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1.
J Neurodev Disord ; 11(1): 18, 2019 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-31395010

RESUMO

BACKGROUND: The SYNGAP1 gene encodes for a small GTPase-regulating protein critical to dendritic spine maturation and synaptic plasticity. Mutations have recently been identified to cause a breadth of neurodevelopmental disorders including autism, intellectual disability, and epilepsy. The purpose of this work is to define the phenotypic spectrum of SYNGAP1 gene mutations and identify potential biomarkers of clinical severity and developmental progression. METHODS: A retrospective clinical data analysis of individuals with SYNGAP1 mutations was conducted. Data included genetic diagnosis, clinical history and examinations, neurophysiologic data, neuroimaging, and serial neurodevelopmental/behavioral assessments. All patients were seen longitudinally within a 6-year period; data analysis was completed on June 30, 2018. Records for all individuals diagnosed with deleterious SYNGAP1 variants (by clinical sequencing or exome sequencing panels) were reviewed. RESULTS: Fifteen individuals (53% male) with seventeen unique SYNGAP1 mutations are reported. Mean age at genetic diagnosis was 65.9 months (28-174 months). All individuals had epilepsy, with atypical absence seizures being the most common semiology (60%). EEG abnormalities included intermittent rhythmic delta activity (60%), slow or absent posterior dominant rhythm (87%), and epileptiform activity (93%), with generalized discharges being more common than focal. Neuroimaging revealed nonspecific abnormalities (53%). Neurodevelopmental evaluation revealed impairment in all individuals, with gross motor function being the least affected. Autism spectrum disorder was diagnosed in 73% and aggression in 60% of cases. Analysis of biomarkers revealed a trend toward a moderate positive correlation between visual-perceptual/fine motor/adaptive skills and language development, with posterior dominant rhythm on electroencephalogram (EEG), independent of age. No other neurophysiology-development associations or correlations were identified. CONCLUSIONS: A broad spectrum of neurologic and neurodevelopmental features are found with pathogenic variants of SYNGAP1. An abnormal posterior dominant rhythm on EEG correlated with abnormal developmental progression, providing a possible prognostic biomarker.

2.
Genome Med ; 11(1): 12, 2019 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-30819258

RESUMO

BACKGROUND: Neurodevelopmental disorders are genetically and phenotypically heterogeneous encompassing developmental delay (DD), intellectual disability (ID), autism spectrum disorders (ASDs), structural brain abnormalities, and neurological manifestations with variants in a large number of genes (hundreds) associated. To date, a few de novo mutations potentially disrupting TCF20 function in patients with ID, ASD, and hypotonia have been reported. TCF20 encodes a transcriptional co-regulator structurally related to RAI1, the dosage-sensitive gene responsible for Smith-Magenis syndrome (deletion/haploinsufficiency) and Potocki-Lupski syndrome (duplication/triplosensitivity). METHODS: Genome-wide analyses by exome sequencing (ES) and chromosomal microarray analysis (CMA) identified individuals with heterozygous, likely damaging, loss-of-function alleles in TCF20. We implemented further molecular and clinical analyses to determine the inheritance of the pathogenic variant alleles and studied the spectrum of phenotypes. RESULTS: We report 25 unique inactivating single nucleotide variants/indels (1 missense, 1 canonical splice-site variant, 18 frameshift, and 5 nonsense) and 4 deletions of TCF20. The pathogenic variants were detected in 32 patients and 4 affected parents from 31 unrelated families. Among cases with available parental samples, the variants were de novo in 20 instances and inherited from 4 symptomatic parents in 5, including in one set of monozygotic twins. Two pathogenic loss-of-function variants were recurrent in unrelated families. Patients presented with a phenotype characterized by developmental delay, intellectual disability, hypotonia, variable dysmorphic features, movement disorders, and sleep disturbances. CONCLUSIONS: TCF20 pathogenic variants are associated with a novel syndrome manifesting clinical characteristics similar to those observed in Smith-Magenis syndrome. Together with previously described cases, the clinical entity of TCF20-associated neurodevelopmental disorders (TAND) emerges from a genotype-driven perspective.


