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1.
NPJ Genom Med ; 6(1): 92, 2021 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-34750377

RESUMO

TET3 encodes an essential dioxygenase involved in epigenetic regulation through DNA demethylation. TET3 deficiency, or Beck-Fahrner syndrome (BEFAHRS; MIM: 618798), is a recently described neurodevelopmental disorder of the DNA demethylation machinery with a nonspecific phenotype resembling other chromatin-modifying disorders, but inconsistent variant types and inheritance patterns pose diagnostic challenges. Given TET3's direct role in regulating 5-methylcytosine and recent identification of syndrome-specific DNA methylation profiles, we analyzed genome-wide DNA methylation in whole blood of TET3-deficient individuals and identified an episignature that distinguishes affected and unaffected individuals and those with mono-allelic and bi-allelic pathogenic variants. Validation and testing of the episignature correctly categorized known TET3 variants and determined pathogenicity of variants of uncertain significance. Clinical utility was demonstrated when the episignature alone identified an affected individual from over 1000 undiagnosed cases and was confirmed upon distinguishing TET3-deficient individuals from those with 46 other disorders. The TET3-deficient signature - and the signature resulting from activating mutations in DNMT1 which normally opposes TET3 - are characterized by hypermethylation, which for BEFAHRS involves CpG sites that may be biologically relevant. This work expands the role of epi-phenotyping in molecular diagnosis and reveals genome-wide DNA methylation profiling as a quantitative, functional readout for characterization of this new biochemical category of disease.

3.
Int J Lab Hematol ; 2021 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-34713980

RESUMO

INTRODUCTION: In most laboratories, next generation sequencing (NGS) has been added without consideration for redundancy compared to conventional cytogenetics (CG). We tested a streamlined approach to genomic testing in patients with suspected myeloid and plasma cell neoplasms using next generation sequencing ("NGS first") as the primary testing modality and limiting cytogenetics (CG) to samples with morphologic abnormalities in the marrow aspirate. METHODS: Based on morphologic interpretation of bone marrow aspirate and flow cytometry, samples were triaged into four groups: (a) Samples with dysplasia or excess blasts had both NGS and karyotyping; (b) Samples without excess blasts or dysplasia had NGS only; (c) Repeat samples with previous NGS and/or CG studies were not retested; (d) Samples for suspected myeloma with less than 5% plasma cell had CG testing cancelled. RESULTS: Seven hundred eleven adult bone marrow (BM) samples met the study criteria. The NGS first algorithm eliminated CG testing in 229/303 (75.6%) of patients, primarily by reducing repeat testing. Potential cost avoided was approximately $124 000 per annum. Hematologists overruled the triage comment in only 11/303 (3.6%) cases requesting CG testing for a specific indication. CONCLUSIONS: Utilizing NGS as the primary genomic testing modality NGS was feasible and well accepted, reducing over three quarters of all CG requests and improving the financial case for adoption of NGS. Key factors for the success of this study were collaboration of clinical and genomic diagnostic teams in developing the algorithm, rapid turnaround time for BM interpretation for triage, and communication between laboratories.

4.
Int J Mol Sci ; 22(16)2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34445317

RESUMO

The 22q11.2 deletion syndrome (22q11.2DS) is the most common genomic disorder in humans and is the result of a recurrent 1.5 to 2.5 Mb deletion, encompassing approximately 20-40 genes, respectively. The clinical presentation of the typical deletion includes: Velocardiofacial, Di George, Opitz G/BBB and Conotruncalanomaly face syndromes. Atypical deletions (proximal, distal or nested) are rare and characterized mainly by normal phenotype or mild intellectual disability and variable clinical features. The pathogenetic mechanisms underlying this disorder are not completely understood. Because the 22q11.2 region harbours genes coding for transcriptional factors and chromatin remodelers, in this study, we performed analysis of genome-wide DNA methylation of peripheral blood from 49 patients with 22q11.2DS using the Illumina Infinium Methylation EPIC bead chip arrays. This cohort comprises 43 typical, 2 proximal and 4 distal deletions. We demonstrated the evidence of a unique and highly specific episignature in all typical and proximal 22q11.2DS. The sensitivity and specificity of this signature was further confirmed by comparing it to over 1500 patients with other neurodevelopmental disorders with known episignatures. Mapping the 22q11.2DS DNA methylation episignature provides both novel insights into the molecular pathogenesis of this disorder and an effective tool in the molecular diagnosis of 22q11.2DS.


