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1.
Cytogenet Genome Res ; 160(4): 185-192, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32316019

RESUMO

A phenotype is emerging for the proximal pair of G-dark bands in 11q (11q14.1 and q14.3) but not yet for the distal pair (11q22.1 and q22.3). A mother and daughter with the same directly transmitted 12.3-Mb interstitial deletion of 11q21q22.3 (GRCh37: 93,551,765-105,817,723) both had initial feeding difficulties and failure to thrive, speech delay, learning difficulties, and mild dysmorphism. Among 17 patients with overlapping deletions, developmental or speech delay, dysmorphism, hypotonia, intellectual disability or learning difficulties, short stature, and coloboma were each found in 2 or more. These results may provide the basis for a consistent phenotype for this region. Among the 53 deleted and additional breakpoint genes, CNTN5, YAP1, and GRI4 were the most likely candidates. Non-penetrance of haploinsufficient genes and dosage compensation among related genes may account for the normal cognition in the mother and variable phenotypes that can extend into the normal range.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 11/genética , Anormalidades Múltiplas/patologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Contactinas/genética , Feminino , Humanos , Fenótipo , Receptores de AMPA/genética , Fatores de Transcrição/genética
2.
BMC Med Genet ; 21(1): 26, 2020 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-32028920

RESUMO

BACKGROUND: While Miller-Dieker syndrome critical region deletions are well known delineated anomalies, submicroscopic duplications in this region have recently emerged as a new distinctive syndrome. So far, only few cases have been described overlapping 17p13.3 duplications. METHODS: In this study, we report on clinical and cytogenetic characterization of two new cases involving 17p13.3 and 3p26 chromosomal regions in two sisters with familial history of lissencephaly. Fluorescent In Situ Hybridization and array Comparative Genomic Hybridization were performed. RESULTS: A deletion including the critical region of the Miller-Dieker syndrome of at least 2,9 Mb and a duplication of at least 3,6 Mb on the short arm of chromosome 3 were highlighted in one case. The opposite rearrangements, 17p13.3 duplication and 3p deletion, were observed in the second case. This double chromosomal aberration is the result of an adjacent 1:1 meiotic segregation of a maternal reciprocal translocation t(3,17)(p26.2;p13.3). CONCLUSIONS: 17p13.3 and 3p26 deletions have a clear range of phenotypic features while duplications still have an uncertain clinical significance. However, we could suggest that regardless of the type of the rearrangement, the gene dosage and interactions of CNTN4, CNTN6 and CHL1 in the 3p26 and PAFAH1B1, YWHAE in 17p13.3 could result in different clinical spectrums.


Assuntos
Lissencefalias Clássicas e Heterotopias Subcorticais em Banda/genética , Lisencefalia/genética , Neurônios/patologia , Translocação Genética/genética , 1-Alquil-2-acetilglicerofosfocolina Esterase/genética , Proteínas 14-3-3/genética , Moléculas de Adesão Celular/genética , Movimento Celular/genética , Pré-Escolar , Deleção Cromossômica , Cromossomos Humanos Par 17/genética , Cromossomos Humanos Par 3/genética , Lissencefalias Clássicas e Heterotopias Subcorticais em Banda/diagnóstico , Lissencefalias Clássicas e Heterotopias Subcorticais em Banda/fisiopatologia , Hibridização Genômica Comparativa , Contactinas/genética , Feminino , Dosagem de Genes/genética , Estudos de Associação Genética , Humanos , Hibridização in Situ Fluorescente , Lisencefalia/diagnóstico , Lisencefalia/fisiopatologia , Meiose/genética , Proteínas Associadas aos Microtúbulos/genética , Neurônios/metabolismo , Fenótipo , Trissomia/genética
4.
Stem Cell Res ; 40: 101556, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31518906

RESUMO

The 3p26.3 microduplication involving the CNTN6 gene cause developmental delay and the intellectual disability. However, the incomplete penetrance is described for this copy number variation (CNV). Here we describe ICAGi002-A line, which is supposed to use as a model for studying of the penetrance of the CNV in 3p26.3. The ICAGi002-A iPSCs line was obtained by the reprogramming of the skin fibroblasts from a healthy donor with 3p26.3 microduplication involving the CNTN6 gene. The ICAGi002-A cells was pluripotent as it was shown by the expression of the pluripotency-associated markers and in vitro differentiation into the cells of three germ layers.