Assuntos
Anormalidades Craniofaciais/genética , Deficiências do Desenvolvimento/genética , Mutação INDEL , Deficiência Intelectual/genética , Hipotonia Muscular/genética , Síndrome de Smith-Magenis/genética , Fatores de Transcrição/genética , Adolescente , Criança , Pré-Escolar , Anormalidades Craniofaciais/patologia , Deficiências do Desenvolvimento/patologia , Feminino , Humanos , Lactente , Deficiência Intelectual/patologia , Masculino , Hipotonia Muscular/patologia , Síndrome de Smith-Magenis/patologia , Fatores de Transcrição/metabolismo , Adulto Jovem
3.
Mol Psychiatry ; 2019 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-30696942

RESUMO

Neurons are sensitive to changes in the dosage of many genes, especially those regulating synaptic functions. Haploinsufficiency of SHANK3 causes Phelan-McDermid syndrome and autism, whereas duplication of the same gene leads to SHANK3 duplication syndrome, a disorder characterized by neuropsychiatric phenotypes including hyperactivity and bipolar disorder as well as epilepsy. We recently demonstrated the functional modularity of Shank3, which suggests that normalizing levels of Shank3 itself might be more fruitful than correcting pathways that function downstream of it for treatment of disorders caused by alterations in SHANK3 dosage. To identify upstream regulators of Shank3 abundance, we performed a kinome-wide siRNA screen and identified multiple kinases that potentially regulate Shank3 protein stability. Interestingly, we discovered that several kinases in the MEK/ERK2 pathway destabilize Shank3 and that genetic deletion and pharmacological inhibition of ERK2 increases Shank3 abundance in vivo. Mechanistically, we show that ERK2 binds Shank3 and phosphorylates it at three residues to promote its poly-ubiquitination-dependent degradation. Altogether, our findings uncover a druggable pathway as a potential therapeutic target for disorders with reduced SHANK3 dosage, provide a rich resource for studying Shank3 regulation, and demonstrate the feasibility of this approach for identifying regulators of dosage-sensitive genes.

4.
Mol Psychiatry ; 2019 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-30610205

RESUMO

Genome sequencing has revealed an increasing number of genetic variations that are associated with neuropsychiatric disorders. Frequently, studies limit their focus to likely gene-disrupting mutations because they are relatively easy to interpret. Missense variants, instead, have often been undervalued. However, some missense variants can be informative for developing a more profound understanding of disease pathogenesis and ultimately targeted therapies. Here we present an example of this by studying a missense variant in a well-known autism spectrum disorder (ASD) causing gene SHANK3. We analyzed Shank3's in vivo phosphorylation profile and identified S685 as one phosphorylation site where one ASD-linked variant has been reported. Detailed analysis of this variant revealed a novel function of Shank3 in recruiting Abelson interactor 1 (ABI1) and the WAVE complex to the post-synaptic density (PSD), which is critical for synapse and dendritic spine development. This function was found to be independent of Shank3's other functions such as binding to GKAP and Homer. Introduction of this human ASD mutation into mice resulted in a small subset of phenotypes seen previously in constitutive Shank3 knockout mice, including increased allogrooming, increased social dominance, and reduced pup USV. Together, these findings demonstrate the modularity of Shank3 function in vivo. This modularity further indicates that there is more than one independent pathogenic pathway downstream of Shank3 and correcting a single downstream pathway is unlikely to be sufficient for clear clinical improvement. In addition, this study illustrates the value of deep biological analysis of select missense mutations in elucidating the pathogenesis of neuropsychiatric phenotypes.

5.
Nat Neurosci ; 21(12): 1-13, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30455457

RESUMO

In addition to cognitive impairments, neurodevelopmental disorders often result in sensory processing deficits. However, the biological mechanisms that underlie impaired sensory processing associated with neurodevelopmental disorders are generally understudied and poorly understood. We found that SYNGAP1 haploinsufficiency in humans, which causes a sporadic neurodevelopmental disorder defined by cognitive impairment, autistic features, and epilepsy, also leads to deficits in tactile-related sensory processing. In vivo neurophysiological analysis in Syngap1 mouse models revealed that upper-lamina neurons in somatosensory cortex weakly encode information related to touch. This was caused by reduced synaptic connectivity and impaired intrinsic excitability within upper-lamina somatosensory cortex neurons. These results were unexpected, given that Syngap1 heterozygosity is known to cause circuit hyperexcitability in brain areas more directly linked to cognitive functions. Thus, Syngap1 heterozygosity causes a range of circuit-specific pathologies, including reduced activity within cortical neurons required for touch processing, which may contribute to sensory phenotypes observed in patients.

