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1.
Cell ; 185(23): 4409-4427.e18, 2022 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-36368308

RESUMO

Fully understanding autism spectrum disorder (ASD) genetics requires whole-genome sequencing (WGS). We present the latest release of the Autism Speaks MSSNG resource, which includes WGS data from 5,100 individuals with ASD and 6,212 non-ASD parents and siblings (total n = 11,312). Examining a wide variety of genetic variants in MSSNG and the Simons Simplex Collection (SSC; n = 9,205), we identified ASD-associated rare variants in 718/5,100 individuals with ASD from MSSNG (14.1%) and 350/2,419 from SSC (14.5%). Considering genomic architecture, 52% were nuclear sequence-level variants, 46% were nuclear structural variants (including copy-number variants, inversions, large insertions, uniparental isodisomies, and tandem repeat expansions), and 2% were mitochondrial variants. Our study provides a guidebook for exploring genotype-phenotype correlations in families who carry ASD-associated rare variants and serves as an entry point to the expanded studies required to dissect the etiology in the ∼85% of the ASD population that remain idiopathic.


Assuntos
Transtorno do Espectro Autista , Transtorno Autístico , Humanos , Transtorno do Espectro Autista/genética , Predisposição Genética para Doença , Variações do Número de Cópias de DNA/genética , Genômica
2.
Genet Med ; 19(11): 1268-1275, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28471434

RESUMO

PurposeWhole-exome (WES) and whole-genome sequencing (WGS) increase the diagnostic yield in autism spectrum disorder (ASD) compared to chromosomal microarray (CMA), but there have been no comprehensive cost analyses. The objective was to perform such an assessment of CMA, WES, and WGS and compare the incremental cost per additional positive finding in hypothetical testing scenarios.MethodsFive-year patient and program costs were estimated from an institutional perspective. WES and WGS estimates were based on HiSeq 2500 with an additional WGS estimate for HiSeq X platforms. Parameter uncertainty was assessed with probabilistic and deterministic sensitivity analysis.ResultsThe cost per ASD sample was CAD$1,655 (95% CI: 1,611; 1,699) for WES, CAD$2,851 (95% CI: 2,750; 2,956) for WGS on HiSeq X, and CAD$5,519 (95% CI: 5,244; 5,785) on HiSeq 2500, compared to CAD$744 (95% CI 714, 773) for CMA. The incremental cost was over CAD$25,000 per additional positive finding if CMA was replaced by newer technology.ConclusionWhile costs for WES and WGS remain high, future reductions in material and equipment costs, and increased understanding of newly discovered variants and variants of unknown significance will lead to improved value.


Assuntos
Transtorno do Espectro Autista/genética , Sequenciamento do Exoma , Análise em Microsséries/economia , Sequenciamento Completo do Genoma/economia , Transtorno do Espectro Autista/diagnóstico , Transtorno do Espectro Autista/economia , Cromossomos Humanos , Custos e Análise de Custo , Genoma Humano , Humanos
3.
Nucleic Acids Res ; 42(20): e156, 2014 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-25249628

RESUMO

Understanding the role of a given transcription factor (TF) in regulating gene expression requires precise mapping of its binding sites in the genome. Chromatin immunoprecipitation-exo, an emerging technique using λ exonuclease to digest TF unbound DNA after ChIP, is designed to reveal transcription factor binding site (TFBS) boundaries with near-single nucleotide resolution. Although ChIP-exo promises deeper insights into transcription regulation, no dedicated bioinformatics tool exists to leverage its advantages. Most ChIP-seq and ChIP-chip analytic methods are not tailored for ChIP-exo, and thus cannot take full advantage of high-resolution ChIP-exo data. Here we describe a novel analysis framework, termed MACE (model-based analysis of ChIP-exo) dedicated to ChIP-exo data analysis. The MACE workflow consists of four steps: (i) sequencing data normalization and bias correction; (ii) signal consolidation and noise reduction; (iii) single-nucleotide resolution border peak detection using the Chebyshev Inequality and (iv) border matching using the Gale-Shapley stable matching algorithm. When applied to published human CTCF, yeast Reb1 and our own mouse ONECUT1/HNF6 ChIP-exo data, MACE is able to define TFBSs with high sensitivity, specificity and spatial resolution, as evidenced by multiple criteria including motif enrichment, sequence conservation, direct sequence pileup, nucleosome positioning and open chromatin states. In addition, we show that the fundamental advance of MACE is the identification of two boundaries of a TFBS with high resolution, whereas other methods only report a single location of the same event. The two boundaries help elucidate the in vivo binding structure of a given TF, e.g. whether the TF may bind as dimers or in a complex with other co-factors.


