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1.
Genet Med ; 2019 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-31776469

RESUMO

PURPOSE: To delineate the genotype-phenotype correlation in individuals with likely pathogenic variants in the CLTC gene. METHODS: We describe 13 individuals with de novo CLTC variants. Causality of variants was determined by using the tolerance landscape of CLTC and computer-assisted molecular modeling where applicable. Phenotypic abnormalities observed in the individuals identified with missense and in-frame variants were compared with those with nonsense or frameshift variants in CLTC. RESULTS: All de novo variants were judged to be causal. Combining our data with that of 14 previously reported affected individuals (n = 27), all had intellectual disability (ID), ranging from mild to moderate/severe, with or without additional neurologic, behavioral, craniofacial, ophthalmologic, and gastrointestinal features. Microcephaly, hypoplasia of the corpus callosum, and epilepsy were more frequently observed in individuals with missense and in-frame variants than in those with nonsense and frameshift variants. However, this difference was not significant. CONCLUSIONS: The wide phenotypic variability associated with likely pathogenic CLTC variants seems to be associated with allelic heterogeneity. The detailed clinical characterization of a larger cohort of individuals with pathogenic CLTC variants is warranted to support the hypothesis that missense and in-frame variants exert a dominant-negative effect, whereas the nonsense and frameshift variants would result in haploinsufficiency.

2.
Arch Microbiol ; 2019 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-31776586

RESUMO

This study aimed to evaluate the effects of seed inoculation with Bradyrhizobium sp. and co-inoculation with Azospirillum brasilense. The seed treatments were as follows: control (without inoculation); A. brasilense (2 mL per kg-1 of seed); A. brasilense (4 mL per kg-1 of seed); Bradyrhizobium sp. (2 mL per kg-1 of seed); Bradyrhizobium sp. (4 mL per kg-1 of seed); A. brasilense + Bradyrhizobium sp. (2 mL of each strain per kg-1 of seed); and A. brasilense + Bradyrhizobium sp. (4 mL of each strain per kg-1 of seed). Peanut plants from seeds inoculated with Bradyrhizobium sp. and A. brasilense exhibited highest leaf concentration of photosynthetic pigments, carotenoids, nitrate, ammonia and amino acids. The inoculation of seeds with Bradyrhizobium sp. resulted in plants with increased concentrations of total soluble sugars, and ureides compared to the untreated plants. In contrast, seeds treated with A. brasilense alone resulted in plants exhibiting highest concentration of amino acids, which represent the highest concentration of nitrogen compounds in peanut plants. Seed inoculation with Bradyrhizobium sp. at a rate of 2 mL kg-1 was identified as the best treatment to promote increased biological nitrogen fixation and generate higher peanut yields.

3.
Genet Med ; 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31723249

RESUMO

PURPOSE: Intellectual disability (ID) and autism spectrum disorder (ASD) are genetically heterogeneous neurodevelopmental disorders. We sought to delineate the clinical, molecular, and neuroimaging spectrum of a novel neurodevelopmental disorder caused by variants in the zinc finger protein 292 gene (ZNF292). METHODS: We ascertained a cohort of 28 families with ID due to putatively pathogenic ZNF292 variants that were identified via targeted and exome sequencing. Available data were analyzed to characterize the canonical phenotype and examine genotype-phenotype relationships. RESULTS: Probands presented with ID as well as a spectrum of neurodevelopmental features including ASD, among others. All ZNF292 variants were de novo, except in one family with dominant inheritance. ZNF292 encodes a highly conserved zinc finger protein that acts as a transcription factor and is highly expressed in the developing human brain supporting its critical role in neurodevelopment. CONCLUSION: De novo and dominantly inherited variants in ZNF292 are associated with a range of neurodevelopmental features including ID and ASD. The clinical spectrum is broad, and most individuals present with mild to moderate ID with or without other syndromic features. Our results suggest that variants in ZNF292 are likely a recurrent cause of a neurodevelopmental disorder manifesting as ID with or without ASD.