6.
Mol Autism ; 9: 31, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29719671

RESUMO

Background: Phelan-McDermid syndrome (PMS) is a neurodevelopmental disorder characterized by psychiatric and neurological features. Most reported cases are caused by 22q13.3 deletions, leading to SHANK3 haploinsufficiency, but also usually encompassing many other genes. While the number of point mutations identified in SHANK3 has increased in recent years due to large-scale sequencing studies, systematic studies describing the phenotype of individuals harboring such mutations are lacking. Methods: We provide detailed clinical and genetic data on 17 individuals carrying mutations in SHANK3. We also review 60 previously reported patients with pathogenic or likely pathogenic SHANK3 variants, often lacking detailed phenotypic information. Results: SHANK3 mutations in our cohort and in previously reported cases were distributed throughout the protein; the majority were truncating and all were compatible with de novo inheritance. Despite substantial allelic heterogeneity, four variants were recurrent (p.Leu1142Valfs*153, p.Ala1227Glyfs*69, p.Arg1255Leufs*25, and c.2265+1G>A), suggesting that these are hotspots for de novo mutations. All individuals studied had intellectual disability, and autism spectrum disorder was prevalent (73%). Severe speech deficits were common, but in contrast to individuals with 22q13.3 deletions, the majority developed single words, including 41% with at least phrase speech. Other common findings were consistent with reports among individuals with 22q13.3 deletions, including hypotonia, motor skill deficits, regression, seizures, brain abnormalities, mild dysmorphic features, and feeding and gastrointestinal problems. Conclusions: Haploinsufficiency of SHANK3 resulting from point mutations is sufficient to cause a broad range of features associated with PMS. Our findings expand the molecular and phenotypic spectrum of PMS caused by SHANK3 point mutations and suggest that, in general, speech impairment and motor deficits are more severe in the case of deletions. In contrast, renal abnormalities associated with 22q13.3 deletions do not appear to be related to the loss of SHANK3.


Assuntos
Transtornos Cromossômicos/genética , Proteínas do Tecido Nervoso/genética , Fenótipo , Mutação Puntual , Adolescente , Adulto , Criança , Pré-Escolar , Deleção Cromossômica , Transtornos Cromossômicos/patologia , Cromossomos Humanos Par 22/genética , Feminino , Haploinsuficiência , Humanos , Masculino
7.
Cell ; 172(5): 924-936.e11, 2018 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-29474920

RESUMO

Certain mutations can cause proteins to accumulate in neurons, leading to neurodegeneration. We recently showed, however, that upregulation of a wild-type protein, Ataxin1, caused by haploinsufficiency of its repressor, the RNA-binding protein Pumilio1 (PUM1), also causes neurodegeneration in mice. We therefore searched for human patients with PUM1 mutations. We identified eleven individuals with either PUM1 deletions or de novo missense variants who suffer a developmental syndrome (Pumilio1-associated developmental disability, ataxia, and seizure; PADDAS). We also identified a milder missense mutation in a family with adult-onset ataxia with incomplete penetrance (Pumilio1-related cerebellar ataxia, PRCA). Studies in patient-derived cells revealed that the missense mutations reduced PUM1 protein levels by ∼25% in the adult-onset cases and by ∼50% in the infantile-onset cases; levels of known PUM1 targets increased accordingly. Changes in protein levels thus track with phenotypic severity, and identifying posttranscriptional modulators of protein expression should identify new candidate disease genes.