Assuntos
Imunoprecipitação da Cromatina/métodos , Análise de Sequência de DNA/métodos , Fatores de Transcrição/metabolismo , Algoritmos , Animais , Sítios de Ligação , Fator de Ligação a CCCTC , Simulação por Computador , Proteínas de Ligação a DNA/metabolismo , Exodesoxirribonucleases , Genoma , Fator 6 Nuclear de Hepatócito/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Repressoras/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo
4.
Am J Hum Genet ; 90(6): 1064-70, 2012 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-22578324

RESUMO

Duplication (dup7q11.23) and deletion (Williams syndrome) of chromosomal region 7q11.23 cause neurodevelopmental disorders with contrasting anxiety phenotypes. We found that 30% of 4- to 12-year-olds with dup7q11.23 but fewer than 5% of children with WS or in the general population met diagnostic criteria for a separation-anxiety disorder. To address the role of one commonly duplicated or deleted gene in separation anxiety, we compared mice that had varying numbers of Gtf2i copies. Relative to mouse pups with one or two Gtf2i copies, pups with additional Gtf2i copies showed significantly increased maternal separation-induced anxiety as measured by ultrasonic vocalizations. This study links the copy number of a single gene from 7q11.23 to separation anxiety in both mice and humans, highlighting the utility of mouse models in dissecting specific gene functions for genomic disorders that span many genes. This study also offers insight into molecular separation-anxiety pathways that might enable the development of targeted therapeutics.


Assuntos
Ansiedade de Separação/genética , Duplicação Gênica , Fatores de Transcrição TFII/genética , Animais , Criança , Pré-Escolar , Cromossomos Humanos Par 7 , Feminino , Deleção de Genes , Humanos , Masculino , Camundongos , Modelos Genéticos , Fenótipo , Fatores de Tempo , Síndrome de Williams/genética
5.
Nat Genet ; 35(2): 125-7, 2003 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-12958597

RESUMO

Lafora progressive myoclonus epilepsy is characterized by pathognomonic endoplasmic reticulum (ER)-associated polyglucosan accumulations. We previously discovered that mutations in EPM2A cause Lafora disease. Here, we identify a second gene associated with this disease, NHLRC1 (also called EPM2B), which encodes malin, a putative E3 ubiquitin ligase with a RING finger domain and six NHL motifs. Laforin and malin colocalize to the ER, suggesting they operate in a related pathway protecting against polyglucosan accumulation and epilepsy.


Assuntos
Proteínas de Transporte/genética , Mutação , Epilepsias Mioclônicas Progressivas/genética , Proteínas Tirosina Fosfatases/genética , Sequência de Bases , Estudos de Coortes , Feminino , Homozigoto , Humanos , Doença de Lafora/genética , Masculino , Dados de Sequência Molecular , Epilepsias Mioclônicas Progressivas/enzimologia , Linhagem , Proteínas Tirosina Fosfatases não Receptoras , Deleção de Sequência , Ubiquitina-Proteína Ligases
6.
Am J Hum Genet ; 83(1): 106-11, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18565486

RESUMO

Infantile spasms (IS) is the most severe and common form of epilepsy occurring in the first year of life. At least half of IS cases are idiopathic in origin, with others presumed to arise because of brain insult or malformation. Here, we identify a locus for IS by high-resolution mapping of 7q11.23-q21.1 interstitial deletions in patients. The breakpoints delineate a 500 kb interval within the MAGI2 gene (1.4 Mb in size) that is hemizygously disrupted in 15 of 16 participants with IS or childhood epilepsy, but remains intact in 11 of 12 participants with no seizure history. MAGI2 encodes the synaptic scaffolding protein membrane-associated guanylate kinase inverted-2 that interacts with Stargazin, a protein also associated with epilepsy in the stargazer mouse.