4.
J Chem Inf Model ; 2019 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-31738549

RESUMO

Flexible protein regions containing cationic and aromatic side-chains exposed to solvent may form transient cation-π interactions with structural and functional roles. To evaluate their stability and identify important intramolecular cation-π contacts, a combination of free energy profiles estimated from umbrella sampling with molecular dynamics simulations and chemical shift perturbations (CSP) obtained from NMR experiments is applied here to the complete catalytic domain of human phosphatase Cdc25B. This protein is a good model system for transient cation-π interactions as it contains only one Trp residue (W550) in the disordered C-terminal segment and a total of 17 Arg residues, many exposed to solvent. Eight putative Arg-Trp pairs were simulated here. Only R482 and R544 show bound profiles corresponding to important transient cation-π interactions, while the others have dissociative or almost flat profiles. These results are corroborated by CSP analysis of three Cdc25B point mutants (W550A, R482A and R544A) disrupting cation-π contacts. The proposed validation of statistically representative molecular simulations by NMR spectroscopy could be applied to identify transient contacts of proteins in general but carefully, as NMR chemical shifts are sensitive to changes in both molecular contacts and conformational distributions.

5.
Mol Genet Genomic Med ; : e962, 2019 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-31595705

RESUMO

BACKGROUND: Maturity-onset diabetes of the young (MODY) is a form of monogenic diabetes with autosomal dominant inheritance. To date, mutations in 11 genes have been frequently associated with this phenotype. In Brazil, few cohorts have been screened for MODY, all using a candidate gene approach, with a high prevalence of undiagnosed cases (MODY-X). METHODS: We conducted a next-generation sequencing target panel (tNGS) study to investigate, for the first time, a Brazilian cohort of MODY patients with a negative prior genetic analysis. One hundred and two patients were selected, of which 26 had an initial clinical suspicion of MODY-GCK and 76 were non-GCK MODY. RESULTS: After excluding all benign and likely benign variants and variants of uncertain significance, we were able to assign a genetic cause for 12.7% (13/102) of the probands. Three rare MODY subtypes were identified (PDX1/NEUROD1/ABCC8), and eight variants had not been previously described/mapped in genomic databases. Important clinical findings were evidenced in some cases after genetic diagnosis, such as MODY-PDX1/HNF1B. CONCLUSION: A multiloci genetic approach allowed the identification of rare MODY subtypes, reducing the large percentage of MODY-X in Brazilian cases and contributing to a better clinical, therapeutic, and prognostic characterization of these rare phenotypes.

6.
J Esthet Restor Dent ; 2019 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-31622014

RESUMO

OBJECTIVE: To evaluate the influence of the degree of dentin moisture on interfacial ultramorphology and bond strength (µTBS) of universal adhesives. MATERIALS AND METHODS: Futurabond U (FBU), Scotchbond Universal (SBU), Adhese Universal (ADU), and Prime&Bond active (PBA) were used. After acid-etching, moist or over-dried dentin surfaces were tested. Teeth were restored for scanning and transmission electron microscopy (n = 3) and µTBS evaluation (n = 5). µTBS results were analyzed by two-way ANOVA and Tukey. RESULTS: For moist dentin, a well-formed hybrid layer (HL) was observed. However, when applied to over-dried dentin, remarkable differences were observed. Defects, gaps, and reduced HL thickness were observed mainly for ADU and FBU. When applied to wet dentin, µTBS values were similar for all adhesives, except for FBU, which was significantly lower. When applied to over-dried dentin, PBA presented the highest µTBS values, followed by SBU, ADU, and FBU. ADU presented significantly lower µTBS when applied to over-dried dentin. CONCLUSION: PBA, SBU, and FBU µTBS values were not sensitive to the degree of moisture. Even though application to over-dried dentin revealed defects, gaps and reduced HL thickness for SBU, ADU, and FBU, µTBS analysis only revealed a significant reduction for ADU. CLINICAL SIGNIFICANCE: Universal adhesives can be applied in either self-etching or etch-and-rinse mode. However, clinicians are not aware which universal adhesives should be strictly applied on a moist dentin for bonding in the etch-and-rinse mode.