Assuntos
Linhagem Celular/citologia , Contactinas/genética , Células-Tronco Pluripotentes Induzidas/citologia , Deficiência Intelectual/genética , Adulto , Diferenciação Celular , Linhagem Celular/metabolismo , Reprogramação Celular , Contactinas/metabolismo , Variações do Número de Cópias de DNA , Fibroblastos/citologia , Fibroblastos/metabolismo , Duplicação Gênica , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Deficiência Intelectual/metabolismo , Deficiência Intelectual/fisiopatologia , Masculino
5.
PLoS One ; 14(7): e0219384, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31318883

RESUMO

The Amyloid Precursor Protein (APP) and Contactin (CNTN) families of cell-surface proteins have been intensively studied in the context of neural development and neuropsychiatric diseases. Earlier studies demonstrated both genetic and biochemical interactions between the extracellular domains of APP and CNTN3, but their precise binding interfaces were not defined. In the present study, we have used binding assays between APP-alkaline phosphatase (AP) fusion proteins and CNTN-Fc fusion proteins, together with alanine substitution mutagenesis, to show that: (i) the second Fibronectin domain (Fn(2)) in CNTN3 mediates APP binding; (ii) the copper binding domain (CuBD) in APP mediates CNTN3 binding; and (iii) the most important amino acids for APP-CNTN3 binding reside on one face of CNTN3-Fn(2) and on one face of APP-CuBD. These experiments define the regions of direct contact that mediate the binding interaction between APP and CNTN3.


Assuntos
Precursor de Proteína beta-Amiloide/metabolismo , Contactinas/química , Contactinas/metabolismo , Mutagênese Sítio-Dirigida , Sequência de Aminoácidos , Aminoácidos/metabolismo , Precursor de Proteína beta-Amiloide/química , Animais , Células HEK293 , Humanos , Camundongos , Modelos Moleculares , Ligação Proteica
6.
Ann Rheum Dis ; 78(10): 1430-1437, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31289104

RESUMO

OBJECTIVE: The first ever genome-wide association study (GWAS) of clinically defined gout cases and asymptomatic hyperuricaemia (AHUA) controls was performed to identify novel gout loci that aggravate AHUA into gout. METHODS: We carried out a GWAS of 945 clinically defined gout cases and 1003 AHUA controls followed by 2 replication studies. In total, 2860 gout cases and 3149 AHUA controls (all Japanese men) were analysed. We also compared the ORs for each locus in the present GWAS (gout vs AHUA) with those in the previous GWAS (gout vs normouricaemia). RESULTS: This new approach enabled us to identify two novel gout loci (rs7927466 of CNTN5 and rs9952962 of MIR302F) and one suggestive locus (rs12980365 of ZNF724) at the genome-wide significance level (p<5.0×10- 8). The present study also identified the loci of ABCG2, ALDH2 and SLC2A9. One of them, rs671 of ALDH2, was identified as a gout locus by GWAS for the first time. Comparing ORs for each locus in the present versus the previous GWAS revealed three 'gout vs AHUA GWAS'-specific loci (CNTN5, MIR302F and ZNF724) to be clearly associated with mechanisms of gout development which distinctly differ from the known gout risk loci that basically elevate serum uric acid level. CONCLUSIONS: This meta-analysis is the first to reveal the loci associated with crystal-induced inflammation, the last step in gout development that aggravates AHUA into gout. Our findings should help to elucidate the molecular mechanisms of gout development and assist the prevention of gout attacks in high-risk AHUA individuals.


Assuntos
Contactinas/genética , Gota/genética , Hiperuricemia/genética , MicroRNAs/genética , Dedos de Zinco/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Adulto , Aldeído-Desidrogenase Mitocondrial/genética , Doenças Assintomáticas , Loci Gênicos/genética , Estudo de Associação Genômica Ampla , Técnicas de Genotipagem , Proteínas Facilitadoras de Transporte de Glucose/genética , Gota/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Fatores de Risco , Ácido Úrico/sangue
7.
Elife ; 82019 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-30747104