8.
Am J Med Genet A ; 176(4): 973-979, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29423971

RESUMO

SHANK3 encodes for a scaffolding protein that links neurotransmitter receptors to the cytoskeleton and is enriched in postsynaptic densities of excitatory synapses. Deletions or mutations in one copy of the SHANK3 gene cause Phelan-McDermid syndrome, also called 22q13.3 deletion syndrome, a neurodevelopmental disorder with common features including global developmental delay, absent to severely impaired language, autistic behavior, and minor dysmorphic features. By whole exome sequencing, we identified two de novo novel variants including one frameshift pathogenic variant and one missense variant of unknown significance in a 14-year-old boy with delayed motor milestones, delayed language acquisition, autism, intellectual disability, ataxia, progressively worsening spasticity of the lower extremities, dysmorphic features, short stature, microcephaly, failure to thrive, chronic constipation, intrauterine growth restriction, and bilateral inguinal hernias. Both changes are within the CpG island in exon 21, separated by a 375 bp sequence. Next generation sequencing of PCR products revealed that the two variants are most frequently associated with each other. Sanger sequencing of the cloned PCR products further confirmed that both changes were on a single allele. The clinical presentation in this individual is consistent with other patients with a truncating mutation in exon 21, suggesting that the missense change contributes none or minimally to the phenotypes. This is the first report of two de novo mutations in one SHANK3 allele.

10.
Epilepsia ; 57(10): 1651-1659, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27554343

RESUMO

OBJECTIVE: The coincidence of autism with epilepsy is 27% in those individuals with intellectual disability.1 Individuals with loss-of-function mutations in SHANK3 have intellectual disability, autism, and variably, epilepsy.2-5 The spectrum of seizure semiologies and electroencephalography (EEG) abnormalities has never been investigated in detail. With the recent report that SHANK3 mutations are present in approximately 2% of individuals with moderate to severe intellectual disabilities and 1% of individuals with autism, determining the spectrum of seizure semiologies and electrographic abnormalities will be critical for medical practitioners to appropriately counsel the families of patients with SHANK3 mutations. METHODS: A retrospective chart review was performed of all individuals treated at the Blue Bird Circle Clinic for Child Neurology who have been identified as having either a chromosome 22q13 microdeletion encompassing SHANK3 or a loss-of-function mutation in SHANK3 identified through whole-exome sequencing. For each subject, the presence or absence of seizures, seizure semiology, frequency, age of onset, and efficacy of therapy were determined. Electroencephalography studies were reviewed by a board certified neurophysiologist. Neuroimaging was reviewed by both a board certified pediatric neuroradiologist and child neurologist. RESULTS: There is a wide spectrum of seizure semiologies, frequencies, and severity in individuals with SHANK3 mutations. There are no specific EEG abnormalities found in our cohort, and EEG abnormalities were present in individuals diagnosed with epilepsy and those without history of a clinical seizure. SIGNIFICANCE: All individuals with a mutation in SHANK3 should be evaluated for epilepsy due to the high prevalence of seizures in this population. The most common semiology is atypical absence seizure, which can be challenging to identify due to comorbid intellectual disability in individuals with SHANK3 mutations; however, no consistent seizure semiology, neuroimaging findings, or EEG findings were present in the majority of individuals with SHANK3 mutations.


Assuntos
Ondas Encefálicas/genética , Epilepsia/genética , Epilepsia/fisiopatologia , Mutação/genética , Proteínas do Tecido Nervoso/genética , Adolescente , Anticonvulsivantes/uso terapêutico , Criança , Pré-Escolar , Aberrações Cromossômicas , Deleção Cromossômica , Transtornos Cromossômicos/complicações , Transtornos Cromossômicos/diagnóstico por imagem , Transtornos Cromossômicos/genética , Cromossomos Humanos Par 22/genética , Eletroencefalografia , Epilepsia/diagnóstico por imagem , Epilepsia/tratamento farmacológico , Feminino , Humanos , Estudos Longitudinais , Imagem por Ressonância Magnética , Masculino , Estudos Retrospectivos , Adulto Jovem
11.
Neurology ; 87(1): 77-85, 2016 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-27281533