7.
Ecotoxicol Environ Saf ; 186: 109747, 2019 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-31634660

RESUMO

Cadmium (Cd) contamination has generated an environmental problem worldwide, leading to harmful effects on human health and damages to plant metabolism. Selenium (Se) is non essential for plants, however it can improve plant growth and reduce the adverse effects of abiotic stress. In addition, ethylene may interplay the positive effects of Se in plants. In order to investigate the role of ethylene in Se-modulation of antioxidant defence system in response to Cd-stress, we tested the hormonal mutant Epinastic (epi) with a subset of constitutive activation of the ethylene response and Micro-Tom (MT) plants. For this purpose, Se mineral uptake, Cd and Se concentrations, pigments, malondialdeyde (MDA) and hydrogen peroxide (H2O2) contents, ethylene production, glutathione (GSH) compound, and superoxide dismutase (SOD), ascorbate peroxidase (APX), catalase (CAT), glutathione reductase (GR) and glutathione peroxidase (GSH-Px) activities were analysed in MT and epi plants submitted to 0.5 mM CdCl2 and 1 µM of selenate or selenite. MT plants treated with both Se forms increased growth in the presence or not of 0.5 mM CdCl2, but not change epi growth. Both Se forms reduced Cd uptake in MT plants and cause reverse effect in epi plants. P, Mg, S, K and Zn uptake increased in epi plants with Se application, irrespective to Cd exposure. Chlorophylls and carotenoids contents decreased in both genotypes under Cd exposure, in contrast to what was observed in epi leaves in the presence of Se. When antioxidant enzymes activities were concerned, Se application increased Mn-SOD, Fe-SOD and APX activities. In the presence of Cd, MT and epi plants exhibited decreased SOD activity and increased CAT, APX and GR activities. MT and epi plants with Se supply exhibited increased APX and GR activities in the presence of Cd. Overall, these results suggest that ethylene may be involved in Se induced-defence responses, that triggers a positive response of the antioxidant system and improve growth under Cd stress. These results showed integrative roles of ethylene and Se in regulating the cell responses to stressful-conditions and, the cross-tolerance to stress could be used to manipulate ethylene regulated gene expression to induce heavy metal tolerance.

8.
Eur J Med Res ; 24(1): 32, 2019 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-31521205

RESUMO

BACKGROUND: Growing demand for risk-reducing surgery in individuals with inherited susceptibility to cancer leads to the question whether these procedures are cost effective for the executing hospitals. This study compared the clinical costs for bilateral risk-reducing mastectomy (BRRM) with and without different types of reconstruction, risk-reducing salpingo-oophorectomy (RRSO), and their combinations with corresponding reimbursements in the statutory health-care system in Germany. PATIENTS AND METHODS: Real total costs of care for BRRM with and without reconstruction, RRSO, and their combinations were calculated as the sum of all personnel and technical costs. These costs calculated in a German University hospital were compared with the sum of all reimbursements in the German DRG-based health-care system. RESULTS: While sole RRSO, BRRM without reconstruction, and BRRM with secondary DIEP (deep inferior epigastric perforator)-reconstruction still result in a small benefit, we even found shortfalls for the hospital with all other prophylactic operations under consideration. The calculated deficits were especially high for BRRM with implant-based breast reconstruction and for combined operations when the risk reduction is achieved with a minimum of separate operations. CONCLUSIONS: Risk-reducing surgery in BRCA-mutation carriers is frequently not cost-covering for the executing hospitals in the German health-care system. Thus, appropriate concepts are required to ensure a nationwide care.

9.
Prenat Diagn ; 39(12): 1136-1147, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31498910

RESUMO

OBJECTIVE: 17q12 microdeletions containing HNF1B and intragenic variants within this gene are associated with variable developmental, endocrine, and renal anomalies, often already noted prenatally as hyperechogenic/cystic kidneys. Here, we describe prenatal and postnatal phenotypes of seven individuals with HNF1B aberrations and compare their clinical and genetic data to those of previous studies. METHODS: Prenatal sequencing and postnatal chromosomal microarray analysis were performed in seven individuals with renal and/or neurodevelopmental phenotypes. We evaluated HNF1B-related clinical features from 82 studies and reclassified 192 reported intragenic HNF1B variants. RESULTS: In a prenatal case, we identified a novel in-frame deletion p.(Gly239del) within the HNF1B DNA-binding domain, a mutational hot spot as demonstrated by spatial clustering analysis and high computational prediction scores. The six postnatally diagnosed individuals harbored 17q12 microdeletions. Literature screening revealed variable reporting of HNF1B-associated clinical traits. Overall, both mutation groups showed a high phenotypic heterogeneity. The reclassification of all previously reported intragenic HNF1B variants provided an up-to-date overview of the mutational spectrum. CONCLUSIONS: We highlight the value of prenatal HNF1B screening in renal developmental diseases. Standardized clinical reporting and systematic classification of HNF1B variants are necessary for a more accurate risk quantification of prenatal and postnatal clinical features, improving genetic counseling and prenatal decision making.

