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3.
Nat Commun ; 9(1): 4619, 2018 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-30397230

RESUMO

Chromatin remodeling is of crucial importance during brain development. Pathogenic alterations of several chromatin remodeling ATPases have been implicated in neurodevelopmental disorders. We describe an index case with a de novo missense mutation in CHD3, identified during whole genome sequencing of a cohort of children with rare speech disorders. To gain a comprehensive view of features associated with disruption of this gene, we use a genotype-driven approach, collecting and characterizing 35 individuals with de novo CHD3 mutations and overlapping phenotypes. Most mutations cluster within the ATPase/helicase domain of the encoded protein. Modeling their impact on the three-dimensional structure demonstrates disturbance of critical binding and interaction motifs. Experimental assays with six of the identified mutations show that a subset directly affects ATPase activity, and all but one yield alterations in chromatin remodeling. We implicate de novo CHD3 mutations in a syndrome characterized by intellectual disability, macrocephaly, and impaired speech and language.

4.
Eur J Hum Genet ; 26(9): 1272-1281, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29904177

RESUMO

Au-Kline syndrome (AKS, OMIM 616580) is a multiple malformation syndrome, first reported in 2015, associated with intellectual disability. AKS has been associated with de novo loss-of-function variants in HNRNPK (heterogeneous ribonucleoprotein K), and to date, only four of these patients have been described in the literature. Recently, an additional patient with a missense variant in HNRNPK was also reported. These patients have striking facial dysmorphic features, including long palpebral fissures, ptosis, deeply grooved tongue, broad nose, and down-turned mouth. Patients frequently also have skeletal and connective tissue anomalies, craniosynostosis, congenital heart malformations, and renal anomalies. In this report, we describe six new patients and review the clinical information on all reported AKS patients, further delineating the phenotype of AKS. There are now a total of 9 patients with de novo loss-of-function variants in HNRNPK, one individual with a de novo missense variant in addition to 3 patients with de novo deletions of 9q21.32 that encompass HNRNPK. While there is considerable overlap between AKS and Kabuki syndrome (KS), these additional patients demonstrate that AKS does have a distinct facial gestalt and phenotype that can be differentiated from KS. This growing AKS patient cohort also informs an emerging approach to management and health surveillance for these patients.

5.
Am J Hum Genet ; 101(1): 139-148, 2017 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-28686853

RESUMO

We report 15 individuals with de novo pathogenic variants in WDR26. Eleven of the individuals carry loss-of-function mutations, and four harbor missense substitutions. These 15 individuals comprise ten females and five males, and all have intellectual disability with delayed speech, a history of febrile and/or non-febrile seizures, and a wide-based, spastic, and/or stiff-legged gait. These subjects share a set of common facial features that include a prominent maxilla and upper lip that readily reveal the upper gingiva, widely spaced teeth, and a broad nasal tip. Together, these features comprise a recognizable facial phenotype. We compared these features with those of chromosome 1q41q42 microdeletion syndrome, which typically contains WDR26, and noted that clinical features are consistent between the two subsets, suggesting that haploinsufficiency of WDR26 contributes to the pathology of 1q41q42 microdeletion syndrome. Consistent with this, WDR26 loss-of-function single-nucleotide mutations identified in these subjects lead to nonsense-mediated decay with subsequent reduction of RNA expression and protein levels. We derived a structural model of WDR26 and note that missense variants identified in these individuals localize to highly conserved residues of this WD-40-repeat-containing protein. Given that WDR26 mutations have been identified in ∼1 in 2,000 of subjects in our clinical cohorts and that WDR26 might be poorly annotated in exome variant-interpretation pipelines, we would anticipate that this disorder could be more common than currently appreciated.