RESUMO

OBJECTIVE: To evaluate the phenotypic spectrum associated with mutations in TBC1D24. METHODS: We acquired new clinical, EEG, and neuroimaging data of 11 previously unreported and 37 published patients. TBC1D24 mutations, identified through various sequencing methods, can be found online (http://lovd.nl/TBC1D24). RESULTS: Forty-eight patients were included (28 men, 20 women, average age 21 years) from 30 independent families. Eighteen patients (38%) had myoclonic epilepsies. The other patients carried diagnoses of focal (25%), multifocal (2%), generalized (4%), and unclassified epilepsy (6%), and early-onset epileptic encephalopathy (25%). Most patients had drug-resistant epilepsy. We detail EEG, neuroimaging, developmental, and cognitive features, treatment responsiveness, and physical examination. In silico evaluation revealed 7 different highly conserved motifs, with the most common pathogenic mutation located in the first. Neuronal outgrowth assays showed that some TBC1D24 mutations, associated with the most severe TBC1D24-associated disorders, are not necessarily the most disruptive to this gene function. CONCLUSIONS: TBC1D24-related epilepsy syndromes show marked phenotypic pleiotropy, with multisystem involvement and severity spectrum ranging from isolated deafness (not studied here), benign myoclonic epilepsy restricted to childhood with complete seizure control and normal intellect, to early-onset epileptic encephalopathy with severe developmental delay and early death. There is no distinct correlation with mutation type or location yet, but patterns are emerging. Given the phenotypic breadth observed, TBC1D24 mutation screening is indicated in a wide variety of epilepsies. A TBC1D24 consortium was formed to develop further research on this gene and its associated phenotypes.


Assuntos
Proteínas de Transporte/genética , Epilepsia/genética , Epilepsia/fisiopatologia , Animais , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Proteínas de Transporte/metabolismo , Crescimento Celular , Células Cultivadas , Criança , Pré-Escolar , Estudos de Coortes , Eletroencefalografia , Epilepsia/diagnóstico por imagem , Epilepsia/psicologia , Feminino , Estudos de Associação Genética , Humanos , Lactente , Masculino , Camundongos , Mutação , Neuritos/fisiologia , Exame Físico , Adulto Jovem
12.
Neurol Genet ; 2(2): e62, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27123481

RESUMO

Genes encoding proteins critical for intracellular vesicular transport are an emerging area of importance for neurologists. In particular, proteins that create and maintain the correct compartmental pH, such as the endosomal Na(+)/H(+) exchangers (NHEs), have been implicated in a wide range of human diseases, including cardiovascular, inflammatory bowel, renal, and neurologic disorders, which demonstrates the critical cellular function of these proteins.(1-3) Two NHEs, NHE6 and NHE9, have been linked to neurologic disorders in children.(4) Pathologic variants in SLC9A6 encoding NHE6 cause an Angelman-like disorder called Christianson syndrome. Fewer variants have been described in SLC9A9 encoding NHE9, but individuals carrying these variants have been diagnosed with neurologic disorders ranging from autism to epilepsy to attention-deficit/hyperactivity disorder. The majority of described variants are missense, resulting in amino acid substitutions, making it difficult to determine their functional consequence.(4).

13.
Am J Med Genet A ; 167A(11): 2737-41, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26138022

RESUMO

Individuals with deletions of chromosome 5q12-13 have rarely been reported and have a range of phenotypes including postnatal growth restriction, intellectual disability, hyperactivity, and ocular abnormalities. Most individuals reported have large deletions or complex rearrangements which have made identifying genes responsible for these phenotypes challenging. Here we report an individual with a chromosome 5q12-13 deletion with intellectual disability, hyperactivity and restricted linear growth. Based on the location of our patient's deletion in relation to the previously reported deletions, we have narrowed the locus for postnatal growth restriction to less than 1 megabase. Further refinement of this locus with reports of additional individuals with deletions of this region will allow for better understanding of the gene(s) responsible for this phenotype.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 5/genética , Loci Gênicos , Crescimento e Desenvolvimento/genética , Adolescente , Criança , Pré-Escolar , Hibridização Genômica Comparativa , Humanos , Hibridização in Situ Fluorescente , Lactente , Recém-Nascido , Masculino , Fenótipo
14.
Eur J Hum Genet ; 23(1): 54-60, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24736736