10.
Sci Total Environ ; 687: 1219-1231, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31412457

RESUMO

Arsenic (As) in native soils of the Amazon rainforest is a concern due to its likely origin from the Andean rivers, which transport loads of sediments containing substantial amounts of trace elements coming from the cordilleras. Yet, unveiling soil As baseline concentrations in the Amazon basin is still a need because most studies in Brazil have been performed in areas with predominantly high concentrations and cannot express a real baseline value for the region. In this study, 414 soil samples (0-20, 20-40 and 40-60 cm layers) were collected from different sites throughout the Amazon basin - including native Amazon rainforest and minimally disturbed areas - and used to determine total and extractable (soluble + available) As concentrations along with relevant soil physicochemical properties. Descriptive statistics of the data was performed and Pearson correlation supported by a Principal Component Analysis (PCA) provided an improved understanding of where and how As concentrations are influenced by soil attributes. Total As concentration ranged from 0.98 to 41.71 mg kg-1 with values usually increasing from the topsoil (0-20 cm) to the deepest layer (40-60 cm) in all sites studied. Considering the proportional contribution given by each fraction (soluble and available) on extractable As concentration, it is noticeable that KH2PO4-extractable As represents the most important fraction, with >70% of the As extracted on average in all the sites studied. Still, the extractable fractions (soluble + available) correspond to ~0.24% of the total As, on average. Total, available, and soluble As fractions were strongly and positively correlated with soil Al3+. The PCA indicated that soil pH in combination with CEC might be the key factors controlling soil As concentrations and the occurrence of each arsenic fraction in the soil layers.

11.
Ann Clin Transl Neurol ; 6(7): 1263-1272, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31353855

RESUMO

OBJECTIVE: To analyze clinical phenotypes associated with KCNC1 variants other than the Progressive Myoclonus Epilepsy-causing variant p.Arg320His, determine the electrophysiological functional impact of identified variants and explore genotype-phenotype-physiological correlations. METHODS: Ten cases with putative pathogenic variants in KCNC1 were studied. Variants had been identified via whole-exome sequencing or gene panel testing. Clinical phenotypic data were analyzed. To determine functional impact of variants detected in the Kv 3.1 channel encoded by KCNC1, Xenopus laevis oocyte expression system and automated two-electrode voltage clamping were used. RESULTS: Six unrelated patients had a Developmental and Epileptic Encephalopathy and a recurrent de novo variant p.Ala421Val (c.1262C > T). Functional analysis of p.Ala421Val revealed loss of function through a significant reduction in whole-cell current, but no dominant-negative effect. Three patients had a contrasting phenotype of Developmental Encephalopathy without seizures and different KCNC1 variants, all of which caused loss of function with reduced whole-cell currents. Evaluation of the variant p.Ala513Val (c.1538C > T) in the tenth case, suggested it was a variant of uncertain significance. INTERPRETATION: These are the first reported cases of Developmental and Epileptic Encephalopathy due to KCNC1 mutation. The spectrum of phenotypes associated with KCNC1 is now broadened to include not only a Progressive Myoclonus Epilepsy, but an infantile onset Developmental and Epileptic Encephalopathy, as well as Developmental Encephalopathy without seizures. Loss of function is a key feature, but definitive electrophysiological separation of these phenotypes has not yet emerged.

