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1.
Nucleic Acids Res ; 51(W1): W39-W45, 2023 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-37216590

RESUMO

Much of the human genetics variant repertoire is composed of single nucleotide variants (SNV) and small insertion/deletions (indel) but structural variants (SV) remain a major part of our modified DNA. SV detection has often been a complex question to answer either because of the necessity to use different technologies (array CGH, SNP array, Karyotype, Optical Genome Mapping…) to detect each category of SV or to get an appropriate resolution (Whole Genome Sequencing). Thanks to the deluge of pangenomic analysis, Human geneticists are accumulating SV and their interpretation remains time consuming and challenging. The AnnotSV webserver (https://www.lbgi.fr/AnnotSV/) aims at being an efficient tool to (i) annotate and interpret SV potential pathogenicity in the context of human diseases, (ii) recognize potential false positive variants from all the SV identified and (iii) visualize the patient variants repertoire. The most recent developments in the AnnotSV webserver are: (i) updated annotations sources and ranking, (ii) three novel output formats to allow diverse utilization (analysis, pipelines), as well as (iii) two novel user interfaces including an interactive circos view.


Assuntos
Mutação INDEL , Polimorfismo de Nucleotídeo Único , Software , Humanos , Genoma Humano , Sequenciamento de Nucleotídeos em Larga Escala , Mapeamento por Restrição , Análise de Sequência de DNA , Sequenciamento Completo do Genoma , Doença/genética
2.
Nucleic Acids Res ; 49(W1): W21-W28, 2021 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-34023905

RESUMO

With the dramatic increase of pangenomic analysis, Human geneticists have generated large amount of genomic data including millions of small variants (SNV/indel) but also thousands of structural variations (SV) mainly from next-generation sequencing and array-based techniques. While the identification of the complete SV repertoire of a patient is getting possible, the interpretation of each SV remains challenging. To help identifying human pathogenic SV, we have developed a web server dedicated to their annotation and ranking (AnnotSV) as well as their visualization and interpretation (knotAnnotSV) freely available at the following address: https://www.lbgi.fr/AnnotSV/. A large amount of annotations from >20 sources is integrated in our web server including among others genes, haploinsufficiency, triplosensitivity, regulatory elements, known pathogenic or benign genomic regions, phenotypic data. An ACMG/ClinGen compliant prioritization module allows the scoring and the ranking of SV into 5 SV classes from pathogenic to benign. Finally, the visualization interface displays the annotated SV in an interactive way including popups, search fields, filtering options, advanced colouring to highlight pathogenic SV and hyperlinks to the UCSC genome browser or other public databases. This web server is designed for diagnostic and research analysis by providing important resources to the user.


Assuntos
Variação Estrutural do Genoma , Software , Genoma Humano , Genômica , Humanos , Internet , Anotação de Sequência Molecular , Fenótipo , Polimorfismo de Nucleotídeo Único
3.
Int J Mol Sci ; 24(8)2023 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-37108493

RESUMO

The transition from targeted to exome or genome sequencing in clinical contexts requires quality standards, such as targeted sequencing, in order to be fully adopted. However, no clear recommendations or methodology have emerged for evaluating this technological evolution. We developed a structured method based on four run-specific sequencing metrics and seven sample-specific sequencing metrics for evaluating the performance of exome sequencing strategies to replace targeted strategies. The indicators include quality metrics and coverage performance on gene panels and OMIM morbid genes. We applied this general strategy to three different exome kits and compared them with a myopathy-targeted sequencing method. After having achieved 80 million reads, all-tested exome kits generated data suitable for clinical diagnosis. However, significant differences in the coverage and PCR duplicates were observed between the kits. These are two main criteria to consider for the initial implementation with high-quality assurance. This study aims to assist molecular diagnostic laboratories in adopting and evaluating exome sequencing kits in a diagnostic context compared to the strategy used previously. A similar strategy could be used to implement whole-genome sequencing for diagnostic purposes.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Laboratórios Clínicos , Sequenciamento do Exoma , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Sequenciamento Completo do Genoma , Sequência de Bases , Análise de Sequência de DNA/métodos
4.
Genet Med ; 22(3): 547-556, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31649276

