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1.
BMC Med ; 19(1): 255, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34593004

RESUMO

BACKGROUND: This study aims to identify the causative strain of SARS-CoV-2 in a cluster of vaccine breakthroughs. Vaccine breakthrough by a highly transmissible SARS-CoV-2 strain is a risk to global public health. METHODS: Nasopharyngeal swabs from suspected vaccine breakthrough cases were tested for SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) by qPCR (quantitative polymerase chain reaction) for Wuhan-Hu1 and alpha variant. Positive samples were then sequenced by Swift Normalase Amplicon Panels to determine the causal variant. GATK (genome analysis toolkit) variants were filtered with allele fraction ≥80 and min read depth 30x. RESULTS: Viral sequencing revealed an infection cluster of 6 vaccinated patients infected with the delta (B.1.617.2) SARS-CoV-2 variant. With no history of vaccine breakthrough, this suggests the delta variant may possess immune evasion in patients that received the Pfizer BNT162b2, Moderna mRNA-1273, and Covaxin BBV152. CONCLUSIONS: Delta variant may pose the highest risk out of any currently circulating SARS-CoV-2 variants, with previously described increased transmissibility over alpha variant and now, possible vaccine breakthrough. FUNDING: Parts of this work was supported by the National Institute of Allergy and Infectious Diseases (1U19AI144297) and Baylor College of Medicine internal funding.


Assuntos
COVID-19 , SARS-CoV-2 , Vacinas contra COVID-19 , Humanos , Evasão da Resposta Imune
2.
Pediatr Diabetes ; 22(7): 960-968, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34387403

RESUMO

OBJECTIVE: Commercial gene panels identify pathogenic variants in as low as 27% of patients suspected to have MODY, suggesting the role of yet unidentified pathogenic variants. We sought to identify novel gene variants associated with MODY. RESEARCH DESIGN AND METHODS: We recruited 10 children with a clinical suspicion of MODY but non-diagnostic commercial MODY gene panels. We performed exome sequencing (ES) in them and their parents. RESULTS: Mean age at diabetes diagnosis was 10 (± 3.8) years. Six were females; 4 were non-Hispanic white, 5 Hispanic, and 1 Asian. Our variant prioritization analysis identified a pathogenic, de novo variant in INS (c.94G > A, p.Gly32Ser), confirmed by Sanger sequencing, in a proband who was previously diagnosed with "autoantibody-negative type 1 diabetes (T1D)" at 3 y/o. This rare variant, absent in the general population (gnomAD database), has been reported previously in neonatal diabetes. We also identified a frameshift deletion (c.2650delC, p.Gln884AsnfsTer57) in RFX6 in a child with a previous diagnosis of "autoantibody-negative T1D" at 12 y/o. The variant was inherited from the mother, who was diagnosed with "thin type 2 diabetes" at 25 y/o. Heterozygous protein-truncating variants in RFX6 gene have been recently reported in individuals with MODY. CONCLUSIONS: We diagnosed two patients with MODY using ES in children initially classified as "T1D". One has a likely pathogenic novel gene variant not previously associated with MODY. We demonstrate the clinical utility of ES in patients with clinical suspicion of MODY.

3.
PLoS One ; 16(8): e0244468, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34432798

RESUMO

The newly emerged and rapidly spreading SARS-CoV-2 causes coronavirus disease 2019 (COVID-19). To facilitate a deeper understanding of the viral biology we developed a capture sequencing methodology to generate SARS-CoV-2 genomic and transcriptome sequences from infected patients. We utilized an oligonucleotide probe-set representing the full-length genome to obtain both genomic and transcriptome (subgenomic open reading frames [ORFs]) sequences from 45 SARS-CoV-2 clinical samples with varying viral titers. For samples with higher viral loads (cycle threshold value under 33, based on the CDC qPCR assay) complete genomes were generated. Analysis of junction reads revealed regions of differential transcriptional activity among samples. Mixed allelic frequencies along the 20kb ORF1ab gene in one sample, suggested the presence of a defective viral RNA species subpopulation maintained in mixture with functional RNA in one sample. The associated workflow is straightforward, and hybridization-based capture offers an effective and scalable approach for sequencing SARS-CoV-2 from patient samples.