Assuntos
Facies , Marcha/genética , Haploinsuficiência/genética , Deficiência Intelectual/genética , Proteínas/genética , Convulsões/genética , Sequência de Aminoácidos , Sequência de Bases , Pré-Escolar , Deleção Cromossômica , Feminino , Crescimento e Desenvolvimento/genética , Humanos , Deficiência Intelectual/complicações , Masculino , Mutação/genética , Proteínas/química , Estabilidade de RNA/genética , Convulsões/complicações , Síndrome
6.
Am J Hum Genet ; 97(6): 922-32, 2015 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-26637982

RESUMO

We describe an X-linked genetic syndrome associated with mutations in TAF1 and manifesting with global developmental delay, intellectual disability (ID), characteristic facial dysmorphology, generalized hypotonia, and variable neurologic features, all in male individuals. Simultaneous studies using diverse strategies led to the identification of nine families with overlapping clinical presentations and affected by de novo or maternally inherited single-nucleotide changes. Two additional families harboring large duplications involving TAF1 were also found to share phenotypic overlap with the probands harboring single-nucleotide changes, but they also demonstrated a severe neurodegeneration phenotype. Functional analysis with RNA-seq for one of the families suggested that the phenotype is associated with downregulation of a set of genes notably enriched with genes regulated by E-box proteins. In addition, knockdown and mutant studies of this gene in zebrafish have shown a quantifiable, albeit small, effect on a neuronal phenotype. Our results suggest that mutations in TAF1 play a critical role in the development of this X-linked ID syndrome.


Assuntos
Deficiências do Desenvolvimento/genética , Histona Acetiltransferases/genética , Deficiência Intelectual/genética , Doenças Neurodegenerativas/genética , Fatores Associados à Proteína de Ligação a TATA/genética , Fator de Transcrição TFIID/genética , Adolescente , Animais , Criança , Pré-Escolar , Deficiências do Desenvolvimento/metabolismo , Deficiências do Desenvolvimento/patologia , Modelos Animais de Doenças , Elementos E-Box , Facies , Família , Regulação da Expressão Gênica , Histona Acetiltransferases/metabolismo , Humanos , Lactente , Padrões de Herança , Deficiência Intelectual/metabolismo , Deficiência Intelectual/patologia , Masculino , Mutação , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Linhagem , Fenótipo , Transdução de Sinais , Fatores Associados à Proteína de Ligação a TATA/metabolismo , Fator de Transcrição TFIID/metabolismo , Adulto Jovem , Peixe-Zebra
7.
Hum Mutat ; 36(10): 1009-1014, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26173930

RESUMO

We report a new syndrome due to loss-of-function variants in the heterogeneous nuclear ribonucleoprotein K gene (HNRNPK). We describe two probands: one with a de novo frameshift (NM_002140.3: c.953+1dup), and the other with a de novo splice donor site variant (NM_002140.3: c.257G>A). Both probands have intellectual disability, a shared unique craniofacial phenotype, and connective tissue and skeletal abnormalities. The identification of this syndrome was made possible by a new online tool, GeneMatcher, which facilitates connections between clinicians and researchers based on shared interest in candidate genes. This report demonstrates that new Web-based approaches can be effective in helping investigators solve exome sequencing projects, and also highlights the newer paradigm of "reverse phenotyping," where characterization of syndromic features follows the identification of genetic variants.


Assuntos
Anormalidades Múltiplas/genética , Anormalidades Craniofaciais/genética , Bases de Dados Genéticas , Deficiência Intelectual/genética , Atrofia Muscular/genética , Polimorfismo de Nucleotídeo Único , Ribonucleoproteínas/genética , Adolescente , Criança , Predisposição Genética para Doença , Ribonucleoproteínas Nucleares Heterogêneas Grupo K , Humanos , Disseminação de Informação , Masculino , Fenótipo , Software , Navegador
8.
Am J Med Genet A ; 164A(2): 441-8, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24357076

RESUMO

A clinically recognizable syndrome associated with 1q41q42 microdeletion has recently been described in the literature (OMIM 612530). Patients with microdeletions in this region of chromosome 1 typically have developmental delay, characteristic dysmorphic features, and a predisposition to seizures. Malformations such as congenital diaphragmatic hernia and cleft lip have also been described. There has been considerable interest in mapping the smallest region of overlap for this syndrome in order to identify the critical pathogenic genes. The smallest region of overlap has recently been refined to a region encompassing four genes. Using array comparative genome hybridization (array CGH), we have identified a female with a 590-kB deletion within chromosome1q41q42. This patient's deletion further refines the previously defined region of overlap to a single gene, FBXO28. We propose that FBXO28 is a possible candidate causative gene contributing to the intellectual disability and seizure phenotype observed in 1q41q42 microdeletion syndrome.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 1 , Deficiência Intelectual/genética , Proteínas Ligases SKP Culina F-Box/genética , Convulsões/genética , Adolescente , Criança , Pré-Escolar , Hibridização Genômica Comparativa , Facies , Feminino , Humanos , Hibridização in Situ Fluorescente , Lactente , Recém-Nascido , Síndrome
9.
Am J Med Genet A ; 164A(3): 676-84, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24357594