Assuntos
Metilação de DNA , Síndrome de DiGeorge/genética , Epigenoma , Feminino , Humanos , Lactente , Masculino
5.
Front Genet ; 12: 698595, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34326862

RESUMO

Background: Hereditary cancer predisposition syndromes account for approximately 10% of cancer cases. Next generation sequencing (NGS) based multi-gene targeted panels is now a frontline approach to identify pathogenic mutations in cancer predisposition genes in high-risk families. Recent evolvement of NGS technologies have allowed simultaneous detection of sequence and copy number variants (CNVs) using a single platform. In this study, we have analyzed frequency and nature of sequence variants and CNVs, in a Canadian cohort of patients, suspected with hereditary cancer syndrome, referred for genetic testing following specific genetic testing guidelines based on patient's personal and/or family history of cancer. Methods: A 2870 patients were subjected to a single NGS based multi-gene targeted hereditary cancer panel testing algorithm to identify sequence variants and CNVs in cancer predisposition genes at our reference laboratory in Southwestern Ontario. CNVs identified by NGS were confirmed by alternative techniques like Multiplex ligation-dependent probe amplification (MLPA). Results: A 15% (431/2870) patients had a pathogenic variant and 36% (1032/2870) had a variant of unknown significance (VUS), in a cancer susceptibility gene. A total of 287 unique pathogenic variant were identified, out of which 23 (8%) were novel. CNVs identified by NGS based approach accounted for 9.5% (27/287) of pathogenic variants, confirmed by alternate techniques with high accuracy. Conclusion: This study emphasizes the utility of NGS based targeted testing approach to identify both sequence and CNVs in patients suspected with hereditary cancer syndromes in clinical setting and expands the mutational spectrum of high and moderate penetrance cancer predisposition genes.

7.
Am J Hum Genet ; 108(3): 502-516, 2021 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-33596411

RESUMO

Deletion 1p36 (del1p36) syndrome is the most common human disorder resulting from a terminal autosomal deletion. This condition is molecularly and clinically heterogeneous. Deletions involving two non-overlapping regions, known as the distal (telomeric) and proximal (centromeric) critical regions, are sufficient to cause the majority of the recurrent clinical features, although with different facial features and dysmorphisms. SPEN encodes a transcriptional repressor commonly deleted in proximal del1p36 syndrome and is located centromeric to the proximal 1p36 critical region. Here, we used clinical data from 34 individuals with truncating variants in SPEN to define a neurodevelopmental disorder presenting with features that overlap considerably with those of proximal del1p36 syndrome. The clinical profile of this disease includes developmental delay/intellectual disability, autism spectrum disorder, anxiety, aggressive behavior, attention deficit disorder, hypotonia, brain and spine anomalies, congenital heart defects, high/narrow palate, facial dysmorphisms, and obesity/increased BMI, especially in females. SPEN also emerges as a relevant gene for del1p36 syndrome by co-expression analyses. Finally, we show that haploinsufficiency of SPEN is associated with a distinctive DNA methylation episignature of the X chromosome in affected females, providing further evidence of a specific contribution of the protein to the epigenetic control of this chromosome, and a paradigm of an X chromosome-specific episignature that classifies syndromic traits. We conclude that SPEN is required for multiple developmental processes and SPEN haploinsufficiency is a major contributor to a disorder associated with deletions centromeric to the previously established 1p36 critical regions.