Assuntos
COVID-19/patologia , SARS-CoV-2/genética , Análise de Sequência de DNA/métodos , COVID-19/virologia , DNA Complementar/química , DNA Complementar/metabolismo , Frequência do Gene , Variação Genética , Genoma Viral , Humanos , Fases de Leitura Aberta/genética , RNA Viral/genética , RNA Viral/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , SARS-CoV-2/isolamento & purificação , Carga Viral
4.
Genet Med ; 2021 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-34363016

RESUMO

PURPOSE: Cardiovascular disease (CVD) is the leading cause of death in adults in the United States, yet the benefits of genetic testing are not universally accepted. METHODS: We developed the "HeartCare" panel of genes associated with CVD, evaluating high-penetrance Mendelian conditions, coronary artery disease (CAD) polygenic risk, LPA gene polymorphisms, and specific pharmacogenetic (PGx) variants. We enrolled 709 individuals from cardiology clinics at Baylor College of Medicine, and samples were analyzed in a CAP/CLIA-certified laboratory. Results were returned to the ordering physician and uploaded to the electronic medical record. RESULTS: Notably, 32% of patients had a genetic finding with clinical management implications, even after excluding PGx results, including 9% who were molecularly diagnosed with a Mendelian condition. Among surveyed physicians, 84% reported medical management changes based on these results, including specialist referrals, cardiac tests, and medication changes. LPA polymorphisms and high polygenic risk of CAD were found in 20% and 9% of patients, respectively, leading to diet, lifestyle, and other changes. Warfarin and simvastatin pharmacogenetic variants were present in roughly half of the cohort. CONCLUSION: Our results support the use of genetic information in routine cardiovascular health management and provide a roadmap for accompanying research.

5.
medRxiv ; 2021 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-34268529

RESUMO

Importance: Vaccine breakthrough by an emergent SARS-CoV-2 variant poses a great risk to global public health. Objective: To determine the SARS-CoV-2 variant responsible for 6 cases of vaccine breakthrough. Design: Nasopharyngeal swabs from suspected vaccine breakthrough cases were tested for SARS-CoV-2 by qPCR for Wuhan-Hu1 and Alpha variant. Positive samples were then sequenced by Swift Normalase Amplicon Panels to determine the causal variant. Setting: Transmission event occurred at events surrounding a wedding outside of Houston, TX. Two patients from India, likely transmitted the Delta variant to other guests. Participants: Following a positive SARS-CoV-2 qPCR test at a third-party site, six fully vaccinated patients were investigated. Three males and three females ranged from 53 to 69 years old. One patient suffered from diabetes while three others were classified as overweight. No significant other comorbidities were identified. None of the patients had a history of failed vaccination. Key Points: Question: Which SARS-CoV-2 variant is responsible for 6 cases of vaccine breakthrough, one interventional monoclonal antibody treatment, and one death?Findings: Viral sequencing revealed 6 vaccinated patients were infected with the Delta SARS-CoV-2 variant. With no histories of vaccine breakthrough, this suggests Delta variant may possess immune evasion in patients that received the Pfizer BNT162b2, Moderna mRNA-1273, and Covaxin BBV152.Meaning: Delta variant may pose the highest risk out of any currently circulating SARS-CoV-2 variants, with increased transmissibility over Alpha variant and possible vaccine breakthrough.