Assuntos
Cromossomos Humanos Par 17 , Deleção de Genes , Proteínas/genética , Espasmos Infantis/genética , Proteínas Adaptadoras de Transdução de Sinal , Proteínas de Transporte , Quebra Cromossômica , Feminino , Marcadores Genéticos , Guanilato Quinases , Humanos , Hibridização in Situ Fluorescente , Lactente , Masculino , Repetições de Microssatélites , Análise de Sequência com Séries de Oligonucleotídeos , Mapeamento Físico do Cromossomo , Polimorfismo de Nucleotídeo Único , Espasmos Infantis/diagnóstico , Espasmos Infantis/fisiopatologia
7.
J Clin Endocrinol Metab ; 106(10): 2915-2937, 2021 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-34125233

RESUMO

CONTEXT: Idiopathic infantile hypercalcemia (IIH), an uncommon disorder characterized by elevated serum concentrations of 1,25 dihydroxyvitamin D (1,25(OH)2D) and low parathyroid hormone (PTH) levels, may present with mild to severe hypercalcemia during the first months of life. Biallelic variants in the CYP24A1 or SLC34A1 genes are associated with severe IIH. Little is known about milder forms. OBJECTIVE: This work aims to characterize the genetic associations and biochemical profile of mild IIH. METHODS: This is a cross-sectional study including children between age 6 months and 17 years with IIH who were followed in the Calcium Clinic at the Hospital for Sick Children (SickKids), Toronto, Canada. Twenty children with mild IIH on calcium-restricted diets were evaluated. We performed a dietary assessment and analyzed biochemical measures including vitamin D metabolites and performed a stepwise molecular genetic analysis. Complementary biochemical assessments and renal ultrasounds were offered to first-degree family members of positive probands. RESULTS: The median age was 16 months. Median serum levels of calcium (2.69 mmol/L), urinary calcium:creatinine ratio (0.72 mmol/mmol), and 1,25(OH)2D (209 pmol/L) were elevated, whereas intact PTH was low normal (22.5 ng/L). Mean 1,25(OH)2D/PTH and 1,25(OH)2D/25(OH)D ratios were increased by comparison to healthy controls. Eleven individuals (55%) had renal calcification. Genetic variants were common (65%), with the majority being heterozygous variants in SLC34A1 and SLC34A3, while a minority showed variants of CYP24A1 and other genes related to hypercalciuria. CONCLUSION: The milder form of IIH has a distinctive vitamin D metabolite profile and is primarily associated with heterozygous SLC34A1 and SLC34A3 variants.


Assuntos
Hipercalcemia/genética , Hormônio Paratireóideo/sangue , Proteínas Cotransportadoras de Sódio-Fosfato Tipo IIa/genética , Proteínas Cotransportadoras de Sódio-Fosfato Tipo IIc/genética , Vitamina D/análogos & derivados , Adolescente , Cálcio/sangue , Cálcio/urina , Criança , Pré-Escolar , Creatinina/urina , Estudos Transversais , Feminino , Variação Genética , Heterozigoto , Humanos , Hipercalcemia/sangue , Hipercalcemia/urina , Lactente , Masculino , Vitamina D/sangue , Vitamina D3 24-Hidroxilase/genética
8.
NPJ Genom Med ; 4: 26, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31602316

RESUMO

Copy number variations (CNVs) are implicated across many neurodevelopmental disorders (NDDs) and contribute to their shared genetic etiology. Multiple studies have attempted to identify shared etiology among NDDs, but this is the first genome-wide CNV analysis across autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), schizophrenia (SCZ), and obsessive-compulsive disorder (OCD) at once. Using microarray (Affymetrix CytoScan HD), we genotyped 2,691 subjects diagnosed with an NDD (204 SCZ, 1,838 ASD, 427 ADHD and 222 OCD) and 1,769 family members, mainly parents. We identified rare CNVs, defined as those found in <0.1% of 10,851 population control samples. We found clinically relevant CNVs (broadly defined) in 284 (10.5%) of total subjects, including 22 (10.8%) among subjects with SCZ, 209 (11.4%) with ASD, 40 (9.4%) with ADHD, and 13 (5.6%) with OCD. Among all NDD subjects, we identified 17 (0.63%) with aneuploidies and 115 (4.3%) with known genomic disorder variants. We searched further for genes impacted by different CNVs in multiple disorders. Examples of NDD-associated genes linked across more than one disorder (listed in order of occurrence frequency) are NRXN1, SEH1L, LDLRAD4, GNAL, GNG13, MKRN1, DCTN2, KNDC1, PCMTD2, KIF5A, SYNM, and long non-coding RNAs: AK127244 and PTCHD1-AS. We demonstrated that CNVs impacting the same genes could potentially contribute to the etiology of multiple NDDs. The CNVs identified will serve as a useful resource for both research and diagnostic laboratories for prioritization of variants.