RESUMO

Induced pluripotent stem cell (iPSC)-derived neurons are increasingly used to model Autism Spectrum Disorder (ASD), which is clinically and genetically heterogeneous. To study the complex relationship of penetrant and weaker polygenic risk variants to ASD, 'isogenic' iPSC-derived neurons are critical. We developed a set of procedures to control for heterogeneity in reprogramming and differentiation, and generated 53 different iPSC-derived glutamatergic neuronal lines from 25 participants from 12 unrelated families with ASD. Heterozygous de novo and rare-inherited presumed-damaging variants were characterized in ASD risk genes/loci. Combinations of putative etiologic variants (GLI3/KIF21A or EHMT2/UBE2I) in separate families were modeled. We used a multi-electrode array, with patch-clamp recordings, to determine a reproducible synaptic phenotype in 25% of the individuals with ASD (other relevant data on the remaining lines was collected). Our most compelling new results revealed a consistent spontaneous network hyperactivity in neurons deficient for CNTN5 or EHMT2. The biobank of iPSC-derived neurons and accompanying genomic data are available to accelerate ASD research. Editorial note: This article has been through an editorial process in which authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).


Assuntos
Transtorno Autístico/fisiopatologia , Contactinas/metabolismo , Antígenos de Histocompatibilidade/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo , Células-Tronco Pluripotentes Induzidas/fisiologia , Rede Nervosa/fisiologia , Neurônios/fisiologia , Adolescente , Adulto , Células Cultivadas , Criança , Contactinas/deficiência , Contactinas/genética , Fenômenos Eletrofisiológicos , Feminino , Heterozigoto , Antígenos de Histocompatibilidade/genética , Histona-Lisina N-Metiltransferase/deficiência , Histona-Lisina N-Metiltransferase/genética , Humanos , Cinesina/genética , Cinesina/metabolismo , Masculino , Pessoa de Meia-Idade , Modelos Teóricos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Técnicas de Patch-Clamp , Enzimas de Conjugação de Ubiquitina/genética , Enzimas de Conjugação de Ubiquitina/metabolismo , Adulto Jovem , Proteína Gli3 com Dedos de Zinco/genética , Proteína Gli3 com Dedos de Zinco/metabolismo
8.
Cytogenet Genome Res ; 156(3): 144-149, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30508811

RESUMO

Submicroscopic chromosomal alterations usually involve different protein-coding genes and regulatory elements that are responsible for rare contiguous gene disorders, which complicate the understanding of genotype-phenotype correlations. Chromosome band 3p26.3 contains 3 genes encoding neuronal cell adhesion molecules: CHL1, CNTN6, and CNTN4. We describe 2 boys aged 8 years and 11 years mainly affected by intellectual disability and autism spectrum disorder, who harbor a paternally inherited 3p26.3 microdeletion and a 3p26.3 microduplication, respectively. Both anomalies involved only the CNTN6 gene, which encodes contactin 6, a member of the contactin family (MIM 607220). Contactins show pronounced brain expression and function. Interestingly, phenotypes in reciprocal microdeletions and microduplications of CNTN6 are very similar. In conclusion, our data, added to those reported in the literature, are particularly significant for understanding the pathogenic effect of single gene dosage alterations. As for other recurrent syndromes with variable phenotype, these findings are challenging in genetic counselling because of an evident variable penetrance.


Assuntos
Transtorno do Espectro Autista/genética , Contactinas/genética , Variações do Número de Cópias de DNA , Deficiência Intelectual/genética , Criança , Deleção Cromossômica , Duplicação Cromossômica , Cromossomos Humanos Par 3 , Humanos , Cariotipagem , Masculino , Fenótipo
9.
Schizophr Res ; 202: 111-112, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29983269

RESUMO

BACKGROUND: Copy number variants have made important contributions to understanding neuropsychiatric disorders, including schizophrenia. Deletions in genes encoding neuronal cell adhesion molecules have identified widely varied neurodevelopmental phenotypes. CASE SUMMARY: A 27-year old woman presented with schizophrenia, borderline intellectual functioning and shortened metacarpal bones. Subsequent electroencephalogram confirmed genetic generalised epilepsy and microarray analysis found a 0.2 megabase deletion of chromosome 3p26.3. CONCLUSIONS: We report the first case of schizophrenia in a proband with a CNTN6 deletion. Schizophrenia has been reported in relatives of probands with this deletion but not in probands themselves. This finding further contributes to the evolving literature regarding schizophrenia pathogenesis.