RESUMO

PURPOSE: Treacher Collins syndrome (TCS) is a rare autosomal dominant mandibulofacial dysostosis, with a prevalence of 0.2-1/10,000. Features include bilateral and symmetrical malar and mandibular hypoplasia and facial abnormalities due to abnormal neural crest cell (NCC) migration and differentiation. To date, three genes have been identified: TCOF1, POLR1C, and POLR1D. Despite a large number of patients with a molecular diagnosis, some remain without a known genetic anomaly. METHODS: We performed exome sequencing for four individuals with TCS but who were negative for pathogenic variants in the known causative genes. The effect of the pathogenic variants was investigated in zebrafish. RESULTS: We identified three novel pathogenic variants in POLR1B. Knockdown of polr1b in zebrafish induced an abnormal craniofacial phenotype mimicking TCS that was associated with altered ribosomal gene expression, massive p53-associated cellular apoptosis in the neuroepithelium, and reduced number of NCC derivatives. CONCLUSION: Pathogenic variants in the RNA polymerase I subunit POLR1B might induce massive p53-dependent apoptosis in a restricted neuroepithelium area, altering NCC migration and causing cranioskeletal malformations. We identify POLR1B as a new causative gene responsible for a novel TCS syndrome (TCS4) and establish a novel experimental model in zebrafish to study POLR1B-related TCS.


Assuntos
Anormalidades Craniofaciais/genética , RNA Polimerases Dirigidas por DNA/genética , Disostose Mandibulofacial/genética , Proteínas Nucleares/genética , Fosfoproteínas/genética , Animais , Apoptose/genética , Diferenciação Celular/genética , Movimento Celular/genética , Anormalidades Craniofaciais/patologia , Predisposição Genética para Doença , Humanos , Disostose Mandibulofacial/patologia , Mutação , Crista Neural/anormalidades , Crista Neural/patologia , Proteína Supressora de Tumor p53/genética , Sequenciamento do Exoma , Peixe-Zebra/genética
5.
Hum Mol Genet ; 26(22): 4367-4374, 2017 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-28973654

RESUMO

In this study, we report a novel duplication causing North Carolina macular dystrophy (NCMD) identified applying whole genome sequencing performed on eight affected members of two presumed unrelated families mapping to the MCDR1 locus. In our families, the NCMD phenotype was associated with a 98.4 kb tandem duplication encompassing the entire CCNC and PRDM13 genes and a common DNase 1 hypersensitivity site. To study the impact of PRDM13 or CCNC dysregulation, we used the Drosophila eye development as a model. Knock-down and overexpression of CycC and CG13296, Drosophila orthologues of CCNC and PRDM13, respectively, were induced separately during eye development. In flies, eye development was not affected, while knocking down either CycC or CG13296 mutant models. Overexpression of CycC also had no effect. Strikingly, overexpression of CG13296 in Drosophila leads to a severe loss of the imaginal eye-antennal disc. This study demonstrated for the first time in an animal model that overexpression of PRDM13 alone causes a severe abnormal retinal development. It is noteworthy that mutations associated with this autosomal dominant foveal developmental disorder are frequently duplications always including an entire copy of PRDM13, or variants in one DNase 1 hypersensitivity site at this locus.


Assuntos
Distrofias Hereditárias da Córnea/genética , Ciclina C/genética , Histona-Lisina N-Metiltransferase/genética , Adulto , Animais , Mapeamento Cromossômico , Cromossomos Humanos Par 6 , Distrofias Hereditárias da Córnea/metabolismo , Ciclina C/metabolismo , Drosophila melanogaster , Proteínas do Olho/genética , Feminino , Ligação Genética , Haplótipos , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Masculino , Domínios PR-SET , Linhagem , Sequenciamento Completo do Genoma
6.
Genet Med ; 20(2): 269-274, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28771243

RESUMO

PurposeBased on prenatal suspicion of the combination of radioulnar or radiohumeral synostosis and a peculiar shape of the skull suggestive of craniosynostosis, we report on six patients from four unrelated consanguineous families in whom Antley-Bixler syndrome was suspected during the prenatal period without mutation in genes known to be associated with the syndrome.MethodsMolecular diagnosis involved whole-exome and gene-panel sequencing. RESULTS: All sequenced patients showed a unique homozygous mutation of c.667G>A, p.Gly223Ser (NM_012200) in the beta-1,3-glucuronyltransferase 3 (B3GAT3) gene known to be involved in linkeropathy syndrome. Linkeropathies correspond to a recently identified group of heterogeneous genetic syndromes along a spectrum of skeletal and connective tissue disorders. These patients featured mainly craniosynostosis, midface hypoplasia, bilateral radioulnar synostosis, multiple neonatal fractures, dislocated joints, joint contracture, long fingers, foot deformity, and cardiovascular abnormalities. All died before 1 year of age.ConclusionWe identified a novel B3GAT3-related disorder with craniosynostosis and bone fragility, due to a unique homozygous mutation in B3GAT3. This syndrome should be considered in the prenatal period in light of the severe outcome and as an alternative diagnosis to Antley-Bixler or Shprintzen-Goldberg syndrome.


