorders.


Assuntos
Comportamento Animal/fisiologia , Remediação Cognitiva , Deficiência Intelectual/reabilitação , Prática Psicológica , Reconhecimento Psicológico/fisiologia , Aprendizagem Espacial/fisiologia , Memória Espacial/fisiologia , Síndrome de Angelman/reabilitação , Animais , Modelos Animais de Doenças , Síndrome de Down/reabilitação , Feminino , Masculino , Camundongos , Camundongos Knockout , Trissomia , Ubiquitina-Proteína Ligases
9.
Mol Med Rep ; 20(2): 1178-1186, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31173236

RESUMO

Angelman syndrome (AS) is a congenital neuro-developmental disorder typically occurring due to functional defects of the UBE3A gene caused by uniparental disomy (UPD), translocation or single gene mutation. UBE3A gene exhibits imprinting expression, and only maternal inherited alleles express functional UBE3A protein in the brain. The common method to diagnose AS is single nucleotide polymorphism array or methylation­specific multiplex ligation­dependent probe amplification (MS­MLPA). In recent years, whole exome sequencing (WES) has been increasingly used in the genetic diagnosis of a variety of indications, exhibiting great advantages as a comprehensive and unbiased testing method. In the present study, the cases of two unrelated patients with Robertsonian­like translocation in chromosome 15, namely 45,XX,der(15;15)(q10;q10) and 45,XY,der(15;15)(q10;q10), are reported. The first case was diagnosed with AS by WES and validated by Sanger sequencing. In contrast to 42.84%  homozygous variants on all chromosomes, 92.69%  homozygosity variants were observed on chromosome 15. A homozygous stretch identifier was applied and identified a homozygous region across the entire chromosome 15. Sanger sequencing was used to further determine the subtype and confirm that two homozygous variants on chromosome 15 with low allele frequency (<0.01) were derived only from the father and not from the mother, thereby indicating a paternal UPD case, classified as isodisomy. MS­MLPA results of the other AS patient with the same karyotype indicated that he had a high possibility of paternal UPD at chromosome 15. Taken together, the current study suggested the potential application of WES in detecting and facilitating the diagnosis of UPD.


Assuntos
Síndrome de Angelman/genética , Metilação de DNA , Dissomia Uniparental , Sequenciamento Completo do Exoma , Alelos , Síndrome de Angelman/diagnóstico , Pré-Escolar , Feminino , Homozigoto , Humanos , Masculino , Reação em Cadeia da Polimerase Multiplex
10.
Psychiatry Clin Neurosci ; 73(9): 541-550, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31215705

RESUMO

Dendritic spines are tiny postsynaptic protrusions from a dendrite that receive most of the excitatory synaptic input in the brain. Functional and structural changes in dendritic spines are critical for synaptic plasticity, a cellular model of learning and memory. Conversely, altered spine morphology and plasticity are common hallmarks of human neurodevelopmental disorders, such as intellectual disability and autism. The advances in molecular and optical techniques have allowed for exploration of dynamic changes in structure and signal transduction at single-spine resolution, providing significant insights into the molecular regulation underlying spine structural plasticity. Here, I review recent findings on: how synaptic stimulation leads to diverse forms of spine structural plasticity; how the associated biochemical signals are initiated and transmitted into neuronal compartments; and how disruption of single genes associated with neurodevelopmental disorders can lead to abnormal spine structure in human and mouse brains. In particular, I discuss the functions of the Ras superfamily of small GTPases in spatiotemporal regulation of the actin cytoskeleton and protein synthesis in dendritic spines. Multiple lines of evidence implicate disrupted Ras signaling pathways in the spine structural abnormalities observed in neurodevelopmental disorders. Both deficient and excessive Ras activities lead to disrupted spine structure and deficits in learning and memory. Dysregulation of spine Ras signaling, therefore, may play a key role in the pathogenesis of multiple neurodevelopmental disorders with distinct etiologies.


Assuntos
Citoesqueleto de Actina/metabolismo , Espinhas Dendríticas/metabolismo , Transtornos do Neurodesenvolvimento/metabolismo , Plasticidade Neuronal , Sinapses/metabolismo , Proteínas ras/metabolismo , Síndrome de Angelman/metabolismo , Síndrome de Angelman/patologia , Animais , Transtorno do Espectro Autista/metabolismo , Transtorno do Espectro Autista/patologia , Espinhas Dendríticas/patologia , Síndrome do Cromossomo X Frágil/metabolismo , Síndrome do Cromossomo X Frágil/patologia , Humanos , Deficiência Intelectual/metabolismo , Deficiência Intelectual/patologia , Transtornos do Neurodesenvolvimento/patologia , Neurônios/metabolismo , Biossíntese de Proteínas , Transdução de Sinais , Esclerose Tuberosa/metabolismo , Esclerose Tuberosa/patologia
11.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(6): 543-546, 2019 Jun 10.
Artigo em Chinês | MEDLINE | ID: mdl-31055801