6.
Genet Med ; 23(10): 1838-1846, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34257418

RESUMO

PURPOSE: Genomic medicine holds great promise for improving health care, but integrating searchable and actionable genetic data into electronic health records (EHRs) remains a challenge. Here we describe Neptune, a system for managing the interaction between a clinical laboratory and an EHR system during the clinical reporting process. METHODS: We developed Neptune and applied it to two clinical sequencing projects that required report customization, variant reanalysis, and EHR integration. RESULTS: Neptune has been applied for the generation and delivery of over 15,000 clinical genomic reports. This work spans two clinical tests based on targeted gene panels that contain 68 and 153 genes respectively. These projects demanded customizable clinical reports that contained a variety of genetic data types including single-nucleotide variants (SNVs), copy-number variants (CNVs), pharmacogenomics, and polygenic risk scores. Two variant reanalysis activities were also supported, highlighting this important workflow. CONCLUSION: Methods are needed for delivering structured genetic data to EHRs. This need extends beyond developing data formats to providing infrastructure that manages the reporting process itself. Neptune was successfully applied on two high-throughput clinical sequencing projects to build and deliver clinical reports to EHR systems. The software is open source and available at https://gitlab.com/bcm-hgsc/neptune .

7.
Life Sci Alliance ; 4(9)2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34301805

RESUMO

Four organ transplant recipients from an organ donor diagnosed with anaplastic pleomorphic xanthoastrocytoma developed fatal malignancies for which the origin could not be confirmed by standard methods. We identified the somatic mutational profiles of the neoplasms using next-generation sequencing technologies and tracked the relationship between the different samples. The data were consistent with the presence of an aggressive clonal entity in the donor and the subsequent proliferation of descendent tumors in each recipient. Deleterious mutations in BRAF, PIK3CA, SDHC, DDR2, and FANCD2, and a chromosomal deletion spanning the CDKN2A/B genes, were shared between the recipients' lesions. In addition to demonstrating that DNA sequencing tracked a donor/recipient cancer transmission, this study established that the genetic profile of a donor tumor and its potential aggressive phenotype could have been determined before transplantation was considered. As the genetic correlates of tumor invasion and metastases become better known, adding genetic profiling by DNA sequencing to the data considered for transplant safety should be considered.

8.
Plant Dis ; 2021 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-34132596

RESUMO

Maize rough dwarf disease (MRDD), caused by a virus, seriously affects maize quality and yield worldwide. MRDD can be most effectively controlled with disease-resistant hybrids of corn. Here, MRDD-resistant (Qi319) and -susceptible (Ye478) parental inbred maize lines and their 314 recombinant inbred lines (RILs) that were derived from a cross between them were evaluated across three environments. A stable resistance QTL, qMrdd2, was identified and mapped using BLUP values to a 0.55 Mb region between the markers MK807 and MK811 on chromosome 2 (B73 RefGen_v3), which was found to explain 8.6 to 11.0% of the total phenotypic variance in MRDD resistance. We validated the effect of qMrdd2 using a chromosome segment substitution line (CSSL) that was derived from a cross between maize inbred Qi319 as the MRDD resistance donor and Ye478 as the recipient. Disease severity index of the CSSL haplotype II harboring qMrdd2 was significantly lower than that of the susceptible parent Ye478. Subsequently, we fine-mapped qMrdd2 to a 315 kb region flanked by the markers RD81 and RD87 by testing recombinant-derived progeny using selfed backcrossed families. In this study, we identified a novel QTL for MRDD-resistance by combining the RIL and CSSL populations, which can be used to breed for MRDD resistant varieties of maize. Keywords: Maize, Maize rough dwarf disease, QTL, Fine-mapping, Recombinant inbred line, Chromosome segment substitution line.

9.
HGG Adv ; 2(1)2021 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-33665635

RESUMO

De novo germline variation in POLR2A was recently reported to associate with a neurodevelopmental disorder. We report twelve individuals harboring putatively pathogenic de novo or inherited variants in POLR2A, detail their phenotypes, and map all known variants to the domain structure of POLR2A and crystal structure of RNA polymerase II. Affected individuals were ascertained from a local data lake, pediatric genetics clinic, and an online community of families of affected individuals. These include six affected by de novo missense variants (including one previously reported individual), four clinical laboratory samples affected by missense variation with unknown inheritance-with yeast functional assays further supporting altered function-one affected by a de novo in-frame deletion, and one affected by a C-terminal frameshift variant inherited from a largely asymptomatic mother. Recurrently observed phenotypes include ataxia, joint hypermobility, short stature, skin abnormalities, congenital cardiac abnormalities, immune system abnormalities, hip dysplasia, and short Achilles tendons. We report a significantly higher occurrence of epilepsy (8/12, 66.7%) than previously reported (3/15, 20%) (p value = 0.014196; chi-square test) and a lower occurrence of hypotonia (8/12, 66.7%) than previously reported (14/15, 93.3%) (p value = 0.076309). POLR2A-related developmental disorders likely represent a spectrum of related, multi-systemic developmental disorders, driven by distinct mechanisms, converging at a single locus.

