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1.
J Am Chem Soc ; 141(21): 8416-8421, 2019 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-31083999

RESUMO

RNA technology is transforming life science research and medicine, but many applications are limited by the accessibility, cost, efficacy, and tolerability of delivery systems. Here we report the first members of a new class of dynamic RNA delivery vectors, oligo(serine ester)-based charge-altering releasable transporters (Ser-CARTs). Composed of lipid-containing oligocarbonates and cationic oligo(serine esters), Ser-CARTs are readily prepared (one flask) by a mild ring-opening polymerization using thiourea anions and, upon simple mixing with mRNA, readily form complexes that degrade to neutral serine-based products, efficiently releasing their mRNA cargo. mRNA/Ser-CART transfection efficiencies of >95% are achieved in vitro. Intramuscular or intravenous (iv) injections of mRNA/Ser-CARTs into living mice result in in vivo expression of a luciferase reporter protein, with spleen localization observed after iv injection.

2.
Am J Med Genet A ; 179(5): 870-874, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30941876

RESUMO

BCORL1, a transcriptional corepressor, is involved in negative gene regulation through associations with several protein complexes including Class II histone deacetylases (HDACs). Acquired somatic mutations in BCORL1 have been implicated in the pathogenesis of several malignancies, but germline mutations of BCORL1 have not been associated with a specific genetic syndrome. We report five individuals from three pedigrees with phenotypes including intellectual disability, behavioral difficulties, and dysmorphic features who were found via whole exome sequencing to have variants in BCORL1. In silico analysis of these variants strongly suggests pathogenicity. We propose that hemizygous pathogenic variants in BCORL1 underlie a newly identified X-linked epigenetic syndrome.

3.
Orphanet J Rare Dis ; 14(1): 37, 2019 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-30744648

RESUMO

BACKGROUND: Barth syndrome (BTHS) is an X-linked disorder caused by defects in TAZ with key clinical features including cardiomyopathy, neutropenia and skeletal myopathy. In order to gain a better understanding of the range of clinical features, identify targets for monitoring, and increase knowledge of natural history of the disease, we conducted muscle strength testing, functional exercise capacity testing, physical activity assessment, balance assessment and motion reaction time testing in 33 affected individuals and 14 controls. We analyzed data points to provide a cross-sectional quantitative spectrum of disease characteristics. We also compared these data points to the matched data points collected two years prior to provide insight into effects of BTHS over time. RESULTS: In comparison to controls, pediatric subjects with BTHS present with significantly impaired balance and motion reaction time while adult subjects with BTHS present with significantly impaired motion reaction time. In comparison to controls, subjects with BTHS presented with decreased functional exercise capacity (assessed via 6 MWT), knee extensor strength (both assessed via handheld dynamometry and five times sit-to-stand (5 TSTS)), and self-reported physical activity. Comparison of functional exercise capacity, knee extensor strength and self-reported physical activity from identical cohorts in 2014 and 2016 BTHS showed that the deficits in 6 MWT do not change significantly over the 2 year time span. CONCLUSION: In this comprehensive assessment of musculoskeletal parameters in a cross-section of individuals with BTHS, we uncovered deficits in motion reaction time and balance, which were previously not known to be abnormal in in BTHS. We also confirmed results of our previous study showing that pediatric and adult subjects with BTHS have decreased functional exercise capacity, knee extensor strength, and physical activity in comparison to controls, r, verifying the importance of including these measures as part of the regular clinical assessment in individuals with BTHS, as well as introducing 5 TSTS as an additional testing parameter. Perhaps most importantly, we demonstrated that 6 MWT results do not significantly vary in pediatric and adult cohorts with BTHS over a 2-year period, supporting this as a reliable quantitative measure of therapeutic outcomes in clinical studies and for clinical monitoring.