Assuntos
Contactinas/genética , Epilepsia Generalizada/genética , Esquizofrenia/genética , Adulto , Deleção Cromossômica , Cromossomos Humanos Par 3/genética , Variações do Número de Cópias de DNA , Feminino , Humanos , Deficiência Intelectual/genética , Herança Materna , Ossos Metacarpais/anormalidades
10.
Mol Psychiatry ; 23(12): 2254-2265, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29880880

RESUMO

Psychiatric disorders are a group of genetically related diseases with highly polygenic architectures. Genome-wide association analyses have made substantial progress towards understanding the genetic architecture of these disorders. More recently, exome- and whole-genome sequencing of cases and families have identified rare, high penetrant variants that provide direct functional insight. There remains, however, a gap in the heritability explained by these complementary approaches. To understand how multiple genetic variants combine to modify both severity and penetrance of a highly penetrant variant, we sequenced 48 whole genomes from a family with a high loading of psychiatric disorder linked to a balanced chromosomal translocation. The (1;11)(q42;q14.3) translocation directly disrupts three genes: DISC1, DISC2, DISC1FP and has been linked to multiple brain imaging and neurocognitive outcomes in the family. Using DNA sequence-level linkage analysis, functional annotation and population-based association, we identified common and rare variants in GRM5 (minor allele frequency (MAF) > 0.05), PDE4D (MAF > 0.2) and CNTN5 (MAF < 0.01) that may help explain the individual differences in phenotypic expression in the family. We suggest that whole-genome sequencing in large families will improve the understanding of the combined effects of the rare and common sequence variation underlying psychiatric phenotypes.


Assuntos
Transtornos Mentais/genética , Análise de Sequência de DNA/métodos , Adulto , Alelos , Contactinas/genética , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/genética , Família/psicologia , Feminino , Frequência do Gene/genética , Ligação Genética/genética , Predisposição Genética para Doença/genética , Testes Genéticos , Estudo de Associação Genômica Ampla , Genômica , Genótipo , Humanos , Escore Lod , Masculino , Transtornos Mentais/fisiopatologia , Pessoa de Meia-Idade , Transtornos do Humor/genética , Herança Multifatorial , Proteínas do Tecido Nervoso/genética , Linhagem , Fenótipo , RNA Mensageiro/genética , Receptor de Glutamato Metabotrópico 5/genética , Proteínas Recombinantes de Fusão/genética , Translocação Genética
11.
Lancet Psychiatry ; 5(4): 327-338, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29503163

RESUMO

BACKGROUND: Antipsychotic drugs improve schizophrenia symptoms and reduce the frequency of relapse, but treatment response is highly variable. Little is known about the genetic factors associated with treatment response. We did a genome-wide association study of antipsychotic treatment response in patients with schizophrenia. METHODS: The discovery cohort comprised patients with schizophrenia from 32 psychiatric hospitals in China that are part of the Chinese Antipsychotics Pharmacogenomics Consortium. Patients who met inclusion criteria were randomly assigned (1:1:1:1:1:1) to six groups (olanzapine, risperidone, quetiapine, aripiprazole, ziprasidone, and haloperidol or perphenazine; those assigned to haloperidol or perphenazine were subsequently assigned [1:1] to one or the other) for 6 weeks. Antipsychotic response was quantified with percentage change on the Positive and Negative Syndrome Scale. Single-nucleotide polymorphisms (SNPs) were tested for their association with treatment response. Linkage-disequilibrium-independent SNPs that exhibited potential associations (ie, p<1 × 10-5) were tested in a validation cohort comprising patients from the Chinese Antipsychotics Pharmacogenetics Consortium from five collaborative hospitals, who were treated with olanzapine, risperidone, or aripiprazole for 8 weeks. FINDINGS: The discovery cohort contained 2413 patients and the validation cohort 1379 patients. In the discovery cohort, we identified three novel SNPs (rs72790443 in MEGF10 [p=1·37 × 10-8], rs1471786 in SLC1A1 [p=1·77 × 10-8], and rs9291547 in PCDH7 [p=4·48 × 10-8]) that were associated with antipsychotic treatment response at a genome-wide significance level. These associations were confirmed in the validation cohort (p<0·05). In the combined sample of the discovery and validation cohorts, we identified five novel loci showing genome-wide significant associations with general antipsychotic treatment response (rs72790443 in MEGF10 [p=1·40 × 10-9], rs1471786 in SLC1A1 [p=2·33 × 10-9], rs9291547 in PCDH7 [p=3·24 × 10-9], rs12711680 in CNTNAP5 [p=2·12 × 10-8], and rs6444970 in TNIK [p=4·85 × 10-8]). In antipsychotic-specific groups, after the combination of results from both samples, the rs2239063 SNP in CACNA1C was associated with treatment response to olanzapine (p=1·10 × 10-8), rs16921385 in SLC1A1 was associated with treatment response to risperidone (p=4·40 × 10-8), and rs17022006 in CNTN4 was associated with treatment response to aripiprazole (p=2·58 × 10-8). INTERPRETATION: We have identified genes related to synaptic function, neurotransmitter receptors, and schizophrenia risk that are associated with response to antipsychotics. These findings improve understanding of the mechanisms underlying treatment responses, and the identified biomarkers could eventually guide choice of antipsychotic in patients with schizophrenia. FUNDING: National Key Technology R&D Program of China, National Natural Science Foundation of China.