10.
Hum Mutat ; 42(5): 577-591, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33644933

RESUMO

Xia-Gibbs syndrome (XGS) is a rare Mendelian disease typically caused by de novo stop-gain or frameshift mutations in the AT-hook DNA binding motif containing 1 (AHDC1) gene. Patients usually present in early infancy with hypotonia and developmental delay and later exhibit intellectual disability (ID). The overall presentation is variable, however, and the emerging clinical picture is still evolving. A detailed phenotypic analysis of 34 XGS individuals revealed five core phenotypes (delayed motor milestones, speech delay, low muscle tone, ID, and hypotonia) in more than 80% of individuals and an additional 12 features that occurred more variably. Seizures and scoliosis were more frequently associated with truncations that arise before the midpoint of the protein although the occurrence of most features could not be predicted by the mutation position. Transient expression of wild type and different patient truncated AHDC1 protein forms in human cell lines revealed abnormal patterns of nuclear localization including a diffuse distribution of a short truncated form and nucleolar aggregation in mid-protein truncated forms. Overall, both the occurrence of variable phenotypes and the different distribution of the expressed protein reflect the heterogeneity of this syndrome.

11.
bioRxiv ; 2020 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-33330863

RESUMO

The newly emerged and rapidly spreading SARS-CoV-2 causes coronavirus disease 2019 (COVID-19). To facilitate a deeper understanding of the viral biology we developed a capture sequencing methodology to generate SARS-CoV-2 genomic and transcriptome sequences from infected patients. We utilized an oligonucleotide probe-set representing the full-length genome to obtain both genomic and transcriptome (subgenomic open reading frames [ORFs]) sequences from 45 SARS-CoV-2 clinical samples with varying viral titers. For samples with higher viral loads (cycle threshold value under 33, based on the CDC qPCR assay) complete genomes were generated. Analysis of junction reads revealed regions of differential transcriptional activity and provided evidence of expression of ORF10. Heterogeneous allelic frequencies along the 20kb ORF1ab gene suggested the presence of a defective interfering viral RNA species subpopulation in one sample. The associated workflow is straightforward, and hybridization-based capture offers an effective and scalable approach for sequencing SARS-CoV-2 from patient samples.

12.
Hum Mutat ; 41(12): 2094-2104, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32935419

RESUMO

KIF1A is a molecular motor for membrane-bound cargo important to the development and survival of sensory neurons. KIF1A dysfunction has been associated with several Mendelian disorders with a spectrum of overlapping phenotypes, ranging from spastic paraplegia to intellectual disability. We present a novel pathogenic in-frame deletion in the KIF1A molecular motor domain inherited by two affected siblings from an unaffected mother with apparent germline mosaicism. We identified eight additional cases with heterozygous, pathogenic KIF1A variants ascertained from a local data lake. Our data provide evidence for the expansion of KIF1A-associated phenotypes to include hip subluxation and dystonia as well as phenotypes observed in only a single case: gelastic cataplexy, coxa valga, and double collecting system. We review the literature and suggest that KIF1A dysfunction is better understood as a single neuromuscular disorder with variable involvement of other organ systems than a set of discrete disorders converging at a single locus.