RESUMO

Shprintzen-Goldberg syndrome (OMIM #182212) is a connective tissue disorder characterized by craniosynostosis, distinctive craniofacial features, skeletal abnormalities, marfanoid body habitus, aortic dilatation, and intellectual disability. Mutations in exon 1 of SKI have recently been identified as being responsible for approximately 90% of reported individuals diagnosed clinically with Shprintzen-Goldberg syndrome. SKI is a known regulator of TGFß signaling. Therefore, like Marfan syndrome and Loeys-Dietz syndrome, Shprintzen-Goldberg syndrome is likely caused by deregulated TGFß signals, explaining the considerable phenotypic overlap between these three disorders. We describe two additional patients with exon 1 SKI mutations and review the clinical features and literature of Shprintzen-Goldberg syndrome.


Assuntos
Aracnodactilia/diagnóstico , Aracnodactilia/genética , Craniossinostoses/diagnóstico , Craniossinostoses/genética , Proteínas de Ligação a DNA/genética , Éxons , Síndrome de Marfan/diagnóstico , Síndrome de Marfan/genética , Mutação de Sentido Incorreto , Proteínas Proto-Oncogênicas/genética , Encéfalo/patologia , Pré-Escolar , Facies , Feminino , Humanos , Imagem por Ressonância Magnética , Fenótipo , Medula Espinal/patologia , Tomografia Computadorizada por Raios X
10.
Clin Cancer Res ; 12(18): 5557-69, 2006 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-17000693

RESUMO

PURPOSE: This study aims to identify a novel therapeutic agent for head and neck cancer and to evaluate its antitumor efficacy. EXPERIMENTAL DESIGN: A cell-based and phenotype-driven high-throughput screening of approximately 2,400 biologically active or clinically used compounds was done using a tetrazolium-based assay on FaDu (hypopharyngeal squamous cancer) and NIH 3T3 (untransformed mouse embryonic fibroblast) cells, with secondary screening done on C666-1 (nasopharyngeal cancer) and GM05757 (primary normal human fibroblast) lines. The "hit" compound was assayed for efficacy in combination with standard therapeutics on a panel of human cancer cell lines. Furthermore, its mode of action (using transmission electron microscopy and flow cytometry) and its in vivo efficacy (using xenograft models) were evaluated. RESULTS: Benzethonium chloride was identified as a novel cancer-specific compound. For benzethonium (48-hour incubation), the dose required to reduce cell viability by 50% was 3.8 micromol/L in FaDu, 42.2 micromol/L in NIH 3T3, 5.3 micromol/L in C666-1, and 17.0 micromol/L in GM05757. In vitro, this compound did not interfere with the effects of cisplatin, 5-fluorouracil, or gamma-irradiation. Benzethonium chloride induced apoptosis and activated caspases after 12 hours. Loss of mitochondrial membrane potential (DeltaPsiM) preceded cytosolic Ca2+ increase and cell death. In vivo, benzethonium chloride ablated the tumor-forming ability of FaDu cells, delayed the growth of xenograft tumors, and combined additively with local tumor radiation therapy. Evaluation of benzethonium chloride on the National Cancer Institute/NIH Developmental Therapeutics Program 60 human cancer cell lines revealed broad-range antitumor activity. CONCLUSIONS: This high-throughput screening identified a novel antimicrobial compound with significant broad-spectrum anticancer activity.