12.
J Sci Food Agric ; 99(13): 5969-5983, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31215030

RESUMO

BACKGROUND: Selenium (Se) is a nutrient for animals and humans, and is considered beneficial to higher plants. Selenium concentrations are low in most soils, which can result in a lack of Se in plants, and consequently in human diets. Phytic acid (PA) is the main storage form of phosphorus in seeds, and it is able to form insoluble complexes with essential minerals in the monogastric gut. This study aimed to establish optimal levels of Se application to cowpea, with the aim of increasing Se concentrations. The efficiency of agronomic biofortification was evaluated by the application of seven levels of Se (0, 2.5, 5, 10, 20, 40, and 60 g ha-1 ) from two sources (selenate and selenite) to the soil under field conditions in 2016 and 2017. RESULTS: Application of Se as selenate led to greater plant Se concentrations than application as selenite in both leaves and grains. Assuming human cowpea consumption of 54.2 g day-1 , Se application of 20 g ha-1 in 2016 or 10 g ha-1 in 2017 as selenate would have provided a suitable daily intake of Se (between 20 and 55 µg day-1 ) for humans. Phytic acid showed no direct response to Se application. CONCLUSION: Selenate provides greater phytoavailability than selenite. The application of 10 g Se ha-1 of selenate to cowpea plants could provide sufficient seed Se to increase daily human intake by 13-14 µg d-1 . © 2019 Society of Chemical Industry.


Assuntos
Biofortificação/métodos , Ácido Fítico/análise , Ácido Selênico/análise , Ácido Selenioso/análise , Selênio/análise , Vigna/química , Fertilizantes/análise , Ácido Fítico/metabolismo , Folhas de Planta/química , Folhas de Planta/metabolismo , Sementes/química , Sementes/metabolismo , Vigna/metabolismo
13.
Molecules ; 24(12)2019 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-31238580

RESUMO

The objective of this study, for the first time, was to optimize Amazonian cyanobacterial culture conditions for improving cell productivity and lipid content, by analyzing the effect of light intensity and nitrogen concentration, for empirically evaluating biodiesel quality parameters. The strains Synechocystis sp. CACIAM05, Microcystis aeruginosa CACIAM08, Pantanalinema rosaneae CACIAM18, and Limnothrix sp. CACIAM25, were previously identified by morphological and molecular analysis (16S rRNA) and were selected based on their production of chlorophyll a and dry cell weight. Then, factorial planning (22) with central points was applied, with light intensity and NaNO3 concentration as independent variables. As response variables, cell productivity and lipid content were determined. Statistical analysis indicated that for all strains, the independent variables were statistically significant for cell productivity. Analysis of the fatty acid composition demonstrated diversity in the composition of the fatty acid profile from the experimental planning assays of each strain. The Biodiesel Analyzer software predicted the biodiesel quality parameters. CACIAM05 and CACIAM25 obtained better parameters with low levels of light intensity and NaNO3 concentration, whereas CACIAM08 and CACIAM18 obtained better parameters with low NaNO3 concentrations and high luminous intensity.

14.
Nat Protoc ; 14(7): 2119-2151, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31217595

RESUMO

Next-generation sequencing (NGS) has been widely adopted to identify genetic variants and investigate their association with disease. However, the analysis of sequencing data remains challenging because of the complexity of human genetic variation and confounding errors introduced during library preparation, sequencing and analysis. We have developed a set of synthetic DNA spike-ins-termed 'sequins' (sequencing spike-ins)-that are directly added to DNA samples before library preparation. Sequins can be used to measure technical biases and to act as internal quantitative and qualitative controls throughout the sequencing workflow. This step-by-step protocol explains the use of sequins for both whole-genome and targeted sequencing of the human genome. This includes instructions regarding the dilution and addition of sequins to human DNA samples, followed by the bioinformatic steps required to separate sequin- and sample-derived sequencing reads and to evaluate the diagnostic performance of the assay. These practical guidelines are accompanied by a broader discussion of the conceptual and statistical principles that underpin the design of sequin standards. This protocol is suitable for users with standard laboratory and bioinformatic experience. The laboratory steps require ~1-4 d and the bioinformatic steps (which can be performed with the provided example data files) take an additional day.


Assuntos
DNA/síntese química , Genoma Humano , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Calibragem , Biologia Computacional/métodos , DNA/genética , Sequenciamento de Nucleotídeos em Larga Escala/normas , Humanos , Células K562 , Células MCF-7 , Neoplasias/genética , Proteínas Proto-Oncogênicas B-raf/genética
15.
J Adhes Dent ; 21(3): 281-286, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31165107