9.
N Engl J Med ; 353(16): 1694-701, 2005 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-16236740

RESUMO

The Williams-Beuren syndrome (WBS) locus, at 7q11.23, is prone to recurrent chromosomal rearrangements, including the microdeletion that causes WBS, a multisystem condition with characteristic cardiovascular, cognitive, and behavioral features. It is hypothesized that reciprocal duplications of the WBS interval should also occur, and here we present such a case description. The most striking phenotype was a severe delay in expressive speech, in contrast to the normal articulation and fluent expressive language observed in persons with WBS. Our results suggest that specific genes at 7q11.23 are exquisitely sensitive to dosage alterations that can influence human language and visuospatial capabilities.


Assuntos
Cromossomos Humanos Par 7 , Duplicação Gênica , Transtornos do Desenvolvimento da Linguagem/genética , Distúrbios da Fala/genética , Transtorno do Deficit de Atenção com Hiperatividade/complicações , Criança , Deleção Cromossômica , Feminino , Dosagem de Genes , Humanos , Transtornos do Desenvolvimento da Linguagem/complicações , Masculino , Fenótipo
10.
Am J Med Genet A ; 146A(14): 1797-806, 2008 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-18553513

RESUMO

Williams-Beuren syndrome (WBS) is caused by a approximately 1.5 million base pair deletion at 7q11.23. A common inversion of the region, WBSinv-1, exists as a polymorphism but was also found in individuals with WBS-like features but no deletion, suggesting it could cause clinical symptoms. We performed a full clinical, developmental and genetic assessment of two previously reported individuals with clinical symptoms and WBSinv-1 but no 7q11.23 deletion. We also examined expression of genes at 7q11.23 in individuals in the general population who have WBSinv-1. We show that individuals with clinical symptoms and WBSinv-1 do not show significant clinical or psychological overlap with individuals with WBS. In addition, a 1.3 Mb duplication of part of the velocardiofacial syndrome region on chromosome 22q11.2 was found in one participant with WBSinv-1 and clinical symptoms. We also demonstrate that individuals with WBSinv-1 show normal expression of genes from the WBS region. These results suggest that WBSinv-1 does not cause clinical symptoms and we advise caution when diagnosing individuals with atypical presentation of rare syndromes. Whole genome analysis may reveal previously unidentified copy number variants that could contribute to syndromic features.


Assuntos
Inversão Cromossômica , Cromossomos Humanos Par 7/genética , Síndrome de Williams/diagnóstico , Síndrome de Williams/genética , Adolescente , Adulto , Sequência de Bases , Comportamento , Primers do DNA/genética , Diagnóstico Diferencial , Feminino , Dosagem de Genes , Expressão Gênica , Variação Genética , Humanos , Inteligência , Penetrância , Fenótipo , Deleção de Sequência , Síndrome de Williams/psicologia
11.
Genome Biol ; 17(1): 182, 2016 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-27582050

RESUMO

BACKGROUND: Type II DNA topoisomerases (TOP2) regulate DNA topology by generating transient double stranded breaks during replication and transcription. Topoisomerase II beta (TOP2B) facilitates rapid gene expression and functions at the later stages of development and differentiation. To gain new insight into the genome biology of TOP2B, we used proteomics (BioID), chromatin immunoprecipitation, and high-throughput chromosome conformation capture (Hi-C) to identify novel proximal TOP2B protein interactions and characterize the genomic landscape of TOP2B binding at base pair resolution. RESULTS: Our human TOP2B proximal protein interaction network included members of the cohesin complex and nucleolar proteins associated with rDNA biology. TOP2B associates with DNase I hypersensitivity sites, allele-specific transcription factor (TF) binding, and evolutionarily conserved TF binding sites on the mouse genome. Approximately half of all CTCF/cohesion-bound regions coincided with TOP2B binding. Base pair resolution ChIP-exo mapping of TOP2B, CTCF, and cohesin sites revealed a striking structural ordering of these proteins along the genome relative to the CTCF motif. These ordered TOP2B-CTCF-cohesin sites flank the boundaries of topologically associating domains (TADs) with TOP2B positioned externally and cohesin internally to the domain loop. CONCLUSIONS: TOP2B is positioned to solve topological problems at diverse cis-regulatory elements and its occupancy is a highly ordered and prevalent feature of CTCF/cohesin binding sites that flank TADs.