Assuntos
Transtornos Cromossômicos/genética , Cromossomos Humanos Par 1/genética , Cromossomos Humanos X/genética , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a RNA/genética , Adolescente , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/patologia , Criança , Pré-Escolar , Deleção Cromossômica , Transtornos Cromossômicos/fisiopatologia , Metilação de DNA/genética , Epigênese Genética/genética , Feminino , Haploinsuficiência/genética , Humanos , Deficiência Intelectual/genética , Deficiência Intelectual/fisiopatologia , Masculino , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/fisiopatologia , Fenótipo , Adulto Jovem
8.
Genet Med ; 23(6): 1065-1074, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33547396

RESUMO

PURPOSE: We describe the clinical implementation of genome-wide DNA methylation analysis in rare disorders across the EpiSign diagnostic laboratory network and the assessment of results and clinical impact in the first subjects tested. METHODS: We outline the logistics and data flow between an integrated network of clinical diagnostics laboratories in Europe, the United States, and Canada. We describe the clinical validation of EpiSign using 211 specimens and assess the test performance and diagnostic yield in the first 207 subjects tested involving two patient subgroups: the targeted cohort (subjects with previous ambiguous/inconclusive genetic findings including genetic variants of unknown clinical significance) and the screening cohort (subjects with clinical findings consistent with hereditary neurodevelopmental syndromes and no previous conclusive genetic findings). RESULTS: Among the 207 subjects tested, 57 (27.6%) were positive for a diagnostic episignature including 48/136 (35.3%) in the targeted cohort and 8/71 (11.3%) in the screening cohort, with 4/207 (1.9%) remaining inconclusive after EpiSign analysis. CONCLUSION: This study describes the implementation of diagnostic clinical genomic DNA methylation testing in patients with rare disorders. It provides strong evidence of clinical utility of EpiSign analysis, including the ability to provide conclusive findings in the majority of subjects tested.


Assuntos
Metilação de DNA , Epigenômica , Canadá , Europa (Continente) , Humanos , Síndrome
10.
Int J Mol Sci ; 22(3)2021 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-33498634

RESUMO

A growing number of genetic neurodevelopmental disorders are known to be associated with unique genomic DNA methylation patterns, called episignatures, which are detectable in peripheral blood. The intellectual developmental disorder, X-linked, syndromic, Armfield type (MRXSA) is caused by missense variants in FAM50A. Functional studies revealed the pathogenesis to be a spliceosomopathy that is characterized by atypical mRNA processing during development. In this study, we assessed the peripheral blood specimens in a cohort of individuals with MRXSA and detected a unique and highly specific DNA methylation episignature associated with this disorder. We used this episignature to construct a support vector machine model capable of sensitive and specific identification of individuals with pathogenic variants in FAM50A. This study contributes to the expanding number of genetic neurodevelopmental disorders with defined DNA methylation episignatures, provides an additional understanding of the associated molecular mechanisms, and further enhances our ability to diagnose patients with rare disorders.


Assuntos
Metilação de DNA , Retardo Mental Ligado ao Cromossomo X/genética , Adulto , Estudos de Casos e Controles , Criança , Proteínas de Ligação a DNA/genética , Epigenoma , Humanos , Masculino , Retardo Mental Ligado ao Cromossomo X/etiologia , Pessoa de Meia-Idade , Modelos Genéticos , Transtornos do Neurodesenvolvimento/genética , Proteínas de Ligação a RNA/genética
11.
Am J Med Genet A ; 185(2): 486-499, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33300680

RESUMO

Diagnosing mitochondrial disorders is a challenge due to the heterogeneous clinical presentation and large number of associated genes. A custom next generation sequencing (NGS) panel was developed incorporating the full mitochondrial genome (mtDNA) plus 19 nuclear genes involved in structural mitochondrial defects and mtDNA maintenance. This assay is capable of simultaneously detecting small gene sequence variations and larger copy number variants (CNVs) in both the nuclear and mitochondrial components along with heteroplasmy detection down to 5%. We describe technical validations of this panel and its implementation for clinical testing in a Canadian reference laboratory, and report its clinical performance in the initial 950 patients tested. Using this assay, we demonstrate a diagnostic yield of 18.1% of patients with known pathogenic variants. In addition to the common 5 kb mtDNA deletion, we describe significant contribution of pathogenic CNVs in both the mitochondrial genome and nuclear genes in this patient population.