Assuntos
Antipsicóticos/uso terapêutico , Farmacogenética , Esquizofrenia/tratamento farmacológico , Esquizofrenia/genética , Adulto , Antipsicóticos/classificação , Caderinas/genética , Moléculas de Adesão Celular Neuronais/genética , China , Contactinas/genética , Transportador 3 de Aminoácido Excitatório/genética , Feminino , Estudo de Associação Genômica Ampla , Quinases do Centro Germinativo , Humanos , Modelos Logísticos , Masculino , Proteínas de Membrana/genética , Polimorfismo de Nucleotídeo Único , Proteínas Serina-Treonina Quinases/genética , Resultado do Tratamento
12.
Mol Neurobiol ; 55(8): 6533-6546, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29327201

RESUMO

Copy number variations (CNVs) of the human CNTN6 gene caused by megabase-scale microdeletions or microduplications in the 3p26.3 region are often the cause of neurodevelopmental disorders, including intellectual disability and developmental delay. Surprisingly, patients with different copy numbers of this gene display notable overlapping of neuropsychiatric symptoms. The complexity of the study of human neuropathologies is associated with the inaccessibility of brain material. This problem can be overcome through the use of reprogramming technologies that permit the generation of induced pluripotent stem (iPS) cells from fibroblasts and their subsequent in vitro differentiation into neurons. We obtained a set of iPS cell lines derived from a patient carrier of the CNTN6 gene duplication and from two healthy donors. All iPS cell lines displayed the characteristics of pluripotent cells. Some iPS cell lines derived from the patient and from healthy donors were differentiated in vitro by exogenous expression of the Ngn2 transcription factor or by spontaneous neural differentiation of iPS cells through the neural rosette stage. The obtained neurons showed the characteristics of mature neurons as judged by the presence of neuronal markers and by their electrophysiological characteristics. Analysis of allele-specific expression of the CNTN6 gene in these neuronal cells by droplet digital PCR demonstrated that the level of expression of the duplicated allele was significantly reduced compared to that of the wild-type allele. Importantly, according to the sequencing data, both copies of the CNTN6 gene, which were approximately 1 Mb in size, showed no any additional structural rearrangements.


Assuntos
Alelos , Duplicação Cromossômica/genética , Cromossomos Humanos Par 3/genética , Contactinas/genética , Regulação da Expressão Gênica , Células-Tronco Pluripotentes Induzidas/patologia , Deficiência Intelectual/genética , Neurônios/patologia , Adolescente , Adulto , Animais , Sequência de Bases , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Deficiência Intelectual/fisiopatologia , Cariotipagem , Camundongos SCID , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo
13.
Transgenic Res ; 27(1): 1-13, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29264679

RESUMO

Contactins (Cntn1-6) are a family of neuronal membrane proteins expressed in the brain. They are required for establishing cell-to-cell contacts between neurons and for the growth and maturation of the axons. In humans, structural genomic variations in the Contactin genes are implicated in neurodevelopmental disorders. In addition, population genetic studies associate Contactins loci with obesity and hypertension. Cntn5 knockout mice were first described in 2003, but showed no gross physiological or behavioral abnormalities (just minor auditory defects). We report a novel Cntn5 knockout mouse line generated by a random transgene integration as an outcome of pronuclear microinjection. Investigation of the transgene integration site revealed that the 6Kbp transgene construct coding for the human granulocyte-macrophage colony-stimulating factor (hGMCSF) replaced 170 Kbp of the Cntn5 gene, including four exons. Reverse transcription PCR analysis of the Cntn5 transcripts in the wild-type and transgenic mouse lines showed that splicing of the transgene leads to a set of chimeric hGMCSF-Cntn5 transcript variants, none of which encode functional Cntn5 protein due to introduction of stop codons. Although Cntn5 knockout animals displayed no abnormalities in behavior, we noted that they were leaner, with less body mass and fat percentage than wild-type animals. Their cardiovascular parameters (heart rate, blood pressure and blood flow speed) were elevated compared to controls. These findings link Cntn5 deficiency to obesity and hypertension.