RESUMO

Patients with terminal deletions of chromosome 6q present with structural brain abnormalities including agenesis of corpus callosum, hydrocephalus, periventricular nodular heterotopia, and cerebellar malformations. The 6q27 region harbors genes that are important for the normal development of brain and delineation of a critical deletion region for structural brain abnormalities may lead to a better genotype-phenotype correlation. We conducted a detailed clinical and molecular characterization of seven unrelated patients with deletions involving chromosome 6q27. All patients had structural brain abnormalities. Using array comparative genomic hybridization, we mapped the size, extent, and genomic content of these deletions. The smallest region of overlap spans 1.7 Mb and contains DLL1, THBS2, PHF10, and C6orf70 (ERMARD) that are plausible candidates for the causation of structural brain abnormalities. Our study reiterates the importance of 6q27 region in normal development of brain and helps identify putative genes in causation of structural brain anomalies.


Assuntos
Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Encéfalo/anormalidades , Deleção Cromossômica , Cromossomos Humanos Par 6 , Encéfalo/patologia , Pré-Escolar , Bandeamento Cromossômico , Hibridização Genômica Comparativa , Facies , Feminino , Genótipo , Humanos , Hibridização in Situ Fluorescente , Lactente , Recém-Nascido , Imagem por Ressonância Magnética , Fenótipo
15.
JAMA Neurol ; 71(6): 782-4, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24756183

RESUMO

IMPORTANCE: Isolated sulfite oxidase deficiency (ISOD) causes severe intellectual disability, epilepsy, and shortened life expectancy. Intractable seizures are invariable in children with ISOD; however, to our knowledge, infantile spasms with a corresponding hypsarrhythmia pattern on electroencephalogram have never been reported. In addition, the nonepileptic paroxysmal movement disorder hyperekplexia has not previously been reported with ISOD. OBSERVATIONS: We describe an infant with ISOD who initially presented with neonatal seizures, diffusion restriction noted on magnetic resonance imaging, and elevated serum S-sulfocysteine consistent with ISOD. A homozygous mutation in the SUOX gene was identified, confirming the diagnosis. Uniquely, this patient developed a profound accentuated startle response that did not have a corresponding electrographic change on electroencephalogram consistent with hyperekplexia. This was followed by a change in the child's electroencephalogram to the chaotic pattern of hypsarrhythmia and brief tonic seizures with attenuation of the hypsarrhythmia pattern characteristic of infantile spasms. CONCLUSIONS AND RELEVANCE: The evolution of seizures associated with ISOD is poorly characterized because of the small number of patients. We report what we believe to be the first case of a child with ISOD who developed infantile spasms and hyperekplexia. This expands the phenotypes associated with ISOD and also should caution clinicians to not assume that all abnormal movements are seizures.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/genética , Mutação/genética , Oxirredutases atuantes sobre Doadores de Grupo Enxofre/genética , Convulsões/genética , Espasmos Infantis/genética , Rigidez Muscular Espasmódica/genética , Sulfito Oxidase/deficiência , Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Eletroencefalografia/métodos , Humanos , Recém-Nascido , Imagem por Ressonância Magnética/métodos , Masculino , Convulsões/etiologia , Espasmos Infantis/etiologia , Rigidez Muscular Espasmódica/etiologia , Sulfito Oxidase/genética
16.
Nature ; 503(7474): 72-7, 2013 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-24153177

RESUMO

Mutations in SHANK3 and large duplications of the region spanning SHANK3 both cause a spectrum of neuropsychiatric disorders, indicating that proper SHANK3 dosage is critical for normal brain function. However, SHANK3 overexpression per se has not been established as a cause of human disorders because 22q13 duplications involve several genes. Here we report that Shank3 transgenic mice modelling a human SHANK3 duplication exhibit manic-like behaviour and seizures consistent with synaptic excitatory/inhibitory imbalance. We also identified two patients with hyperkinetic disorders carrying the smallest SHANK3-spanning duplications reported so far. These findings indicate that SHANK3 overexpression causes a hyperkinetic neuropsychiatric disorder. To probe the mechanism underlying the phenotype, we generated a Shank3 in vivo interactome and found that Shank3 directly interacts with the Arp2/3 complex to increase F-actin levels in Shank3 transgenic mice. The mood-stabilizing drug valproate, but not lithium, rescues the manic-like behaviour of Shank3 transgenic mice raising the possibility that this hyperkinetic disorder has a unique pharmacogenetic profile.