Assuntos
Antineoplásicos/isolamento & purificação , Benzetônio/isolamento & purificação , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Análise Serial de Tecidos/métodos , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Benzetônio/farmacologia , Benzetônio/uso terapêutico , Cálcio/metabolismo , Caspases/metabolismo , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Sobrevivência Celular/efeitos dos fármacos , Quimioterapia Combinada , Feminino , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/radioterapia , Humanos , Potenciais da Membrana/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos SCID , Membranas Mitocondriais/efeitos dos fármacos , Modelos Biológicos , Células NIH 3T3 , Neoplasias/tratamento farmacológico , Neoplasias/radioterapia , Radiossensibilizantes/farmacologia , Radiossensibilizantes/uso terapêutico , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
11.
Mol Cancer Ther ; 5(9): 2234-40, 2006 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16985057

RESUMO

Despite advances in surgery, radiation, and chemotherapy, novel therapeutics are needed for head and neck cancer treatment. The objective of this current study was to evaluate alexidine dihydrochloride as a novel compound lead for head and neck cancers. Using a tetrazolium-based assay, the dose required to reduce cell viability by 50% (ED50) was found to be approximately 1.8 micromol/L in FaDu (human hypopharyngeal squamous cancer) and approximately 2.6 micromol/L in C666-1 (human undifferentiated nasopharyngeal cancer) cells. In contrast, the ED50 values were much higher in untransformed cells, specifically at approximately 8.8 micromol/L in GM05757 (primary normal human fibroblast), approximately 8.9 micromol/L in HNEpC (primary normal human nasal epithelial), and approximately 19.6 micromol/L in NIH/3T3 (mouse embryonic fibroblast) cells. Alexidine dihydrochloride did not interfere with the activities of cisplatin, 5-fluorouracil, or radiation, and interacted in a less-than-additive manner. DNA content analyses and Hoechst 33342 staining revealed that this compound induced apoptosis. Alexidine dihydrochloride-induced mitochondrial damage was visualized using transmission electron microscopy. Mitochondrial membrane potential (DeltaPsiM) depolarization was detectable after only 3 hours of treatment, and was followed by cytosolic Ca2+ increase along with loss of membrane integrity/cell death. Caspase-2 and caspase-9 activities were detectable at 12 hours, caspase-8 at 24 hours, and caspase-3 at 48 hours. FaDu cell clonogenic survival was reduced to < 5% with 1 micromol/L alexidine dihydrochloride, and, correspondingly, this compound decreased the in vivo tumor-forming potential of FaDu cells. Thus, we have identified alexidine dihydrochloride as the first bisbiguanide compound with anticancer specificity.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Biguanidas/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias Hipofaríngeas/tratamento farmacológico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Biguanidas/administração & dosagem , Carcinoma de Células Escamosas/patologia , Caspase 2/metabolismo , Caspase 9/metabolismo , Cisplatino/administração & dosagem , Ativação Enzimática/efeitos dos fármacos , Feminino , Fluoruracila/administração & dosagem , Humanos , Neoplasias Hipofaríngeas/patologia , Potenciais da Membrana/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos SCID , Membranas Mitocondriais/efeitos dos fármacos , Membranas Mitocondriais/fisiologia , Células NIH 3T3 , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Clin Cancer Res ; 11(22): 8131-44, 2005 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-16299246

RESUMO

PURPOSE: A wide variety of tumors depend on the dysregulation of Bcl-2 family proteins for survival. The resulting apoptotic block can often provide a mechanism for resistance to anticancer treatments, such as chemotherapy and radiation. This current study evaluates the efficacy of combining systemically delivered Bcl-2 phosphorothioate antisense (Bcl-2 ASO) and radiation for nasopharyngeal cancer therapy. RESULTS: Antisense uptake was unaffected by 0, 3, or 6 Gy radiation. Radiation decreased the fraction of viable C666-1 cells to 60%, with a further decrease to 40% in combination with Bcl-2 ASO. Despite a modest in vitro effect, Bcl-2 ASO alone caused the regression of established xenograft tumors in mice, extending survival by 15 days in a C666-1 and by 6 days in a C15 model. The survival times for mice treated with both Bcl-2 ASO and radiation increased by 52 days in C666-1 and by 20 days in C15 tumors. This combination resulted in a more-than-additive effect in C666-1 tumors. Less impressive gains observed in C15 tumors might be attributable to higher expression of antiapoptotic Bcl-2 family proteins and limited drug distribution in the tumor. Retreatment of C666-1 tumors with the Bcl-2 ASO-radiation combination, however, was effective, resulting in mice surviving for >80 days relative to untreated controls. CONCLUSIONS: Our results show that the Bcl-2 ASO and radiation combination is a highly potent therapy for nasopharyngeal cancer. Further examination of combination therapy with radiation and other Bcl-2 family-targeted anticancer agents in both preclinical and clinical settings is definitely warranted.