Assuntos
Síndrome de Barth/fisiopatologia , Adolescente , Adulto , Criança , Estudos Transversais , Exercício/fisiologia , Humanos , Doenças Musculares/fisiopatologia , Tempo de Reação/fisiologia , Teste de Caminhada , Adulto Jovem
4.
Chemosphere ; 212: 262-271, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30145418

RESUMO

Academics researchers and "citizen scientists" from 22 countries confirmed that yellow mealworms, the larvae of Tenebrio molitor Linnaeus, can survive by eating polystyrene (PS) foam. More detailed assessments of this capability for mealworms were carried out by12 sources: five from the USA, six from China, and one from Northern Ireland. All of these mealworms digested PS foam. PS mass decreased and depolymerization was observed, with appearance of lower molecular weight residuals and functional groups indicative of oxidative transformations in extracts from the frass (insect excrement). An addition of gentamycin (30 mg g-1), a bactericidal antibiotic, inhibited depolymerization, implicating the gut microbiome in the biodegradation process. Microbial community analyses demonstrated significant taxonomic shifts for mealworms fed diets of PS plus bran and PS alone. The results indicate that mealworms from diverse locations eat and metabolize PS and support the hypothesis that this capacity is independent of the geographic origin of the mealworms, and is likely ubiquitous to members of this species.


Assuntos
Bactérias/metabolismo , Biodegradação Ambiental , Besouros/metabolismo , Microbioma Gastrointestinal/fisiologia , Larva/metabolismo , Poliestirenos/metabolismo , Animais , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , China , Besouros/crescimento & desenvolvimento , Microbioma Gastrointestinal/efeitos dos fármacos , Gentamicinas/farmacologia , Larva/crescimento & desenvolvimento
5.
Angew Chem Int Ed Engl ; 57(41): 13582-13586, 2018 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-30112821

RESUMO

RNAs are a promising class of therapeutics given their ability to regulate protein concentrations at the cellular level. Developing safe and effective strategies to deliver RNAs remains important for realizing their full clinical potential. Here, we develop lipid nanoparticle formulations that can deliver short interfering RNAs (for gene silencing) or messenger RNAs (for gene upregulation). Specifically, we study how the tail length, tail geometry, and linker spacing in diketopiperazine lipid materials influences LNP potency with siRNAs and mRNAs. Eight lipid materials are synthesized, and 16 total formulations are screened for activity in vitro; the lead material is evaluated with mRNA for in vivo use and demonstrates luciferase protein expression in the spleen. In undertaking this approach, not only do we develop synthetic routes to delivery materials, but we also reveal structural criteria that could be useful for developing next-generation delivery materials for RNA therapeutics.

6.
Am J Med Genet A ; 176(4): 925-935, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29436146

RESUMO

SATB2-associated syndrome (SAS) is an autosomal dominant disorder characterized by significant neurodevelopmental disabilities with limited to absent speech, behavioral issues, and craniofacial anomalies. Previous studies have largely been restricted to case reports and small series without in-depth phenotypic characterization or genotype-phenotype correlations. Seventy two study participants were identified as part of the SAS clinical registry. Individuals with a molecularly confirmed diagnosis of SAS were referred after clinical diagnostic testing. In this series we present the most comprehensive phenotypic and genotypic characterization of SAS to date, including prevalence of each clinical feature, neurodevelopmental milestones, and when available, patient management. We confirm that the most distinctive features are neurodevelopmental delay with invariably severely limited speech, abnormalities of the palate (cleft or high-arched), dental anomalies (crowding, macrodontia, abnormal shape), and behavioral issues with or without bone or brain anomalies. This comprehensive clinical characterization will help clinicians with the diagnosis, counseling and management of SAS and help provide families with anticipatory guidance.

7.
Adv Mater ; 29(33)2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28681930

RESUMO

B lymphocytes regulate several aspects of immunity including antibody production, cytokine secretion, and T-cell activation; moreover, B cell misregulation is implicated in autoimmune disorders and cancers such as multiple sclerosis and non-Hodgkin's lymphomas. The delivery of messenger RNA (mRNA) into B cells can be used to modulate and study these biological functions by means of inducing functional protein expression in a dose-dependent and time-controlled manner. However, current in vivo mRNA delivery systems fail to transfect B lymphocytes and instead primarily target hepatocytes and dendritic cells. Here, the design, synthesis, and biological evaluation of a lipid nanoparticle (LNP) system that can encapsulate mRNA, navigate to the spleen, transfect B lymphocytes, and induce more than 60 pg of protein expression per million B cells within the spleen is described. Importantly, this LNP induces more than 85% of total protein production in the spleen, despite LNPs being observed transiently in the liver and other organs. These results demonstrate that LNP composition alone can be used to modulate the site of protein induction in vivo, highlighting the critical importance of designing and synthesizing new nanomaterials for nucleic acid delivery.