Assuntos
Contactinas/genética , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Camundongos Transgênicos/genética , Transgenes , Animais , Composição Corporal/genética , Composição Corporal/fisiologia , Ingestão de Líquidos/genética , Ingestão de Alimentos/genética , Feminino , Regulação da Expressão Gênica , Humanos , Hipertensão/genética , Masculino , Camundongos Knockout , Fenótipo , Reação em Cadeia da Polimerase
14.
Atherosclerosis ; 269: 42-49, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29258006

RESUMO

BACKGROUND AND AIMS: Elevated urinary 11-dehydro thromboxane B2 (TxB2), a measure of thromboxane A2 formation in vivo, predicts future atherothrombotic events. To further understand this relationship, the genetic determinants of 11-dehydro TxB2 and their associations with cardiovascular morbidity were investigated in this study. METHODS: Genome-wide and targeted genetic association studies of urinary 11-dehydro TxB2 were conducted in 806 Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) participants. RESULTS: The strongest associations were in PPARGC1B (rs4235745, rs32582, rs10515638) and CNTN4 (rs10510230, rs4684343), these 5 single nucleotide polymorphisms (SNPs) were independently associated with 11-dehydro TxB2 formation. Haplotypes of 11-dehydro TxB2 increasing alleles for both PPARGC1B and CNTN4 were significantly associated with 11-dehydro TxB2, explaining 5.2% and 4.5% of the variation in the whole cohort, and 8.8% and 7.9% in participants not taking aspirin, respectively. In a second ASCOT population (n = 6199), addition of these 5 SNPs significantly improved the covariate-only Cox proportional hazards model for cardiovascular events (chisq = 14.7, p=0.01). Two of the risk alleles associated with increased urinary 11-dehydro TxB2 were individually associated with greater incidences of cardiovascular events - rs10515638 (HR = 1.31, p=0.01) and rs10510230 (HR = 1.25, p=0.007); effect sizes were larger in those not taking aspirin. CONCLUSIONS: PPARGC1B and CNTN4 genotypes are associated with elevated thromboxane A2 formation and with an excess of cardiovascular events. Aspirin appears to blunt these associations. If specific protection of PPARGC1B and CNTN4 variant carriers by aspirin is confirmed by additional studies, PPARGC1B and CNTN4 genotyping could potentially assist in clinical decision making regarding the use of aspirin in primary prevention.


Assuntos
Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/genética , Proteínas de Transporte/genética , Contactinas/genética , Polimorfismo de Nucleotídeo Único , Tromboxano A2/metabolismo , Idoso , Aspirina/uso terapêutico , Fármacos Cardiovasculares/uso terapêutico , Doenças Cardiovasculares/etnologia , Doenças Cardiovasculares/prevenção & controle , Europa (Continente)/epidemiologia , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Frequência do Gene , Marcadores Genéticos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Haplótipos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Fenótipo , Prevenção Primária , Intervalo Livre de Progressão , Proteínas de Ligação a RNA , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Tromboxano B2/análogos & derivados , Tromboxano B2/urina , Fatores de Tempo
15.
Cell Adh Migr ; 12(1): 5-18, 2018 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-28346043

RESUMO

Contactin-5 (Cntn5) is an immunoglobulin cell adhesion molecule that is exclusively expressed in the central nervous system. In view of its association with neurodevelopmental disorders, particularly autism spectrum disorder (ASD), this study focused on Cntn5-positive areas in the forebrain and aimed to explore the morphological and behavioral phenotypes of the Cntn5 null mutant (Cntn5-/-) mouse in relation to these areas and ASD symptomatology. A newly generated antibody enabled us to elaborately describe the spatial expression pattern of Cntn5 in P7 wild type (Cntn5+/+) mice. The Cntn5 expression pattern included strong expression in the cerebral cortex, hippocampus and mammillary bodies in addition to described previously brain nuclei of the auditory pathway and the dorsal thalamus. Thinning of the primary somatosensory (S1) cortex was found in Cntn5-/- mice and ascribed to a misplacement of Cntn5-ablated cells. This phenotype was accompanied by a reduction in the barrel/septa ratio of the S1 barrel field. The structure and morphology of the hippocampus was intact in Cntn5-/- mice. A set of behavioral experiments including social, exploratory and repetitive behaviors showed that these were unaffected in Cntn5-/- mice. Taken together, these data demonstrate a selective role of Cntn5 in development of the cerebral cortex without overt behavioral phenotypes.