Assuntos
Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/fisiopatologia , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Complexo 2-3 de Proteínas Relacionadas à Actina/metabolismo , Actinas/metabolismo , Adulto , Animais , Comportamento Animal , Transtorno Bipolar/genética , Cromossomos Humanos Par 22/genética , Modelos Animais de Doenças , Potenciais Pós-Sinápticos Excitadores , Feminino , Dosagem de Genes/genética , Expressão Gênica/genética , Genes Duplicados/genética , Humanos , Hipercinese/genética , Hipercinese/fisiopatologia , Potenciais Pós-Sinápticos Inibidores , Lítio/farmacologia , Masculino , Camundongos , Camundongos Transgênicos , Convulsões/genética , Ácido Valproico/farmacologia , Ácido Valproico/uso terapêutico
17.
Am J Med Genet A ; 158A(8): 1962-6, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22488736

RESUMO

Chromosome 14q32.3 deletions are uncommon, with most described patients harboring a ring chromosome 14. Only 15 deletions have been described not associated with ring formation or other complex chromosomal rearrangements. Here, we describe a child with the smallest deletion of chromosome 14q32.3 reported in the literature. This child's deletion encompasses at most 0.305 Mb and six genes including NUDT14, BRF1, BTBD6, PACS2, MTA1, and TEX22. He has similar clinical findings, including mild facial dysmorphisms and intellectual disability, as other individuals with much larger deletions of the terminus of the long arm of chromosome 14. This suggests that the genes deleted in our patient contribute to the 14q32 deletion syndrome.


Assuntos
Anormalidades Múltiplas/genética , Deleção Cromossômica , Cromossomos Humanos Par 14 , Pré-Escolar , Hibridização Genômica Comparativa , Humanos , Hibridização in Situ Fluorescente , Masculino , Síndrome
18.
Expert Opin Pharmacother ; 12(16): 2573-81, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21967409

RESUMO

INTRODUCTION: Epilepsy affects approximately 3 million people in the USA and up to 2% of the worldwide population. The yearly direct medical cost of epilepsy in the USA alone is estimated to be $9.5 billion. Epilepsy affects both children and adults and can significantly impair quality of life. Zonisamide is a second-generation antiepileptic drug (AED) that has broad-spectrum efficacy, a favorable side-effect profile and simpler dosing than earlier drugs. AREAS COVERED: The history of the development of zonisamide is reviewed in this paper. The data available demonstrating zonisamide's mechanism of action as a voltage-gated sodium channel inhibitor, a T-type calcium channel inhibitor, an enhancer of GABA release and an inhibitor of glutamate release are also reviewed. Four key Phase III clinical trials are reviewed in detail, as are subsequent postmarketing trials that have expanded the therapeutic indication for zonisamide. EXPERT OPINION: From the available clinical data, zonisamide is a viable first-line and adjunctive therapeutic for partial-onset epilepsy and should be considered as an adjunctive therapeutic for a wide-range of generalized epilepsies.


Assuntos
Anticonvulsivantes/uso terapêutico , Epilepsia/tratamento farmacológico , Isoxazóis/uso terapêutico , Animais , Anticonvulsivantes/farmacocinética , Anticonvulsivantes/farmacologia , Bloqueadores dos Canais de Cálcio/farmacocinética , Bloqueadores dos Canais de Cálcio/farmacologia , Bloqueadores dos Canais de Cálcio/uso terapêutico , Canais de Cálcio Tipo T/metabolismo , Epilepsia/metabolismo , Humanos , Isoxazóis/farmacocinética , Isoxazóis/farmacologia , Bloqueadores dos Canais de Sódio/farmacocinética , Bloqueadores dos Canais de Sódio/farmacologia , Bloqueadores dos Canais de Sódio/uso terapêutico , Zonisamida
19.
Mol Endocrinol ; 20(10): 2483-92, 2006 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16728530