RESUMO

OBJECTIVE: To explore the genetic basis for a fetus featuring growth restriction and validate the effectiveness of a novel noninvasive prenatal testing (NIPT) technique for the detection of chromosomal microdeletions. METHODS: Next-generation sequencing(NGS) and fluorescence in situ hybridization(FISH) were used to analyze the DNA of the fetus. Conventional G-banding was used to analyze the karyotypes of the fetus and its parents. High-throughput sequencing was used to analyze free fetal DNA. RESULTS: NGS analysis has revealed a 4.88 Mb deletion at 15q11.2-q13.1 region in the fetus, which has a 99% overlap with the critical region of Prader-Willi syndrome (Type 2) and Angelman syndrome (Type 2) and encompassed critical genes including SNRPN and UBE3A. NIPT also revealed a 4.6 Mb deletion at 15q12, which was consistent with the results of fetal cord blood and amniotic DNA testing. FISH assay has confirmed the result of NGS. By karyotying, all subjects showed a normal karyotypes at a level of 320~400 bands. CONCLUSION: It is quite necessary to carry out genetic testing on fetuses showing growth restriction. NIPT for fetal chromosomal microdeletions/microduplication syndromes is highly accurate for the diagnosis of Prader-Willi/Angelman syndrome.


Assuntos
Síndrome de Angelman , Síndrome de Prader-Willi , Bandeamento Cromossômico , Cromossomos Humanos Par 15 , Feminino , Feto , Humanos , Hibridização in Situ Fluorescente , Gravidez
12.
Dev Neurorehabil ; 22(8): 516-526, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31116614

RESUMO

Purpose: This study was designed to assess memory, imitation of motor actions and motor performance by 12 children (age range 40-151 months) with Angelman syndrome (AS), a rare neurogenetic disorder associated with learning and memory impairments. Methods: Children's functioning was assessed at several time points over a 3-month period. Results: Memory and motor performance tests had acceptable test-retest and inter-rater reliability whereas the motor imitation test did not. Children were able to recall action sequences after a 24-h delay. Memory and motor performance scores were correlated with children's chronological age and raw scores on subdomains of the Vineland-II. Conclusions: These behavioral tests require further development and evaluation but may show promise to accompany standardized assessments that are currently in use with children with AS.


Assuntos
Síndrome de Angelman/diagnóstico , Comportamento Imitativo , Memória , Destreza Motora , Síndrome de Angelman/psicologia , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Testes Neuropsicológicos/normas , Reprodutibilidade dos Testes
13.
Dev Med Child Neurol ; 61(11): 1266-1274, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31074506

RESUMO

AIM: A scoping review was conducted to examine and evaluate empirical data on the communication profile of Angelman syndrome beyond the described dissociation between receptive language and speech. METHOD: Three databases (PsycINFO, Embase, and Web of Science) were searched to retrieve articles investigating communication in Angelman syndrome. Seventeen articles investigating the broader communication profile were found; their methodology was evaluated against quality criteria. RESULTS: Despite the absence of speech, individuals with Angelman syndrome have a wide repertoire of non-verbal communicative behaviours, mainly characterized by gestures, although advanced forms such as symbolic communication are used by some individuals. The use of communicative forms differs between the genetic aetiologies of Angelman syndrome; individuals with non-deletion aetiologies typically have greater communicative abilities. INTERPRETATION: The broader communication profile of Angelman syndrome is characterized by diverse and multimodal abilities, including some use of symbolic forms of communication that appears atypical given the absence of speech. This is suggestive of a probable dissociation between speech and other expressive forms of communication, indicating an isolated speech production impairment. This highlights a need in this population for alternative communication and specific input from services tailored to support the nuances of the communication profile of Angelman syndrome. WHAT THIS PAPER ADDS: Although absent speech is near universal, a diverse profile of other communicative abilities has been reported. Parental reporting has been predominantly used to assess the communication profile of Angelman syndrome. Literature that investigates the specificities and possible dissociations in such a communication profile is limited.


Assuntos
Síndrome de Angelman/psicologia , Comunicação , Síndrome de Angelman/epidemiologia , Humanos , Comunicação não Verbal , Fala
16.
Am J Intellect Dev Disabil ; 124(3): 263-285, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31026205

RESUMO

Although social communication skills are commonly delayed in children with neurogenetic syndromes (NGS), skill profiles in very young children are largely under characterized, in part due to the lack of validated assessment measures appropriate for these populations. We addressed this gap by validating and applying a popular early social communication screening measure, the Communication and Symbolic Behavior Scales Developmental Profile - Infant-Toddler Checklist (CSBS-ITC) in three previously understudied neurogenetic groups: Angelman, Prader-Willi, and Williams syndromes. Our results suggest that when used within the appropriate scope of screening and surveillance, the CSBS-ITC detects meaningful variability in skills across ages in young children with NGS and may provide useful information about both individual- and population-level social communication profiles in these populations.