Assuntos
Comportamento Animal/fisiologia , Córtex Cerebral/crescimento & desenvolvimento , Contactinas/deficiência , Córtex Somatossensorial/anormalidades , Animais , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/patologia , Contactinas/metabolismo , Hipocampo/patologia , Camundongos Knockout , Proteínas do Tecido Nervoso/metabolismo
16.
J Clin Endocrinol Metab ; 103(1): 46-55, 2018 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-28938490

RESUMO

Context: Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine, usually benign, tumors. Currently, the only reliable criterion of malignancy is the presence of metastases. Objective: The aim of this study was to identify genes associated with malignancy in PPGLs. Design: Transcriptomic profiling was performed on 40 benign and 11 malignant PPGLs. Genes showing a significantly different expression between benign and malignant PPGLs with a ratio ≥4 were confirmed and tested in an independent series by quantitative real-time polymerase chain reaction (qRT-PCR). Immunohistochemistry was performed for the validated genes on 109 benign and 32 malignant PPGLs. Functional assays were performed with hPheo1 cells. Setting: This study was conducted at the Department of Pathology of the Erasmus MC University Medical Center Rotterdam Human Molecular Genetics laboratory of the de Duve Institute, University of Louvain. Patients: PPGL samples from 179 patients, diagnosed between 1972 and 2015, were included. Main outcome measures: Associations between gene expression and malignancy were tested using supervised clustering approaches. Results: Ten differentially expressed genes were selected based on messenger RNA (mRNA) expression array data. Contactin 4 (CNTN4) was overexpressed in malignant vs benign tumors [4.62-fold; false discovery rate (FDR), 0.001]. Overexpression at the mRNA level was confirmed using qRT-PCR (2.90-fold, P = 0.02; validation set: 4.26-fold, P = 0.005). Consistent findings were obtained in The Cancer Genome Atlas cohort (2.7-fold; FDR, 0.02). CNTN4 protein was more frequently expressed in malignant than in benign PPGLs by immunohistochemistry (58% vs 17%; P = 0.002). Survival after 7 days of culture under starvation conditions was significantly enhanced in hPheo1 cells transfected with CNTN4 complementary DNA. Conclusion: CNTN4 expression is consistently associated with malignant behavior in PPGLs.


Assuntos
Neoplasias das Glândulas Suprarrenais/diagnóstico , Biomarcadores Tumorais/metabolismo , Contactinas/metabolismo , Paraganglioma/diagnóstico , Feocromocitoma/diagnóstico , RNA Mensageiro/metabolismo , Neoplasias das Glândulas Suprarrenais/genética , Neoplasias das Glândulas Suprarrenais/metabolismo , Biomarcadores Tumorais/genética , Contactinas/genética , Perfilação da Expressão Gênica , Humanos , Paraganglioma/genética , Paraganglioma/metabolismo , Feocromocitoma/genética , Feocromocitoma/metabolismo , Prognóstico , RNA Mensageiro/genética
18.
Gene ; 630: 1-7, 2017 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-28782576

RESUMO

Colorectal cancer (CRC) is increasingly common worldwide, including in China. Therefore, there is an increasing need to detect CRC at an early stage and to discover and evaluate diagnostic and prognostic biomarkers. DNA methylation of genes in CRC is a potential epigenetic biomarker for the early detection of CRC. This study was performed to analyze the methylation frequency of six candidate genes, CMTM3, SSTR2, MDFI, NDRG4, TGFB2, and BCL2L11, in fresh-frozen CRC tissues and adjacent normal colorectal tissues, from 42 patients with CRC. DNA isolation, bisulphite modification, and pyrosequencing were performed. The sensitivity, specificity, and the area under the receiver operator characteristic (ROC) curve (AUC) were evaluated to determine whether these genes showed any associations with tumor grade, stage, or diagnostic features. Among the tested genes, three genes, CMTM3, SSTR2, and MDFI were significantly methylated in CRC tissues when compared with adjacent normal colorectal tissues. The ROC analysis showed that a multigene model, including CMTM3, SSTR2, and MDFI, had a sensitivity of 81% and a specificity of 91% with an AUC value of 0.92. The findings of this study have shown that DNA methylation of the genes, CMTM3, SSTR2, and MDFI should be studied further with a view to determining their potential role as biomarkers for CRC.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , Contactinas/genética , Metilação de DNA , Fatores de Regulação Miogênica/genética , Receptores de Somatostatina/genética , Proteína 11 Semelhante a Bcl-2/genética , Neoplasias Colorretais/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Musculares/genética , Proteínas do Tecido Nervoso/genética , Fator de Crescimento Transformador beta2/genética
19.
Neuron ; 95(4): 869-883.e6, 2017 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-28781169