8.
Neurology ; 89(4): 385-394, 2017 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-28667181

RESUMO

OBJECTIVE: To evaluate the phenotypic spectrum caused by mutations in dynamin 1 (DNM1), encoding the presynaptic protein DNM1, and to investigate possible genotype-phenotype correlations and predicted functional consequences based on structural modeling. METHODS: We reviewed phenotypic data of 21 patients (7 previously published) with DNM1 mutations. We compared mutation data to known functional data and undertook biomolecular modeling to assess the effect of the mutations on protein function. RESULTS: We identified 19 patients with de novo mutations in DNM1 and a sibling pair who had an inherited mutation from a mosaic parent. Seven patients (33.3%) carried the recurrent p.Arg237Trp mutation. A common phenotype emerged that included severe to profound intellectual disability and muscular hypotonia in all patients and an epilepsy characterized by infantile spasms in 16 of 21 patients, frequently evolving into Lennox-Gastaut syndrome. Two patients had profound global developmental delay without seizures. In addition, we describe a single patient with normal development before the onset of a catastrophic epilepsy, consistent with febrile infection-related epilepsy syndrome at 4 years. All mutations cluster within the GTPase or middle domains, and structural modeling and existing functional data suggest a dominant-negative effect on DMN1 function. CONCLUSIONS: The phenotypic spectrum of DNM1-related encephalopathy is relatively homogeneous, in contrast to many other genetic epilepsies. Up to one-third of patients carry the recurrent p.Arg237Trp variant, which is now one of the most common recurrent variants in epileptic encephalopathies identified to date. Given the predicted dominant-negative mechanism of this mutation, this variant presents a prime target for therapeutic intervention.


Assuntos
Encefalopatias/genética , Encefalopatias/metabolismo , GTP Fosfo-Hidrolases/genética , GTP Fosfo-Hidrolases/metabolismo , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Mutação , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Análise Mutacional de DNA , Feminino , Proteínas de Homeodomínio , Humanos , Lactente , Masculino , Modelos Moleculares , Fenótipo , Proteína de Homoeobox de Baixa Estatura , Irmãos , Vesículas Sinápticas/metabolismo , Adulto Jovem
9.
Genet Med ; 18(10): 1001-10, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-26845103

RESUMO

PURPOSE: Barth syndrome (BTHS), an X-linked disorder caused by defects in TAZ, is the only known single-gene disorder of cardiolipin remodeling. We hypothesized that through analysis of affected individuals, we would gain a better understanding of the range of clinical features and identify targets for monitoring and therapy. METHODS: We conducted a multidisciplinary investigation involving 42 patients with BTHS, including echocardiograms, muscle strength testing, functional exercise capacity testing, physical activity assessments, cardiolipin analysis, 3-methylglutaconic acid analysis, and review of genotype data. We analyzed data points to provide a quantitative spectrum of disease characteristics and to identify relationships among phenotype, genotype, and relevant metabolites. RESULTS: Echocardiography revealed considerable variability in cardiac features. By contrast, almost all patients had significantly reduced functional exercise capacity. Multivariate analysis revealed significant relationships between cardiolipin ratio and left ventricular mass and between cardiolipin ratio and functional exercise capacity. We additionally identified genotypes associated with a less severe metabolic and clinical profile. CONCLUSION: We defined previously unrecognized metabolite/phenotype/genotype relationships, established targets for therapeutic monitoring, and validated avenues for clinical assessment. In addition to providing insight into BTHS, these studies also provide insight into the myriad of multifactorial disorders that converge on the cardiolipin pathway.Genet Med 18 10, 1001-1010.