13.
bioRxiv ; 2020 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-32766579

RESUMO

The newly emerged and rapidly spreading SARS-CoV-2 causes coronavirus disease 2019 (COVID-19). To facilitate a deeper understanding of the viral biology we developed a capture sequencing methodology to generate SARS-CoV-2 genomic and transcriptome sequences from infected patients. We utilized an oligonucleotide probe-set representing the full-length genome to obtain both genomic and transcriptome (subgenomic open reading frames [ORFs]) sequences from 45 SARS-CoV-2 clinical samples with varying viral titers. For samples with higher viral loads (cycle threshold value under 33, based on the CDC qPCR assay) complete genomes were generated. Analysis of junction reads revealed regions of differential transcriptional activity and provided evidence of expression of ORF10. Heterogeneous allelic frequencies along the 20kb ORF1ab gene suggested the presence of a defective interfering viral RNA species subpopulation in one sample. The associated workflow is straightforward, and hybridization-based capture offers an effective and scalable approach for sequencing SARS-CoV-2 from patient samples.

14.
Mol Genet Genomic Med ; 8(10): e1439, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32767738

RESUMO

BACKGROUND: Establishing a genetic diagnosis for individuals with intellectual disability (ID) benefits patients and their families as it may inform the prognosis, lead to appropriate therapy, and facilitate access to medical and supportive services. Exome sequencing has been successfully applied in a diagnostic setting, but most clinical exome referrals are pediatric patients, with many adults with ID lacking a comprehensive genetic evaluation. METHODS: Our unique recruitment strategy involved partnering with service and education providers for individuals with ID. We performed exome sequencing and analysis, and clinical variant interpretation for each recruited family. RESULTS: All five families enrolled in the study opted-in for the return of genetic results. In three out of five families exome sequencing analysis identified pathogenic or likely pathogenic variants in KANSL1, TUSC3, and MED13L genes. Families discussed the results and any potential medical follow-up in an appointment with a board certified clinical geneticist. CONCLUSION: Our study suggests high yield of exome sequencing as a diagnostic tool in adult patients with ID who have not undergone comprehensive sequencing-based genetic testing. Research studies including an option of return of results through a genetic clinic could help minimize the disparity in exome diagnostic testing between pediatric and adult patients with ID.


Assuntos
Testes Genéticos/métodos , Deficiência Intelectual/genética , Seleção de Pacientes , Sequenciamento Completo do Exoma/métodos , Adulto , Feminino , Testes Genéticos/normas , Humanos , Vida Independente , Deficiência Intelectual/diagnóstico , Masculino , Complexo Mediador/genética , Proteínas de Membrana/genética , Proteínas Nucleares/genética , Sensibilidade e Especificidade , Proteínas Supressoras de Tumor/genética , Sequenciamento Completo do Exoma/normas
15.
Breed Sci ; 70(2): 183-192, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32523400

RESUMO

Maize rough dwarf disease (MRDD) is caused by viruses in the Fijivirus genus in the family Reoviridae. MRDD resistance can be improved by a combination of marker-assisted selection (MAS) and conventional breeding strategies. In our previous study, we fine-mapped a major QTL qMrdd8 and developed the functional Indel marker IDP25K. In the present study, qMrdd8 from the donor parent X178 was introgressed into elite inbred lines derived from the three corn heterotic groups using multi-generation backcrossing and MAS. Recipient lines included Huangzao4, Chang7-2, Ye478, Zheng58, Zhonghuang68, B73, and Ji846. Markers used for foreground selection included IDRQ4, IDRQ47, IDP25K, and IDP27K. Background selection was carried out in the BC3 or BC4 using 107 SSR markers to select lines with the highest rate of recovery of the particular recurrent parent genome. Plants from BC4F2 and BC3F2 that carried the shortest qMrdd8 interval from X178 and those with the highest rate of recovery of the recurrent parent genome were then selected to create converted homozygous inbred lines. In 2017, seven converted inbred lines and five hybrids exhibited enhanced resistance to MRDD, while other agronomic traits were not affected under nonpathogenic stress conditions. Thus, the MRDD resistance allele at the qMrdd8 locus, or IDP25K, should be valuable for maize breeding programs in China.