Assuntos
Síndrome de Angelman/diagnóstico , Escala de Avaliação Comportamental/normas , Desenvolvimento Infantil , Comunicação , Síndrome de Prader-Willi/diagnóstico , Escalas de Graduação Psiquiátrica/normas , Habilidades Sociais , Síndrome de Williams/diagnóstico , Síndrome de Angelman/fisiopatologia , Desenvolvimento Infantil/fisiologia , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Síndrome de Prader-Willi/fisiopatologia , Reprodutibilidade dos Testes , Síndrome de Williams/fisiopatologia
17.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(5): 491-494, 2019 May 10.
Artigo em Chinês | MEDLINE | ID: mdl-31030441

RESUMO

OBJECTIVE: To provide genetic testing for two brothers with mental retardation and epilepsy. METHODS: Array comparative genomic hybridization (aCGH) was used to detect copy number variations in the two patients, their parents and maternal grandparents. Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) was utilized to delineate the deleted region in the pedigree. RESULTS: A 138 kb deletion in 15q11.2 region was detected by aCGH in both patients, which encompassed part of the UBE3A gene. MS-MLPA has narrowed down the region to exons 8 to 14 of the UBE3A gene. The same deletion was also found in their mother and grandfather. CONCLUSION: The pathogenesis of this rare form of recurrent Angelman syndrome may be attributed to the partial deletion of maternal UBE3A gene.


Assuntos
Síndrome de Angelman , Hibridização Genômica Comparativa , Variações do Número de Cópias de DNA , Feminino , Deleção de Genes , Humanos , Masculino , Deleção de Sequência , Ubiquitina-Proteína Ligases
18.
BMC Med Genomics ; 12(Suppl 2): 42, 2019 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-30871545

RESUMO

BACKGROUND: Thousands of long non-coding RNA (lncRNA) genes are annotated in the human genome. Recent studies showed the key role of lncRNAs in a variety of fundamental cellular processes. Dysregulation of lncRNAs can drive tumorigenesis and they are now considered to be a promising therapeutic target in cancer. However, how lncRNAs contribute to the development of hereditary diseases in human is still mostly unknown. RESULTS: This review is focused on hereditary diseases in the pathogenesis of which long non-coding RNAs play an important role. CONCLUSIONS: Fundamental research in the field of molecular genetics of lncRNA is necessary for a more complete understanding of their significance. Future research will help translate this knowledge into clinical practice which will not only lead to an increase in the diagnostic rate but also in the future can help with the development of etiotropic treatments for hereditary diseases.


Assuntos
Doenças Genéticas Inatas/patologia , RNA Longo não Codificante/metabolismo , Síndrome de Angelman/genética , Síndrome de Angelman/patologia , Síndrome de Beckwith-Wiedemann/genética , Síndrome de Beckwith-Wiedemann/patologia , Biomarcadores/metabolismo , Doenças Genéticas Inatas/genética , Estudo de Associação Genômica Ampla , Humanos , Síndrome de Prader-Willi/genética , Síndrome de Prader-Willi/patologia , Pseudo-Hipoparatireoidismo/genética , Pseudo-Hipoparatireoidismo/patologia , Síndrome de Silver-Russell/genética , Síndrome de Silver-Russell/patologia
20.
Psychiatry Res ; 275: 94-99, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30897394

RESUMO

The maternally expressed imprinted gene UBE3A has been implicated in autism, schizophrenia and psychosis. The phenotype of Angelman syndrome, caused by loss of UBE3A expression, involves autism spectrum traits, while Prader-Willi syndrome, where the genotype of maternal disomy increases dosage of UBE3A, shows high penetrance for the development of psychosis. Maternal duplications of the 15q11-q13 chromosome region that overlap the imprinted region also show an association with schizophrenia, further implying a connection between increased dosage of UBE3A and the development of schizophrenia and psychosis. We phenotyped a large population of typical individuals for autism spectrum and schizotypal traits and genotyped them for a set of SNPs in UBE3A. Genetic variation of rs732739, an intronic SNP tagging a large haplotype spanning nearly the entire range of UBE3A, was significantly associated with variation in total schizotypy. Our results provide an independent line of evidence, connecting the imprinted UBE3A gene to the schizophrenia spectrum.


Assuntos
Impressão Genômica , Herança Materna , Transtornos Psicóticos/genética , Transtorno da Personalidade Esquizotípica/genética , Ubiquitina-Proteína Ligases/genética , Síndrome de Angelman/genética , Transtorno Autístico/genética , Cromossomos Humanos Par 15/genética , Feminino , Dosagem de Genes , Genótipo , Humanos , Masculino , Fenótipo , Polimorfismo de Nucleotídeo Único , Síndrome de Prader-Willi/genética
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