Assuntos
Proteínas de Ciclo Celular/genética , Proteínas Cromossômicas não Histona/genética , DNA Topoisomerases Tipo II/genética , Proteínas de Ligação a DNA/genética , Mapas de Interação de Proteínas/genética , Proteínas Repressoras/genética , Transcrição Gênica , Alelos , Animais , Sítios de Ligação , Fator de Ligação a CCCTC , Proteínas de Ciclo Celular/metabolismo , Cromatina/genética , Imunoprecipitação da Cromatina , Proteínas Cromossômicas não Histona/metabolismo , Cromossomos , DNA Topoisomerases Tipo II/metabolismo , DNA Ribossômico/genética , Proteínas de Ligação a DNA/metabolismo , Genoma , Humanos , Camundongos , Proteínas de Ligação a Poli-ADP-Ribose , Regiões Promotoras Genéticas , Ligação Proteica , Proteômica , Proteínas Repressoras/metabolismo , Coesinas
12.
J Clin Oncol ; 33(9): 1015-22, 2015 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-25667294

RESUMO

PURPOSE: To uncover the genetic events leading to transformation of pediatric low-grade glioma (PLGG) to secondary high-grade glioma (sHGG). PATIENTS AND METHODS: We retrospectively identified patients with sHGG from a population-based cohort of 886 patients with PLGG with long clinical follow-up. Exome sequencing and array CGH were performed on available samples followed by detailed genetic analysis of the entire sHGG cohort. Clinical and outcome data of genetically distinct subgroups were obtained. RESULTS: sHGG was observed in 2.9% of PLGGs (26 of 886 patients). Patients with sHGG had a high frequency of nonsilent somatic mutations compared with patients with primary pediatric high-grade glioma (HGG; median, 25 mutations per exome; P = .0042). Alterations in chromatin-modifying genes and telomere-maintenance pathways were commonly observed, whereas no sHGG harbored the BRAF-KIAA1549 fusion. The most recurrent alterations were BRAF V600E and CDKN2A deletion in 39% and 57% of sHGGs, respectively. Importantly, all BRAF V600E and 80% of CDKN2A alterations could be traced back to their PLGG counterparts. BRAF V600E distinguished sHGG from primary HGG (P = .0023), whereas BRAF and CDKN2A alterations were less commonly observed in PLGG that did not transform (P < .001 and P < .001 respectively). PLGGs with BRAF mutations had longer latency to transformation than wild-type PLGG (median, 6.65 years [range, 3.5 to 20.3 years] v 1.59 years [range, 0.32 to 15.9 years], respectively; P = .0389). Furthermore, 5-year overall survival was 75% ± 15% and 29% ± 12% for children with BRAF mutant and wild-type tumors, respectively (P = .024). CONCLUSION: BRAF V600E mutations and CDKN2A deletions constitute a clinically distinct subtype of sHGG. The prolonged course to transformation for BRAF V600E PLGGs provides an opportunity for surgical interventions, surveillance, and targeted therapies to mitigate the outcome of sHGG.


Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/secundário , Inibidor p16 de Quinase Dependente de Ciclina/genética , Deleção de Genes , Glioma/genética , Glioma/secundário , Proteínas Proto-Oncogênicas B-raf/genética , Adolescente , Transformação Celular Neoplásica , Criança , Pré-Escolar , Cromatina/química , Progressão da Doença , Feminino , Seguimentos , Humanos , Lactente , Masculino , Mutação , Mutação Puntual , Estudos Retrospectivos , Telômero/ultraestrutura , Resultado do Tratamento
13.
Hum Mutat ; 23(2): 170-176, 2004 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-14722920

RESUMO

Lafora disease is the most severe teenage-onset progressive epilepsy, a unique form of glycogenosis with perikaryal accumulation of an abnormal form of glycogen, and a neurodegenerative disorder exhibiting an unusual generalized organellar disintegration. The disease is caused by mutations of the EPM2A gene, which encodes two isoforms of the laforin protein tyrosine phosphatase, having alternate carboxyl termini, one localized in the cytoplasm (endoplasmic reticulum) and the other in the nucleus. To date, all documented disease mutations, including the knockout mouse model deletion, have been in the segment of the protein common to both isoforms. It is therefore not known whether dysfunction of the cytoplasmic, nuclear, or both isoforms leads to the disease. In the present work, we identify six novel mutations, one of which, c.950insT (Q319fs), is the first mutation specific to the cytoplasmic laforin isoform, implicating this isoform in disease pathogenesis. To confirm this mutation's deleterious effect on laforin, we studied the resultant protein's subcellular localization and function and show a drastic reduction in its phosphatase activity, despite maintenance of its location at the endoplasmic reticulum.