Assuntos
Osso e Ossos/anormalidades , Osso e Ossos/metabolismo , Craniossinostoses/diagnóstico , Craniossinostoses/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Glucuronosiltransferase/genética , Mutação , Osso e Ossos/patologia , Diagnóstico Diferencial , Humanos , Fenótipo , Análise de Sequência de DNA , Crânio/anormalidades , Crânio/diagnóstico por imagem , Síndrome , Ultrassonografia Pré-Natal , Sequenciamento Completo do Genoma
7.
Front Oncol ; 14: 1355715, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38487723

RESUMO

Introduction: Accurate identification and characterization of Large Genomic Rearrangements (LGR), especially duplications, are crucial for precise diagnosis and risk assessment. In this report, we characterized an intragenic duplication breakpoint of PALB2 to determine its pathogenicity significance. Methods: A 52-year-old female with triple-negative breast cancer was diagnosed with a novel PALB2 LGR. An efficient and accurate methodology was applied, combining long-read sequencing and transcript analysis for the rapid characterization of the duplication. Results: Duplication of exons 5 and 6 of PALB2 was validated by transcript analysis. Long-read sequencing enabled the localization of breakpoints within Alu elements, providing insights into the mechanism of duplication via non-allelic homologous recombination. Conclusion: Using our combined methodology, we reclassified the PALB2 duplication as a pathogenic variant. This reclassification suggests a possible causative link between this specific genetic alteration and the aggressive phenotype of the patient.

8.
Front Cell Dev Biol ; 11: 1112270, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36819107

RESUMO

Introduction: Retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA) are two groups of inherited retinal diseases (IRDs) where the rod photoreceptors degenerate followed by the cone photoreceptors of the retina. A genetic diagnosis for IRDs is challenging since >280 genes are associated with these conditions. While whole exome sequencing (WES) is commonly used by diagnostic facilities, the costs and required infrastructure prevent its global applicability. Previous studies have shown the cost-effectiveness of sequence analysis using single molecule Molecular Inversion Probes (smMIPs) in a cohort of patients diagnosed with Stargardt disease and other maculopathies. Methods: Here, we introduce a smMIPs panel that targets the exons and splice sites of all currently known genes associated with RP and LCA, the entire RPE65 gene, known causative deep-intronic variants leading to pseudo-exons, and part of the RP17 region associated with autosomal dominant RP, by using a total of 16,812 smMIPs. The RP-LCA smMIPs panel was used to screen 1,192 probands from an international cohort of predominantly RP and LCA cases. Results and discussion: After genetic analysis, a diagnostic yield of 56% was obtained which is on par with results from WES analysis. The effectiveness and the reduced costs compared to WES renders the RP-LCA smMIPs panel a competitive approach to provide IRD patients with a genetic diagnosis, especially in countries with restricted access to genetic testing.

9.
J Mol Diagn ; 24(7): 719-726, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35580751

RESUMO

Titin protein is responsible for muscle elasticity. The TTN gene, composed of 364 exons, is subjected to extensive alternative splicing and leads to different isoforms expressed in skeletal and cardiac muscle. Variants in TTN are responsible for myopathies with a wide phenotypic spectrum and autosomal dominant or recessive transmission. The I-band coding domain, highly subject to alternative splicing, contains a three-zone block of repeated sequences with 99% homology. Sequencing and localization of variants in these areas are complex when using short-reads sequencing, a second-generation sequencing technique. We have implemented a protocol based on the third-generation sequencing technology (long-reads sequencing). This new method allows us to localize variants in these repeated areas to improve the diagnosis of TTN-related myopathies and offer the analysis of relatives in postnatal or in prenatal screening.