16.
Cell ; 176(6): 1310-1324.e10, 2019 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-30827684

RESUMO

DNA rearrangements resulting in human genome structural variants (SVs) are caused by diverse mutational mechanisms. We used long- and short-read sequencing technologies to investigate end products of de novo chromosome 17p11.2 rearrangements and query the molecular mechanisms underlying both recurrent and non-recurrent events. Evidence for an increased rate of clustered single-nucleotide variant (SNV) mutation in cis with non-recurrent rearrangements was found. Indel and SNV formation are associated with both copy-number gains and losses of 17p11.2, occur up to ∼1 Mb away from the breakpoint junctions, and favor C > G transversion substitutions; results suggest that single-stranded DNA is formed during the genesis of the SV and provide compelling support for a microhomology-mediated break-induced replication (MMBIR) mechanism for SV formation. Our data show an additional mutational burden of MMBIR consisting of hypermutation confined to the locus and manifesting as SNVs and indels predominantly within genes.


Assuntos
Cromossomos Humanos Par 17 , Mutação , Anormalidades Múltiplas/genética , Pontos de Quebra do Cromossomo , Transtornos Cromossômicos/genética , Duplicação Cromossômica/genética , Variações do Número de Cópias de DNA , Reparo do DNA/genética , Replicação do DNA , Rearranjo Gênico , Genoma Humano , Variação Estrutural do Genoma , Humanos , Mutação INDEL , Modelos Genéticos , Polimorfismo de Nucleotídeo Único , Recombinação Genética , Análise de Sequência de DNA/métodos , Síndrome de Smith-Magenis/genética
17.
Am J Med Genet A ; 176(6): 1315-1326, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29696776

RESUMO

Xia-Gibbs syndrome (XGS: OMIM # 615829) results from de novo truncating mutations within the AT-Hook DNA Binding Motif Containing 1 gene (AHDC1). To further define the phenotypic and molecular spectrum of this disorder, we established an XGS Registry and recruited patients from a worldwide pool of approximately 60 probands. Additional de novo truncating mutations were observed among 25 individuals, extending both the known number of mutation sites and the range of positions within the coding region that were sensitive to alteration. Detailed phenotypic examination of 20 of these patients via clinical records review and data collection from additional surveys showed a wider age range than previously described. Data from developmental milestones showed evidence for delayed speech and that males were more severely affected. Neuroimaging from six available patients showed an associated thinning of the corpus callosum and posterior fossa cysts. An increased risk of both scoliosis and seizures relative to the population burden was also observed. Data from a modified autism screening tool revealed that XGS shares significant overlap with autism spectrum disorders. These details of the phenotypic heterogeneity of XGS implicate specific genotype/phenotype correlations and suggest potential clinical management guidelines.


Assuntos
Transtorno do Espectro Autista/etiologia , Proteínas de Ligação a DNA/genética , Deficiências do Desenvolvimento/etiologia , Mutação , Criança , Cognição/fisiologia , Corpo Caloso/diagnóstico por imagem , Corpo Caloso/patologia , Face/anormalidades , Feminino , Humanos , Masculino , Linhagem , Fenótipo , Sistema de Registros , Convulsões/etiologia , Síndrome , Adulto Jovem
18.
Plant Physiol Biochem ; 127: 25-31, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29544210

RESUMO

In plants, various proteins are regulated by the ubiquitin-mediated system in response to different environmental stresses, such as drought, cold and heat. The Skp1-Cullin-F-box (SCF) complex, one of the multisubunit E3 ligases, has been shown to be involved in abiotic response pathways. In this study, Glycine max SKP1-like 1 (GmSK1), which had the typical characteristics of an SKP1 protein, with an alpha/beta structure, targeted to the cytoplasm and nucleus, was isolated from soybean [Glycine max (L.)]. GmSK1 was constitutively expressed in all the tested tissues, especially in the roots. Furthermore, the expression of GmSK1 was simultaneously induced by abscisic acid (ABA), jasmonic acid (JA), salicylic acid (SA), NaCl, low temperatures and drought, which suggests important roles for GmSK1 in plant responses to hormone treatments and abiotic stress. GmSK1-overexpressing transgenic tobacco (Nicotiana tobacum cv. Samsun) plants showed enhanced tolerance to high salinity and drought stress; exhibited significantly reduced inhibition of growth, greenness and water loss; and exhibited increased MDA accumulation compared with wild-type controls. Our results suggest that GmSK1 might play a role in the crosstalk between ubiquitination and abiotic stress responses in plants.