Assuntos
Citoplasma/química , Doença de Lafora/genética , Proteínas Tirosina Fosfatases/deficiência , Proteínas Tirosina Fosfatases/genética , Adulto , Sequência de Aminoácidos/genética , Animais , Sequência de Bases/genética , Células COS , Linhagem Celular , Chlorocebus aethiops , Citoplasma/genética , Fosfatases de Especificidade Dupla , Retículo Endoplasmático/química , Retículo Endoplasmático/genética , Feminino , Humanos , Masculino , Camundongos , Camundongos Knockout , Dados de Sequência Molecular , Mutação/genética , Mutação de Sentido Incorreto/genética , Linhagem , Isoformas de Proteínas/deficiência , Isoformas de Proteínas/genética , Isoformas de Proteínas/fisiologia , Proteínas Tirosina Fosfatases/fisiologia , Proteínas Tirosina Fosfatases não Receptoras
14.
J Neurodev Disord ; 2(2): 99-108, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20585377

RESUMO

Williams-Beuren syndrome (WBS) is a neurodevelopmental disorder caused by the hemizygous deletion of 28 genes on chromosome 7, including the general transcription factor GTF2IRD1. Mice either hemizygously (Gtf2ird1(+/-)) or homozygously (Gtf2ird1(-/-)) deleted for this transcription factor exhibit low innate anxiety, low aggression and increased social interaction, a phenotype that shares similarities to the high sociability and disinhibition seen in individuals with WBS. Here, we investigated the inhibitory effects of serotonin (5-HT) on the major output neurons of the prefrontal cortex in Gtf2ird1(-/-) mice and their wildtype (WT) siblings. Prefrontal 5-HT receptors are known to modulate anxiety-like behaviors, and the Gtf2ird1(-/-) mice have altered 5-HT metabolism in prefrontal cortex. Using whole cell recording from layer V neurons in acute brain slices of prefrontal cortex, we found that 5-HT elicited significantly larger inhibitory, outward currents in Gtf2ird1(-/-) mice than in WT controls. In both genotypes, these currents were resistant to action potential blockade with TTX and were suppressed by the selective 5-HT(1A) receptor antagonist WAY-100635, suggesting that they are mediated directly by 5-HT(1A) receptors on the recorded neurons. Control experiments suggest a degree of layer and receptor specificity in this enhancement since 5-HT(1A) receptor-mediated responses in layer II/III pyramidal neurons were unchanged as were responses mediated by two other inhibitory receptors in layer V pyramidal neurons. Furthermore, we demonstrate GTF2IRD1 protein expression by neurons in layer V of the prefrontal cortex. Our finding that 5-HT(1A)-mediated responses are selectively enhanced in layer V pyramidal neurons of Gtf2ird1(-/-) mice gives insight into the cellular mechanisms that underlie reduced innate anxiety and increased sociability in these mice, and may be relevant to the low social anxiety and disinhibition in patients with WBS and their sensitivity to serotonergic medicines. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11689-010-9044-5) contains supplementary material, which is available to authorized users.

15.
Science ; 307(5706): 81, 2005 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-15637270

RESUMO

Epilepsy afflicts 1% of humans and 5% of dogs. We report a canine epilepsy mutation and evidence for the existence of repeat-expansion disease outside humans. A canid-specific unstable dodecamer repeat in the Epm2b (Nhlrc1) gene recurrently expands, causing a fatal epilepsy and contributing to the high incidence of canine epilepsy. Tracing the repeat origins revealed two successive events, starting 50 million years ago, unique to canid evolution. A genetic test, presented here, will allow carrier and presymptomatic diagnosis and disease eradication. Clinicopathologic characterization establishes affected animals as a model for Lafora disease, the most severe teenage-onset human epilepsy.


Assuntos
Expansão das Repetições de DNA , Doenças do Cão/genética , Cães/genética , Doença de Lafora/veterinária , Alelos , Animais , Mapeamento Cromossômico , Clonagem Molecular , Feminino , Doença de Lafora/genética , Masculino , Músculo Esquelético/metabolismo , Linhagem , Reação em Cadeia da Polimerase , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Análise de Sequência de DNA
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