Assuntos
Doenças Musculares , Processamento Alternativo/genética , Conectina/genética , Éxons/genética , Humanos , Doenças Musculares/genética , Isoformas de Proteínas/genética
10.
Eur J Hum Genet ; 30(9): 1076-1082, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35729264

RESUMO

This monocentric study included fifteen children under a year old in intensive care with suspected monogenic conditions for rapid trio exome sequencing (rES) between April 2019 and April 2021. The primary outcome was the time from blood sampling to rapid exome sequencing report to parents. All results were available within 16 days and were reported to parents in or under 16 days in 13 of the 15 individuals (86%). Six individuals (40%) received a diagnosis with rES, two had a genetic condition not diagnosed by rES. Eight individuals had their care impacted by their rES results, four were discharged or died before the results. This small-scale study shows that rES can be implemented in a regional University hospital with rapid impactful diagnosis to improve care in critically ill infants.


Assuntos
Estado Terminal , Exoma , Adolescente , Criança , Hospitais , Humanos , Lactente , Pais , Sequenciamento do Exoma/métodos
11.
J Biol Chem ; 285(24): 18759-68, 2010 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-20356843

RESUMO

The isomerization of all-trans retinol (vitamin A) to 11-cis retinol in the retinal pigment epithelium (RPE) is a key step in the visual process for the regeneration of the visual pigment chromophore, 11-cis retinal. LRAT and RPE65 are recognized as the minimal isomerase catalytic components. However, regulators of this rate-limiting step are not fully identified and could account for the phenotypic variability associated with inherited retinal degeneration (RD) caused by mutations in the RPE65 gene. To identify new RPE65 partners, we screened a porcine RPE mRNA library using a yeast two-hybrid assay with full-length human RPE65. One identified clone (here named FATP1c), containing the cytosolic C-terminal sequence from the fatty acid transport protein 1 (FATP1 or SLC27A1, solute carrier family 27 member 1), was demonstrated to interact dose-dependently with the native RPE65 and with LRAT. Furthermore, these interacting proteins colocalize in the RPE. Cellular reconstitution of human interacting proteins shows that FATP1 markedly inhibits 11-cis retinol production by acting on the production of all-trans retinyl esters and the isomerase activity of RPE65. The identification of this new visual cycle inhibitory component in RPE may contribute to further understanding of retinal pathogenesis.


Assuntos
Aciltransferases/metabolismo , Proteínas de Transporte/metabolismo , Proteínas do Olho/metabolismo , Proteínas de Transporte de Ácido Graxo/metabolismo , Vitamina A/antagonistas & inibidores , Animais , Glutationa Transferase/metabolismo , Humanos , Insetos , Camundongos , Fenótipo , Retina/metabolismo , Frações Subcelulares/metabolismo , Suínos , Fatores de Tempo , Técnicas do Sistema de Duplo-Híbrido , Vitamina A/química , cis-trans-Isomerases
12.
Eur J Hum Genet ; 29(2): 356-360, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33161418

RESUMO

MobiDetails is an expert tool, online application which gathers useful data for the interpretation of DNA variants in the context of molecular diagnosis. It brings together in a single tool many sources of data, such as population genetics, various kinds of predictors, Human Genome Variation Society (HGVS) nomenclatures, curated databases, and access to various annotations. Accurate interpretation of DNA variants is crucial and can impact the patient care or have familial outcomes (prenatal diagnosis). Its importance will increase in the coming years with the expansion of the personalized medicine. MobiDetails is specifically designed to help with this task. Exonic or intronic substitutions and small insertions/deletions related to more than 18,000 human genes are easily submitted and annotated in real-time. It is a responsive website that can be accessed using mobiles or tablets during medical staff meetings. MobiDetails is based on publicly available resources, does not include any specific data on patients or phenotypes, and is freely available for academic use at https://mobidetails.iurc.montp.inserm.fr/MD/ .