Assuntos
Variações do Número de Cópias de DNA/genética , Genética Populacional , Sequenciamento de Nucleotídeos em Larga Escala , Doenças Mitocondriais/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Canadá/epidemiologia , Núcleo Celular/genética , Criança , Pré-Escolar , DNA Mitocondrial/genética , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Mitocôndrias/genética , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/epidemiologia , Doenças Mitocondriais/patologia , Adulto Jovem
12.
Hum Mol Genet ; 29(R1): R27-R32, 2020 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-32644126

RESUMO

The breadth and complexity of genetic testing in patients with suspected Mendelian neurodevelopmental disorders has rapidly expanded in the past two decades. However, in spite of advances in genomic technologies, genetic diagnosis remains elusive in more than half of these patients. Epigenomics, and in particular genomic DNA methylation profiles, are now known to be associated with the underpinning genetic defects in a growing number of Mendelian disorders. These often highly specific and sensitive molecular biomarkers have been used to screen these patient populations, resolve ambiguous clinical cases and interpret genetic variants of unknown clinical significance. Increasing the diagnostic yield beyond genomic sequencing technologies has rapidly propelled epigenomics to clinical utilization, with recent introduction of DNA methylation 'EpiSign' analysis in clinical diagnostic laboratories. This review provides an overview of the principles, applications and limitations of DNA methylation episignature analysis in patients with neurodevelopmental Mendelian disorders, and discusses clinical implications of this emerging diagnostic technology.


Assuntos
Biomarcadores/análise , Metilação de DNA , Epigênese Genética , Epigenômica , Variação Genética , Genoma , Transtornos do Neurodesenvolvimento/diagnóstico , Animais , Testes Genéticos , Humanos , Transtornos do Neurodesenvolvimento/genética , Fenótipo
13.
Am J Hum Genet ; 106(3): 356-370, 2020 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-32109418

RESUMO

Genetic syndromes frequently present with overlapping clinical features and inconclusive or ambiguous genetic findings which can confound accurate diagnosis and clinical management. An expanding number of genetic syndromes have been shown to have unique genomic DNA methylation patterns (called "episignatures"). Peripheral blood episignatures can be used for diagnostic testing as well as for the interpretation of ambiguous genetic test results. We present here an approach to episignature mapping in 42 genetic syndromes, which has allowed the identification of 34 robust disease-specific episignatures. We examine emerging patterns of overlap, as well as similarities and hierarchical relationships across these episignatures, to highlight their key features as they are related to genetic heterogeneity, dosage effect, unaffected carrier status, and incomplete penetrance. We demonstrate the necessity of multiclass modeling for accurate genetic variant classification and show how disease classification using a single episignature at a time can sometimes lead to classification errors in closely related episignatures. We demonstrate the utility of this tool in resolving ambiguous clinical cases and identification of previously undiagnosed cases through mass screening of a large cohort of subjects with developmental delays and congenital anomalies. This study more than doubles the number of published syndromes with DNA methylation episignatures and, most significantly, opens new avenues for accurate diagnosis and clinical assessment in individuals affected by these disorders.


Assuntos
Metilação de DNA , Transtornos do Neurodesenvolvimento/genética , Fenótipo , Estudos de Coortes , Heterogeneidade Genética , Humanos , Síndrome
14.
Eur J Haematol ; 103(3): 178-189, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31177553

RESUMO

OBJECTIVES: The diagnosis of hematologic malignancies integrates multiple diagnostic and clinical disciplines. Historically, targeted (single-analyte) genetic testing has been used as reflex to initial prescreening by other diagnostic modalities including flow cytometry, anatomic pathology, and clinical cytogenetics. Given the wide range of mutations associated with hematologic malignancies a DNA/RNA-based NGS panel can provide a more effective and economical approach to comprehensive testing of patients as an initial, tier-1 screen. METHODS: Using a cohort of 380 patients, we performed clinical validation of a gene panel designed to assess 40 genes (DNA), and 29 fusion driver genes with over 600 gene fusion partners (RNA), including sample exchange data across three clinical laboratories, and correlation with cytogenetic testing results. RESULTS: The clinical validation of this technology demonstrated that its accuracy, sensitivity, and specificity are comparable to the majority of targeted single-gene approaches, while assessment of the initial patient cohort data demonstrated a high diagnostic yield of 50.5%. CONCLUSIONS: Implementation of a tier-1 NGS-based protocol for gene panel screening provides a comprehensive alternative to targeted molecular testing in patients with suspected hematologic malignancies, with increased diagnostic yield, scalability, reproducibility, and cost effectiveness, making it ideally suited for implementation in clinical laboratories.