RESUMO

PURPOSE: To evaluate the bond strength to dentin produced by experimental adhesives formulated with an elastomeric methacrylate monomer (EMM) and an alternative initiator system based on a Thioxanthone derivative (QTX). MATERIALS AND METHODS: A self-etching primer was used. For the bonding resin, a model adhesive (G1) was formulated containing bis-GMA/TEG-DMA/HEMA (co-monomeric blend) + CQ/EDAB (initiator system). The other groups were formulated by adding to this formulation: EMM only (G2), QTX (G3), or EMM and QTX (G4). Clearfil SE Bond was used as the commercial control group. Fifty bovine teeth (n = 5) were restored with each one of the five adhesives. After restorative procedures, half of the specimens were stored in distilled water at 37°C for 24 h. The other half was fixed on a metal stub and subjected to 200,000 mechanical (50 N loading at 2 Hz frequency) and 1000 thermal cycles (5°C and 55°C). Afterwards, specimens were serially sectioned into beams and tested in tension until fracture. Bond strengths were statistically analyzed by two-way ANOVA and Tukey's test (α = 5%). RESULTS: After 24 h, significantly higher µTBS was observed for the formulation containing EMM and QTX (G4) when compared to Clearfil SE Bond (p < 0.05). No significant differences in µTBS were detected among the experimental groups after 24 h (p>0.05). After thermomechanical cycling, no significant differences were observed among groups. CONCLUSION: The addition of EMM and QTX can be considered as possible alternative in dental adhesive formulations.


Assuntos
Colagem Dentária , Animais , Bis-Fenol A-Glicidil Metacrilato , Bovinos , Resinas Compostas , Cimentos Dentários , Dentina , Adesivos Dentinários , Teste de Materiais , Metacrilatos , Cimentos de Resina , Resistência à Tração
16.
Arch. endocrinol. metab. (Online) ; 63(3): 250-257, May-June 2019. tab, graf
Artigo em Inglês | LILACS-Express | ID: biblio-1011159

RESUMO

ABSTRACT Objective To verify the presence of variants in HNF1B in a sample of the Brazilian population selected according to the presence of renal cysts associated with hyperglycemia. Subjects and methods We evaluated 28 unrelated patients with clinical suspicion of HNF1B mutation because of the concomitant presence of diabetes mellitus (DM) or prediabetes and renal cysts. Genotyping was accomplished using Sanger sequencing or multiplex ligation-dependent probe amplification (MLPA). In positive cases, available relatives were recruited. Results We found two patients with HNF1B mutations. The first presented the variant p.Pro328Leufs*48(c.983delC) and had DM, renal cysts, and hypomagnesemia. The second presented a heterozygous whole gene deletion in HNF1B, DM, renal cysts, body and tail pancreatic agenesis, and hypomagnesemia; this alteration was also found in his two siblings and his father. Conclusion The recruitment of suspected cases of HNF1B gene mutations in Brazilians due to hyperglycemia and renal cysts presents two positive cases. Our cases contribute to the annotation of clinical and biochemical phenotypes of this rare form of maturity-onset diabetes of the young (MODY).

17.
BMC Cancer ; 19(1): 435, 2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-31077186

RESUMO

BACKGROUND: Several subunits of the SWI/SNF chromatin remodeling complex are implicated in both cancer and neurodevelopmental disorders (NDD). Though there is no clinical evidence for an increased tumor risk in individuals with NDDs due to germline mutations in most of these genes so far, this has been repeatedly proposed and discussed. A young woman with NDD due to a de novo mutation in ARID1B now presented with a large renal (> 19 cm in diameter) and multiple hepatic angiomyolipomas (AMLs) but no other signs of tuberous sclerosis complex. METHODS: We analyzed tumor and healthy tissue samples with exome and panel sequencing. RESULTS: Additionally to the previously known, germline ARID1B variant we identified a post-zygotic truncating TSC2 variant in both renal and hepatic AMLs but not in any of the healthy tissues. We did not detect any further, obvious tumor driver events. The identification of a passenger variant in SIPA1L3 in both AMLs points to a common clonal origin. Metastasis of the renal AML into the liver is unlikely on the basis of discordant histopathological features. Our findings therefore point to very low-grade mosaicism for the TSC2 variant, possibly in a yet unknown mesenchymal precursor cell that expanded clonally during tumor development. A possible contribution of the germline ARID1B variant to the tumorigenesis remains unclear but cannot be excluded given the absence of any other evident tumor drivers in the AMLs. CONCLUSION: This unique case highlights the blurred line between tumor genetics and post-zygotic events that can complicate exact molecular diagnoses in patients with rare manifestations. It also demonstrates the relevance of multiple disorders in a single individual, the challenges of detecting low-grade mosaicisms, and the importance of proper diagnosis for treatment and surveillance.