Assuntos
DNA , Bases de Dados Genéticas , Variação Genética , Medicina de Precisão , Biologia Computacional , Genoma Humano , Humanos , Mutação INDEL , Fenótipo , Software
13.
Eur J Med Genet ; 62(3): 161-166, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30006060

RESUMO

Alazami syndrome (AS) (MIM# 615071) is an autosomal recessive microcephalic primordial dwarfism (PD) with recognizable facial features and severe intellectual disability due to depletion or loss of function variants in LARP7. To date, 15 patients with AS have been reported. Here we describe two consanguineous Algerian sisters with Alazami PD due to LARP7 homozygous pathogenic variants detected by whole exome sequencing. By comparing these two additional cases with those previously reported, we strengthen the key features of AS: severe growth restriction, severe intellectual disability and some distinguishing facial features such as broad nose, malar hypoplasia, wide mouth, full lips and abnormally set teeth. We also report significant new findings enabling further delineation of this syndrome: disproportionately mild microcephaly, stereotypic hand wringing and severe anxiety, thickened skin over the hands and feet, and skeletal, eye and heart malformations. From previous reviews, we summarize the main etiologies of PD according to the involved mechanisms and cellular pathways, highlighting their clinical core features.


Assuntos
Nanismo/genética , Deficiência Intelectual/genética , Microcefalia/genética , Fenótipo , Ribonucleoproteínas/genética , Criança , Nanismo/patologia , Feminino , Humanos , Deficiência Intelectual/patologia , Mutação com Perda de Função , Microcefalia/patologia , Irmãos , Síndrome
14.
BMC Med Genomics ; 12(1): 116, 2019 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-31375103

RESUMO

BACKGROUND: Balanced structural variants are mostly described in disease with gene disruption or subtle rearrangement at breakpoints. CASE PRESENTATION: Here we report a patient with mild intellectual deficiency who carries a de novo balanced translocation t(3;5). Breakpoints were fully explored by microarray, Array Painting and Sanger sequencing. No gene disruption was found but the chromosome 5 breakpoint was localized 228-kb upstream of the MEF2C gene. The predicted Topologically Associated Domains analysis shows that it contains only the MEF2C gene and a long non-coding RNA LINC01226. RNA studies looking for MEF2C gene expression revealed an overexpression of MEF2C in the lymphoblastoid cell line of the patient. CONCLUSIONS: Pathogenicity of MEF2C overexpression is still unclear as only four patients with mild intellectual deficiency carrying 5q14.3 microduplications containing MEF2C are described in the literature. The microduplications in these individuals also contain other genes expressed in the brain. The patient presented the same phenotype as 5q14.3 microduplication patients. We report the first case of a balanced translocation leading to an overexpression of MEF2C similar to a functional duplication.


Assuntos
Cromatina/metabolismo , Deficiência Intelectual/genética , Criança , Pré-Escolar , Bandeamento Cromossômico , Cromossomos Humanos Par 3/genética , Cromossomos Humanos Par 5/genética , Feminino , Duplicação Gênica , Humanos , Lactente , Recém-Nascido , Fatores de Transcrição MEF2/genética
15.
Eur J Hum Genet ; 27(11): 1692-1700, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31285529

RESUMO

Early infantile epileptic encephalopathy (EIEE) is a heterogeneous group of severe forms of age-related developmental and epileptic encephalopathies with onset during the first weeks or months of life. The interictal electroencephalogram (EEG) shows a "suppression burst" (SB) pattern. The prognosis is usually poor and most children die within the first two years or survive with very severe intellectual disabilities. EIEE type 3 is caused by variants affecting function, in SLC25A22, which is also responsible for epilepsy of infancy with migrating focal seizures (EIMFS). We report a family with a less severe phenotype of EIEE type 3. We performed exome sequencing and identified two unreported variants in SLC25A22 in the compound heterozygous state: NM_024698.4: c.[813_814delTG];[818 G>A] (p.[Ala272Glnfs*144];[Arg273Lys]). Functional studies in cultured skin fibroblasts from a patient showed that glutamate oxidation was strongly defective, based on a literature review. We clustered the 18 published patients (including those from this family) into three groups according to the severity of the SLC25A22-related disorders. In an attempt to identify genotype-phenotype correlations, we compared the variants according to the location depending on the protein domains. We observed that patients with two variants located in helical transmembrane domains presented a severe phenotype, whereas patients with at least one variant outside helical transmembrane domains presented a milder phenotype. These data are suggestive of a continuum of disorders related to SLC25A22 that could be called SLC25A22-related disorders. This might be a first clue to enable geneticists to outline a prognosis based on genetic molecular data regarding the SLC25A22 gene.