Assuntos
Biomarcadores Tumorais , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/genética , Sequenciamento de Nucleotídeos em Larga Escala , Proteínas de Fusão Oncogênica/genética , Biologia Computacional/métodos , Predisposição Genética para Doença , Testes Genéticos , Variação Genética , Genômica/métodos , Neoplasias Hematológicas/epidemiologia , Humanos , Mutação , Estudos Retrospectivos
15.
Clin Epigenetics ; 11(1): 64, 2019 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-31029150

RESUMO

BACKGROUND: ADNP syndrome is a rare Mendelian disorder characterized by global developmental delay, intellectual disability, and autism. It is caused by truncating mutations in ADNP, which is involved in chromatin regulation. We hypothesized that the disruption of chromatin regulation might result in specific DNA methylation patterns that could be used in the molecular diagnosis of ADNP syndrome. RESULTS: We identified two distinct and partially opposing genomic DNA methylation episignatures in the peripheral blood samples from 22 patients with ADNP syndrome. The "epi-ADNP-1" episignature included ~ 6000 mostly hypomethylated CpGs, and the "epi-ADNP-2" episignature included ~ 1000 predominantly hypermethylated CpGs. The two signatures correlated with the locations of the ADNP mutations. Epi-ADNP-1 mutations occupy the N- and C-terminus, and epi-ADNP-2 mutations are centered on the nuclear localization signal. The episignatures were enriched for genes involved in neuronal system development and function. A classifier trained on these profiles yielded full sensitivity and specificity in detecting patients with either of the two episignatures. Applying this model to seven patients with uncertain clinical diagnosis enabled reclassification of genetic variants of uncertain significance and assigned new diagnosis when the primary clinical suspicion was not correct. When applied to a large cohort of unresolved patients with developmental delay (N = 1150), the model predicted three additional previously undiagnosed patients to have ADNP syndrome. DNA sequencing of these subjects, wherever available, identified pathogenic mutations within the gene domains predicted by the model. CONCLUSIONS: We describe the first Mendelian condition with two distinct episignatures caused by mutations in a single gene. These highly sensitive and specific DNA methylation episignatures enable diagnosis, screening, and genetic variant classifications in ADNP syndrome.


Assuntos
Metilação de DNA , Proteínas de Homeodomínio/genética , Mutação , Proteínas do Tecido Nervoso/genética , Transtornos do Neurodesenvolvimento/diagnóstico , Transtornos do Neurodesenvolvimento/genética , Transtorno do Espectro Autista/genética , Criança , Pré-Escolar , Biologia Computacional/métodos , Ilhas de CpG , Diagnóstico Precoce , Epigênese Genética , Feminino , Humanos , Deficiência Intelectual/genética , Masculino , Modelos Genéticos
16.
Am J Hum Genet ; 104(4): 685-700, 2019 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-30929737

RESUMO

Conventional genetic testing of individuals with neurodevelopmental presentations and congenital anomalies (ND/CAs), i.e., the analysis of sequence and copy number variants, leaves a substantial proportion of them unexplained. Some of these cases have been shown to result from DNA methylation defects at a single locus (epi-variants), while others can exhibit syndrome-specific DNA methylation changes across multiple loci (epi-signatures). Here, we investigate the clinical diagnostic utility of genome-wide DNA methylation analysis of peripheral blood in unresolved ND/CAs. We generate a computational model enabling concurrent detection of 14 syndromes using DNA methylation data with full accuracy. We demonstrate the ability of this model in resolving 67 individuals with uncertain clinical diagnoses, some of whom had variants of unknown clinical significance (VUS) in the related genes. We show that the provisional diagnoses can be ruled out in many of the case subjects, some of whom are shown by our model to have other diseases initially not considered. By applying this model to a cohort of 965 ND/CA-affected subjects without a previous diagnostic assumption and a separate assessment of rare epi-variants in this cohort, we identify 15 case subjects with syndromic Mendelian disorders, 12 case subjects with imprinting and trinucleotide repeat expansion disorders, as well as 106 case subjects with rare epi-variants, a portion of which involved genes clinically or functionally linked to the subjects' phenotypes. This study demonstrates that genomic DNA methylation analysis can facilitate the molecular diagnosis of unresolved clinical cases and highlights the potential value of epigenomic testing in the routine clinical assessment of ND/CAs.