Assuntos
Angiomiolipoma/genética , Deficiência Intelectual/complicações , Neoplasias Renais/genética , Neoplasias Hepáticas/genética , Proteína 2 do Complexo Esclerose Tuberosa/genética , Proteínas de Ligação a DNA/genética , Feminino , Mutação em Linhagem Germinativa , Humanos , Deficiência Intelectual/genética , Mosaicismo , Fatores de Transcrição/genética , Sequenciamento Completo do Exoma , Adulto Jovem
18.
Arch Endocrinol Metab ; 63(3): 250-257, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31066763

RESUMO

OBJECTIVE: To verify the presence of variants in HNF1B in a sample of the Brazilian population selected according to the presence of renal cysts associated with hyperglycemia. SUBJECTS AND METHODS: We evaluated 28 unrelated patients with clinical suspicion of HNF1B mutation because of the concomitant presence of diabetes mellitus (DM) or prediabetes and renal cysts. Genotyping was accomplished using Sanger sequencing or multiplex ligation-dependent probe amplification (MLPA). In positive cases, available relatives were recruited. RESULTS: We found two patients with HNF1B mutations. The first presented the variant p.Pro328Leufs*48(c.983delC) and had DM, renal cysts, and hypomagnesemia. The second presented a heterozygous whole gene deletion in HNF1B, DM, renal cysts, body and tail pancreatic agenesis, and hypomagnesemia; this alteration was also found in his two siblings and his father. CONCLUSION: The recruitment of suspected cases of HNF1B gene mutations in Brazilians due to hyperglycemia and renal cysts presents two positive cases. Our cases contribute to the annotation of clinical and biochemical phenotypes of this rare form of maturity-onset diabetes of the young (MODY).


Assuntos
Nefropatias Diabéticas/genética , Fator 1-beta Nuclear de Hepatócito/genética , Hiperglicemia/genética , Doenças Renais Císticas/genética , Mutação , Adulto , Brasil , Estudos de Coortes , Nefropatias Diabéticas/complicações , Deleção de Genes , Humanos , Hiperglicemia/complicações , Doenças Renais Císticas/complicações , Pessoa de Meia-Idade , Fenótipo , Polimorfismo Genético/genética
20.
PLoS Genet ; 15(4): e1008088, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31034465

RESUMO

PIK3C2A is a class II member of the phosphoinositide 3-kinase (PI3K) family that catalyzes the phosphorylation of phosphatidylinositol (PI) into PI(3)P and the phosphorylation of PI(4)P into PI(3,4)P2. At the cellular level, PIK3C2A is critical for the formation of cilia and for receptor mediated endocytosis, among other biological functions. We identified homozygous loss-of-function mutations in PIK3C2A in children from three independent consanguineous families with short stature, coarse facial features, cataracts with secondary glaucoma, multiple skeletal abnormalities, neurological manifestations, among other findings. Cellular studies of patient-derived fibroblasts found that they lacked PIK3C2A protein, had impaired cilia formation and function, and demonstrated reduced proliferative capacity. Collectively, the genetic and molecular data implicate mutations in PIK3C2A in a new Mendelian disorder of PI metabolism, thereby shedding light on the critical role of a class II PI3K in growth, vision, skeletal formation and neurological development. In particular, the considerable phenotypic overlap, yet distinct features, between this syndrome and Lowe's syndrome, which is caused by mutations in the PI-5-phosphatase OCRL, highlight the key role of PI metabolizing enzymes in specific developmental processes and demonstrate the unique non-redundant functions of each enzyme. This discovery expands what is known about disorders of PI metabolism and helps unravel the role of PIK3C2A and class II PI3Ks in health and disease.


Assuntos
Doenças do Desenvolvimento Ósseo/genética , Catarata/genética , Transtornos da Motilidade Ciliar/genética , Nanismo/genética , Mutação , Fosfatidilinositol 3-Quinases/genética , Adolescente , Adulto , Criança , Consanguinidade , Feminino , Fibroblastos/metabolismo , Humanos , Masculino , Linhagem , Fenótipo , Adulto Jovem
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