Assuntos
Estudos de Associação Genética/métodos , Predisposição Genética para Doença/genética , Proteínas de Transporte da Membrana Mitocondrial/genética , Espasmos Infantis/genética , Adolescente , Sequência de Bases , Criança , Pré-Escolar , Eletroencefalografia , Exoma , Feminino , Fibroblastos , Humanos , Masculino , Linhagem , Fenótipo , Pele
16.
Methods Mol Biol ; 1769: 353-361, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29564835

RESUMO

Apparition of next-generation sequencing (NGS) was a breakthrough on knowledge of genome structure. Bioinformatic tools are a key point to analyze this huge amount of data from NGS and characterize the three-dimensional organization of chromosomes. This chapter describes usage of different browsers to explore publicly available online data and to search for possible 3D chromatin changes involved during complex chromosomal rearrangements as chromothripsis. Their pathogenic impact on clinical phenotype and gene misexpression can also be evaluated with annotated databases.


Assuntos
Cromotripsia , Genômica/métodos , Translocação Genética , Biologia Computacional/métodos , Variações do Número de Cópias de DNA , Elementos Facilitadores Genéticos , Epigênese Genética , Epigenômica/métodos , Rearranjo Gênico , Estudos de Associação Genética , Humanos , Regiões Promotoras Genéticas , Navegador
17.
J Mol Diagn ; 20(4): 465-473, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29689380

RESUMO

Interpretation of next-generation sequencing constitutes the main limitation of molecular diagnostics. In diagnosing myopathies and muscular dystrophies, another issue is efficiency in predicting the pathogenicity of variants identified in large genes, especially TTN; current in silico prediction tools show limitations in predicting and ranking the numerous variants of such genes. We propose a variant-prioritization tool, the MoBiDiCprioritization algorithm (MPA). MPA is based on curated interpretation of data on previously reported variants, biological assumptions, and splice and missense predictors, and is used to prioritize all types of single-nucleotide variants. MPA was validated by comparing its sensitivity and specificity to those of dbNSFP database prediction tools, using a data set composed of DYSF, DMD, LMNA, NEB, and TTN variants extracted from expert-reviewed and ExAC databases. MPA obtained the best annotation rates for missense and splice variants. As MPA aggregates the results from several predictors, individual predictor errors are counterweighted, improving the sensitivity and specificity of missense and splice variant predictions. We propose a sequential use of MPA, beginning with the selection of variants with higher scores and followed by, in the absence of candidate pathologic variants, consideration of variants with lower scores. We provide scripts and documentation for free academic use and a validated annotation pipeline scaled for panel and exome sequencing to prioritize single-nucleotide variants from a VCF file.


Assuntos
Algoritmos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Técnicas de Diagnóstico Molecular/métodos , Anotação de Sequência Molecular/métodos , Polimorfismo de Nucleotídeo Único/genética , Simulação por Computador , Humanos , Mutação de Sentido Incorreto/genética , Splicing de RNA/genética
19.
Nat Neurosci ; 14(1): 37-44, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21131955

RESUMO

Developmental axon pruning is a general mechanism that is required for maturation of neural circuits. During Drosophila metamorphosis, the larval-specific dendrites and axons of early γ neurons of the mushroom bodies are pruned and replaced by adult-specific processes. We found that the nuclear receptor ftz-f1 is required for this pruning, activates expression of the steroid hormone receptor EcR-B1, whose activity is essential for γ remodeling, and represses expression of Hr39, an ftz-f1 homologous gene. If inappropriately expressed in the γ neurons, HR39 inhibits normal pruning, probably by competing with endogenous FTZ-F1, which results in decreased EcR-B1 expression. EcR-B1 was previously identified as a target of the TGFß signaling pathway. We found that the ftz-f1 and Hr39 pathway apparently acts independently of TGFß signaling, suggesting that EcR-B1 is the target of two parallel molecular pathways that act during γ neuron remodeling.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Proteínas de Drosophila/fisiologia , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Metamorfose Biológica/fisiologia , Corpos Pedunculados/metabolismo , Neurônios/metabolismo , Receptores de Esteroides/metabolismo , Receptores de Esteroides/fisiologia , Fatores de Transcrição/metabolismo , Animais , Proteínas de Ligação a DNA/genética , Drosophila , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/genética , Metamorfose Biológica/genética , Corpos Pedunculados/crescimento & desenvolvimento , Proteínas Mutantes/metabolismo , Proteínas Mutantes/fisiologia , Neurônios/fisiologia , Receptores de Esteroides/genética , Fatores de Transcrição/genética
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