Assuntos
Anormalidades Congênitas/genética , Metilação de DNA , Doenças Genéticas Inatas/diagnóstico , Estudo de Associação Genômica Ampla , Estudos de Coortes , Simulação por Computador , Anormalidades Congênitas/diagnóstico , Variações do Número de Cópias de DNA , Epigenômica , Dosagem de Genes , Doenças Genéticas Inatas/genética , Variação Genética , Impressão Genômica , Humanos , Fenótipo , Análise de Sequência de DNA , Síndrome , Expansão das Repetições de Trinucleotídeos
17.
Epigenomics ; 11(5): 563-575, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30875234

RESUMO

Epigenetic and genetic mechanisms regulate the establishment and maintenance of gene expression in its proper context. Recent genome-wide mapping approaches have identified DNA methylation (DNAm) signatures in patients clinically diagnosed with syndromes manifesting as developmental disabilities with intellectual impairments. Here, we review recent studies in which these DNA methylation signatures have enabled highly sensitive and specific screening of such individuals and have clarified ambiguous cases where subjects present with genetic sequence variants of unknown clinical significance (VUS). We propose that these episignatures be considered as echoes and/or legacies of the initiating mutational events within proteins of the so-called epigenetic machinery. As well, we discuss approaches to directly confirm the functional consequences and the implications of these episignatures to patient management and treatment.


Assuntos
Metilação de DNA , Deficiências do Desenvolvimento/diagnóstico , Deficiência Intelectual/diagnóstico , Biomarcadores/sangue , Deficiências do Desenvolvimento/genética , Epigenômica , Expressão Gênica , Genótipo , Humanos , Deficiência Intelectual/genética , Fenótipo
18.
Hum Mol Genet ; 24(7): 1824-35, 2015 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-25452430

RESUMO

ATRX is a chromatin remodeling protein involved in deposition of the histone variant H3.3 at telomeres and pericentromeric heterochromatin. It also influences the expression level of specific genes; however, deposition of H3.3 at transcribed genes is currently thought to occur independently of ATRX. We focused on a set of genes, including the autism susceptibility gene Neuroligin 4 (Nlgn4), that exhibit decreased expression in ATRX-null cells to investigate the mechanisms used by ATRX to promote gene transcription. Overall TERRA levels, as well as DNA methylation and histone modifications at ATRX target genes are not altered and thus cannot explain transcriptional dysregulation. We found that ATRX does not associate with the promoter of these genes, but rather binds within regions of the gene body corresponding to high H3.3 occupancy. These intragenic regions consist of guanine-rich DNA sequences predicted to form non-B DNA structures called G-quadruplexes during transcriptional elongation. We demonstrate that ATRX deficiency corresponds to reduced H3.3 incorporation and stalling of RNA polymerase II at these G-rich intragenic sites. These findings suggest that ATRX promotes the incorporation of histone H3.3 at particular transcribed genes and facilitates transcriptional elongation through G-rich sequences. The inability to transcribe genes such as Nlgn4 could cause deficits in neuronal connectivity and cognition associated with ATRX mutations in humans.


Assuntos
DNA Helicases/metabolismo , Regulação da Expressão Gênica , Guanina/metabolismo , Retardo Mental Ligado ao Cromossomo X/metabolismo , Proteínas Nucleares/metabolismo , Transcrição Genética , Talassemia alfa/metabolismo , Animais , Cromatina/genética , Cromatina/metabolismo , DNA Helicases/genética , Metilação de DNA , Quadruplex G , Histonas/metabolismo , Humanos , Masculino , Retardo Mental Ligado ao Cromossomo X/embriologia , Retardo Mental Ligado ao Cromossomo X/genética , Camundongos , Camundongos Knockout , Mutação , Proteínas Nucleares/genética , Fases de Leitura Aberta , Regiões Promotoras Genéticas , Proteína Nuclear Ligada ao X , Talassemia alfa/embriologia , Talassemia alfa/genética
19.
Environ Manage ; 54(5): 1153-62, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25195033