Assuntos
Regulação Enzimológica da Expressão Gênica , Regulação da Expressão Gênica de Plantas , Proteínas Ligases SKP Culina F-Box , Tolerância ao Sal , Soja , Desidratação/enzimologia , Desidratação/genética , Plantas Geneticamente Modificadas/enzimologia , Plantas Geneticamente Modificadas/genética , Proteínas Ligases SKP Culina F-Box/biossíntese , Proteínas Ligases SKP Culina F-Box/genética , Soja/enzimologia , Soja/genética , Tabaco/enzimologia , Tabaco/genética
19.
J Allergy Clin Immunol ; 142(2): 605-617.e7, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29330011

RESUMO

BACKGROUND: Heterozygous gain-of-function mutations in PI3K110δ lead to lymphadenopathy, lymphoid hyperplasia, EBV and cytomegalovirus viremia, and sinopulmonary infections. OBJECTIVE: The known role of natural killer (NK) cell function in the control of EBV and cytomegalovirus prompted us to investigate the functional and phenotypic effects of PI3K110δ mutations on NK cell subsets and cytotoxic function. METHODS: Mutations in patients were identified by using whole-exome or targeted sequencing. We performed NK cell phenotyping and functional analysis of patients' cells using flow cytometry, standard Cr51 cytotoxicity assays, and quantitative confocal microscopy. RESULTS: PI3K110δ mutations led to an altered NK cell developmental phenotype and cytotoxic dysfunction. Impaired NK cell cytotoxicity was due to decreased conjugate formation with susceptible target cells and abrogated activation of cell machinery required for target cell killing. These defects were restored partially after initiation of treatment with rapamycin in 3 patients. CONCLUSION: We describe novel NK cell functional deficiency caused by PI3K110δ mutation, which is a likely contributor to the severe viremia observed in these patients. Rapamycin treatment partially restores NK cell function, providing a further rationale for its use in patients with this disease.


Assuntos
Infecções por Citomegalovirus/genética , Citomegalovirus/fisiologia , Infecções por Vírus Epstein-Barr/genética , Herpesvirus Humano 4/fisiologia , Síndromes de Imunodeficiência/genética , Células Matadoras Naturais/fisiologia , Mutação/genética , Fosfatidilinositol 3-Quinases/genética , Sirolimo/uso terapêutico , Diferenciação Celular , Células Cultivadas , Classe I de Fosfatidilinositol 3-Quinases , Citotoxicidade Imunológica/efeitos dos fármacos , Heterozigoto , Humanos , Síndromes de Imunodeficiência/tratamento farmacológico , Sinapses Imunológicas/metabolismo , Imunofenotipagem , Ativação Linfocitária , Microscopia Confocal , Viremia , Sequenciamento Completo do Exoma
20.
PLoS One ; 12(12): e0189441, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29232707

RESUMO

Leaf width is an important component of plant architecture that affects light capture during photosynthesis and wind circulation under dense planting conditions. To improve understanding of the genetic mechanisms involved in leaf width at different positions, a comprehensive evaluation using the RIL (Recombinant Inbred Line) and IF2 (Immortalized F2) populations and a subsequent meta-analysis were performed. Forty-seven QTL associated with leaf width at different positions below the tassel were detected. The individual effects of QTL explained 3.5% to 17.0% of the observed phenotypic variation, and ten QTL explained over 10%. The initial QTL were integrated into eight mQTL (meta-QTL) through a meta-analysis. Our results suggested that leaf widths at different positions may be affected by several of the same mQTL and may also be regulated by many different mQTL. These results provide useful information for breeding high density tolerant inbred lines and hybrid cultivars, as well as for using marker-assisted selection for important mQTL.


Assuntos
Genes de Plantas , Zea mays/genética , Mapeamento Cromossômico , Cromossomos de Plantas , Folhas de Planta , Locos de Características Quantitativas
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