RESUMO

The size and shape of dendritic arbors are prime determinants of neuronal connectivity and function. We asked how ON-OFF direction-selective ganglion cells (ooDSGCs) in mouse retina acquire their bistratified dendrites, in which responses to light onset and light offset are segregated to distinct strata. We found that the transcriptional regulator Satb1 is selectively expressed by ooDSGCs. In Satb1 mutant mice, ooDSGC dendrites lack ON arbors, and the cells selectively lose ON responses. Satb1 regulates expression of a homophilic adhesion molecule, Contactin 5 (Cntn5). Both Cntn5 and its co-receptor Caspr4 are expressed not only by ooDSGCs, but also by interneurons that form a scaffold on which ooDSGC ON dendrites fasciculate. Removing Cntn5 from either ooDSGCs or interneurons partially phenocopies Satb1 mutants, demonstrating that Satb1-dependent Cntn5 expression in ooDSGCs leads to branch-specific homophilic interactions with interneurons. Thus, Satb1 directs formation of a morphologically and functionally specialized compartment within a complex dendritic arbor.


Assuntos
Moléculas de Adesão Celular Neuronais/metabolismo , Contactinas/metabolismo , Dendritos/metabolismo , Retina/citologia , Células Ganglionares da Retina/citologia , Animais , Animais Recém-Nascidos , Caderinas/metabolismo , Moléculas de Adesão Celular Neuronais/genética , Citometria de Fluxo , Regulação da Expressão Gênica no Desenvolvimento/genética , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Células HEK293 , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Técnicas In Vitro , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Camundongos , Proteínas do Tecido Nervoso/metabolismo , Receptores de Dopamina D4/genética , Receptores de Dopamina D4/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Transdução Genética , beta-Galactosidase/genética , beta-Galactosidase/metabolismo
20.
Dev Biol ; 429(1): 35-43, 2017 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-28602954

RESUMO

Neuron-glial interactions are crucial for growth, guidance and ensheathment of axons across species. In the Drosophila CNS midline, neuron-glial interactions underlie ensheathment of commissural axons by midline glial (MG) cells in a manner similar to mammalian oligodendrocytes. Although there has been some advance in the study of neuron-glial interactions and ensheathment of axons in the CNS midline, key aspects of axonal ensheathment are still not fully understood. One of the limitations has been the unavailability of MG membrane markers that could highlight the glial processes wrapping the axons. Previous studies have identified two key molecular players from the neuronal and glial cell types in the CNS midline. These are the neuronal transmembrane protein Neurexin IV (Nrx IV) and the membrane-anchored MG protein Wrapper, both of which interact in trans to mediate neuron-glial interactions and ensheathment of commissural axons. In the current study, we attempt to further our understanding of MG biology and try to overcome some of the technical difficulties posed by the lack of a robust MG driver that will specifically allow expression or knockdown of genes in MG. We report the generation of BAC transgenic flies of wrapper-GAL4 and demonstrate how these flies could be used as a genetic tool to understand MG biology. We have utilized the GAL4/UAS system to drive GFP-reporter lines (membrane-bound mCD8-GFP; microtubule-associated tau-GFP) and nuclear lacZ using wrapper-GAL4 to highlight the MG cells and/or their processes that surround and perform axonal ensheathment functions in the embryonic midline. We also describe the utility of the wrapper-GAL4 driver line to down-regulate known MG genes specifically in Wrapper-positive cells. Finally, we validate the functionality of the wrapper-GAL4 driver by rescue of wrapper mutant phenotypes and lethality. Together, these studies provide us with a versatile genetic tool to investigate MG functions and will aid in future investigations where genetic screens using wrapper-GAL4 could be designed to identify novel molecular players at the Drosophila midline and unravel key aspects of MG biology.


Assuntos
Drosophila melanogaster/citologia , Técnicas Genéticas , Neuroglia/metabolismo , Animais , Contactinas/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Mutação/genética , Proteínas do Tecido Nervoso/metabolismo , Fenótipo , Fatores de Transcrição/metabolismo
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