RESUMO

Surface mining followed by reclamation to pasture is a major driver of land use and cover change in Appalachia. Prior research suggests that many aspects of ecosystem recovery are either slow or incomplete. We examined ecosystem structure-including soil physical and chemical properties, arbuscular mycorrhizal fungal (AMF) infectivity and community composition, and plant diversity and community composition-on a chronosequence of pasture-reclaimed surface mines and a non-mined pasture in northern West Virginia. Surface mining and reclamation dramatically altered ecosystem structure. Some aspects of ecosystem structure, including many measures of soil chemistry and infectivity of AMF, returned rapidly to levels found on the non-mined reference site. Other aspects of ecosystem structure, notably soil physical properties and AMF and plant communities, showed incomplete or no recovery over the short-to-medium term. In addition, invasive plants were prevalent on reclaimed mine sites. The results point to the need for investigation on how reclamation practices could minimize establishment of exotic invasive plant species and reduce the long-term impacts of mining on ecosystem structure and function.


Assuntos
Ecossistema , Recuperação e Remediação Ambiental/métodos , Espécies Introduzidas/estatística & dados numéricos , Mineração , Micorrizas/crescimento & desenvolvimento , Desenvolvimento Vegetal/fisiologia , Solo/química , Análise de Variância , Recuperação e Remediação Ambiental/estatística & dados numéricos , Funções Verossimilhança , West Virginia
20.
J Neurosci ; 28(47): 12570-80, 2008 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-19020049

RESUMO

ATRX, a chromatin remodeling protein of the Snf2 family, participates in diverse cellular functions including regulation of gene expression and chromosome alignment during mitosis and meiosis. Mutations in the human gene cause alpha thalassemia mental retardation, X-linked (ATR-X) syndrome, a rare disorder characterized by severe cognitive deficits, microcephaly and epileptic seizures. Conditional inactivation of the Atrx gene in the mouse forebrain leads to neonatal lethality and defective neurogenesis manifested by increased cell death and reduced cellularity in the developing neocortex and hippocampus. Here, we show that Atrx-null forebrains do not generate dentate granule cells due to a reduction in precursor cell number and abnormal migration of differentiating granule cells. In addition, fewer GABA-producing interneurons are generated that migrate from the ventral telencephalon to the cortex and hippocampus. Staining for cleaved caspase 3 demonstrated increased apoptosis in both the hippocampal hem and basal telencephalon concurrent with p53 pathway activation. Elimination of the tumor suppressor protein p53 in double knock-out mice rescued cell death in the embryonic telencephalon but only partially ameliorated the Atrx-null phenotypes at birth. Together, these findings show that ATRX deficiency leads to p53-dependent neuronal apoptosis which is responsible for some but not all of the phenotypic consequences of ATRX deficiency in the forebrain.


Assuntos
DNA Helicases/metabolismo , Neurônios/fisiologia , Proteínas Nucleares/metabolismo , Prosencéfalo/citologia , Proteína Supressora de Tumor p53/fisiologia , Animais , Animais Recém-Nascidos , Bromodesoxiuridina/metabolismo , Morte Celular/efeitos dos fármacos , Morte Celular/genética , Diferenciação Celular/genética , Movimento Celular/genética , Proliferação de Células , DNA Helicases/deficiência , Embrião de Mamíferos , Feminino , Regulação da Expressão Gênica no Desenvolvimento/genética , Hipocampo/embriologia , Hipocampo/metabolismo , Proteínas de Homeodomínio/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Mutação , Neurônios/efeitos dos fármacos , Proteínas Nucleares/deficiência , Gravidez , Transdução de Sinais/genética , Células-Tronco/fisiologia , Proteína Supressora de Tumor p53/genética , Proteínas Supressoras de Tumor/metabolismo , Proteína Nuclear Ligada ao X , Ácido gama-Aminobutírico/metabolismo
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