Assuntos
Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/radioterapia , Oligonucleotídeos Antissenso/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Animais , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Vasos Sanguíneos/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Terapia Combinada , Feminino , Fluoresceína-5-Isotiocianato/química , Fluoresceína-5-Isotiocianato/farmacocinética , Humanos , Rim/metabolismo , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos SCID , Microscopia de Fluorescência , Neoplasias Nasofaríngeas/patologia , Oligonucleotídeos Antissenso/genética , Oligonucleotídeos Antissenso/farmacocinética , Radiação Ionizante , Distribuição Tecidual , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
13.
Oncogene ; 24(19): 3196-205, 2005 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-15735680

RESUMO

Tumor necrosis factor (TNF) induces both cell death and survival signals. NF-kappaB, a transcription factor activated by TNF, is critical for controlling survival signals through trans-activation of downstream target genes. However, few NF-kappaB target survival genes have been identified with direct roles in oncogenesis. We report that platelet-derived growth factor B (PDGF-B), an oncogene and growth factor, is highly induced by TNF in fibroblasts in an NF-kappaB-dependent manner. PDGF-B can rescue NF-kappaB-deficient fibroblasts from TNF-mediated killing, and inhibition of PDGF-B signaling sensitizes wild-type cells to TNF-induced death. Interestingly, PDGF-B-transformed NIH-3T3 cells are even more highly sensitized to TNF-induced cell death with PDGF-B inhibition. Our results suggest that while normal cells contain multiple TNF-induced survival signals, tumor cells may favor a specific survival gene that is abnormally upregulated in order to evade death signals.


Assuntos
Proteínas Proto-Oncogênicas c-sis/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Células 3T3 , Animais , Apoptose , Northern Blotting , Western Blotting , Caspase 3 , Caspases/metabolismo , Morte Celular , Linhagem Celular Transformada , Separação Celular , Sobrevivência Celular , Células Cultivadas , Meios de Cultura Livres de Soro/farmacologia , Fibroblastos/metabolismo , Citometria de Fluxo , Quinase I-kappa B , Camundongos , Modelos Biológicos , NF-kappa B/metabolismo , Células NIH 3T3 , Proteínas Serina-Treonina Quinases/metabolismo , Receptores do Fator de Crescimento Derivado de Plaquetas/metabolismo , Transdução de Sinais , Fatores de Tempo , Transcrição Genética , Regulação para Cima
14.
Genes Dev ; 17(7): 883-95, 2003 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-12654726

RESUMO

Defects in death receptor-mediated apoptosis have been linked to cancer and autoimmune disease in humans. The in vivo role of caspase 8, a component of this pathway, has eluded analysis in postnatal tissues because of the lack of an appropriate animal model. Targeted disruption of caspase 8 is lethal in utero. We generated mice with a targeted caspase 8 mutation that is restricted to the T-cell lineage. Despite normal thymocyte development in the absence of caspase 8, we observed a marked decrease in the number of peripheral T-cells and impaired T-cell response ex vivo to activation stimuli. caspase 8 ablation protected thymocytes and activated T-cells from CD95 ligand but not anti-CD3-induced apoptosis, or apoptosis activated by agents that are known to act through the mitochondria. caspase 8 mutant mice were unable to mount an immune response to viral infection, indicating that caspase 8 deletion in T-cells leads to immunodeficiency. These findings identify an essential, cell-stage-specific role for caspase 8 in T-cell homeostasis and T-cell-mediated immunity. This is consistent with the recent identification of caspase 8 mutations in human immunodeficiency.


Assuntos
Caspases/genética , Caspases/metabolismo , Imunidade Celular/fisiologia , Ativação Linfocitária/genética , Linfócitos T/fisiologia , Animais , Sequência de Bases , Caspase 8 , Caspase 9 , Caspases/deficiência , Primers do DNA , Eletroporação , Regulação da Expressão Gênica no Desenvolvimento , Genótipo , Homeostase , Camundongos , Camundongos Knockout , Reação em Cadeia da Polimerase , Linfócitos T/imunologia , Timidina Quinase/genética
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