RESUMO

Single-minded 1 (SIM1) is one of only six genes implicated in human monogenic obesity. Haploinsufficiency of this hypothalamic transcription factor is associated with hyperphagic obesity and increased linear growth in both humans and mice. Additionally, Sim1 heterozygous mice show enhanced hyperphagia and obesity in response to a high-fat diet. Thus the phenotype of Sim1 haploinsufficiency is similar to that of agouti yellow (Ay), and melanocortin 4 receptor (Mc4r) knockout mice, both of which are defective in hypothalamic melanocortin signaling. Sim1 and Mc4r are both expressed in the paraventricular nucleus (PVN). Here we report that Sim1 heterozygous mice, which have normal energy expenditure, are hyperphagic despite having elevated hypothalamic proopiomelanocortin (Pomc) expression. In response to the melanocortin agonist melanotan-2 (MTII) they exhibit a blunted suppression of feeding yet increase their energy expenditure normally. They also fail to activate PVN neurons in response to the drug at a dose that induces robust c-Fos expression in a subset of Sim1 PVN neurons in wild-type mice. The resistance to melanocortin signaling in Sim1 heterozygotes is not due to a reduced number of Sim1 neurons in the PVN. Hypothalamic Sim1 gene expression is induced by leptin and MTII treatment. Our results demonstrate that Sim1 heterozygotes are resistant to hypothalamic melanocortin signaling and suggest that Sim1-expressing PVN neurons regulate feeding, but not energy expenditure, in response to melanocortin signaling.


Assuntos
Anorexia/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Comportamento Alimentar/fisiologia , Regulação da Expressão Gênica/efeitos dos fármacos , Núcleo Hipotalâmico Paraventricular/metabolismo , Pró-Opiomelanocortina/metabolismo , Proteínas Repressoras/metabolismo , Transdução de Sinais/fisiologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Primers do DNA , Comportamento Alimentar/efeitos dos fármacos , Heterozigoto , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos C57BL , Modelos Biológicos , Peptídeos Cíclicos/farmacologia , Pró-Opiomelanocortina/agonistas , Proteínas Repressoras/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , alfa-MSH/análogos & derivados , alfa-MSH/farmacologia
20.
Endocrinology ; 147(10): 4542-9, 2006 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16709610

RESUMO

Single-minded 1 (SIM1) mutations are associated with obesity in mice and humans. Haploinsufficiency of mouse Sim1 causes hyperphagic obesity with increased linear growth and enhanced sensitivity to a high-fat diet, a phenotype similar to that of agouti yellow and melanocortin 4 receptor knockout mice. To investigate the effects of increased Sim1 dosage, we generated transgenic mice that overexpress human SIM1 and examined their phenotype. Compared with wild-type mice, SIM1 transgenic mice had no obvious phenotype on a low-fat chow diet but were resistant to diet-induced obesity on a high-fat diet due to reduced food intake with no change in energy expenditure. The SIM1 transgene also completely rescued the hyperphagia and partially rescued the obesity of agouti yellow mice, in which melanocortin signaling is abrogated. Our results indicate that the melanocortin 4 receptor signals through Sim1 or its transcriptional targets in controlling food intake but not energy expenditure.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/fisiologia , Ingestão de Alimentos/genética , Ingestão de Alimentos/fisiologia , Obesidade/genética , Proteínas Repressoras/genética , Proteínas Repressoras/fisiologia , Animais , Composição Corporal/fisiologia , Dieta , Metabolismo Energético/genética , Metabolismo Energético/fisiologia , Feminino , Genótipo , Crescimento/genética , Crescimento/fisiologia , Humanos , Hiperfagia/genética , Hiperfagia/psicologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pró-Opiomelanocortina/genética , Pró-Opiomelanocortina/fisiologia , Receptor Tipo 4 de Melanocortina/genética , Receptor Tipo 4 de Melanocortina/fisiologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transgenes , alfa-MSH/fisiologia
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