Assuntos
Síndrome de Barth/sangue , Cardiolipinas/sangue , Cardiomiopatias/sangue , Fatores de Transcrição/genética , Adolescente , Adulto , Síndrome de Barth/genética , Síndrome de Barth/fisiopatologia , Cardiolipinas/genética , Cardiomiopatias/genética , Cardiomiopatias/fisiopatologia , Criança , Pré-Escolar , Ecocardiografia , Genótipo , Glutaratos/sangue , Humanos , Masculino , Força Muscular/genética , Fenótipo , Adulto Jovem
10.
Adv Mater ; 28(15): 2939-43, 2016 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-26889757

RESUMO

Thousands of human diseases could be treated by selectively controlling the expression of specific proteins in vivo. A new series of alkenyl amino alcohol (AAA) ionizable lipid nanoparticles (LNPs) capable of delivering human mRNA with unprecedented levels of in vivo efficacy is demonstrated. This study highlights the importance of utilizing synthesis tools in tandem with biological inspiration to understand and improve nucleic acid delivery in vivo.


Assuntos
Alcenos/química , Amino Álcoois/química , Materiais Biomiméticos/química , Portadores de Fármacos/química , Lipídeos/química , Nanopartículas/química , Eritropoetina/genética , Humanos , RNA Mensageiro/química , RNA Mensageiro/genética
11.
Am J Med Genet A ; 167A(5): 1147-51, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25851414

RESUMO

Recently, mutations in FARS2, which encodes for mitochondrial phenylalanyl-tRNA synthetase, have been implicated in autosomal recessive combined oxidative phosphorylation deficiency 14. Associated clinical features in three previously reported patients with confirmed FARS2 mutations include infantile onset epilepsy, and a fatal Alpers-like encephalopathy. Herein, we report on two siblings with global developmental delay, dysarthria and tremor and compound heterozygous FARS2 abnormalities. They have a heterozygous missense mutation, c.1255C>T which predicts p.Arg419Cys in exon 7 of FARS2, inherited from their father and uncovered on exome sequencing, and an interstitial deletion of chromosome 6p25.1 inherited from their mother and uncovered on SNP array. This interstitial deletion includes all of exon 6 and parts of introns 5 and 6 of FARS2. Biochemical studies were also consistent with a mitochondrial disorder. While these siblings had considerable developmental difficulties, they are making consistent developmental progress and appear to be considerably less severely affected than the other patients reported in the literature with FARS2 associated mitochondrial disease. Thus, this study expands the phenotypic spectrum of FARS2 related disease and emphasizes intragenic deletion in the list of causative mutations.


Assuntos
Lobo Frontal/fisiopatologia , Mitocôndrias/genética , Doenças Mitocondriais/genética , Fenilalanina-tRNA Ligase/genética , Adolescente , Criança , Pré-Escolar , Exoma/genética , Éxons/genética , Feminino , Lobo Frontal/diagnóstico por imagem , Humanos , Imagem por Ressonância Magnética , Masculino , Mitocôndrias/enzimologia , Mitocôndrias/patologia , Doenças Mitocondriais/diagnóstico por imagem , Doenças Mitocondriais/fisiopatologia , Mutação de Sentido Incorreto , Linhagem , Radiografia , Irmãos , Substância Branca/diagnóstico por imagem , Substância Branca/fisiopatologia
12.
Cold Spring Harb Mol Case Stud ; 1(1): a000455, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27148570

RESUMO

Seven patients with similar phenotypes of developmental delay and microcephaly were found by whole-exome sequencing to have de novo loss-of-function mutations in POGZ. POGZ is a pogo transposable element-derived protein with a zinc finger cluster. The protein is involved in normal kinetochore assembly and mitotic sister chromatid cohesion and mitotic chromosome segregation. POGZ deficiency may affect mitosis, disrupting brain development and function.

13.
Ann Neurol ; 76(4): 473-83, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25131622

RESUMO

OBJECTIVE: Whole exome sequencing (WES) represents a significant breakthrough in clinical genetics as a powerful tool for etiological discovery in neurodevelopmental disorders. To better characterize the genetic landscape of neurodevelopmental disorders, we analyzed patients in our pediatric neurogenetics clinic who underwent WES. METHODS: We performed a retrospective cohort study on 78 patients with various neurodevelopmental disabilities and unrevealing workup prior to WES. We characterized their molecular diagnoses, clinical features, and whether their previous treatment plan changed due to WES results. RESULTS: The overall presumptive diagnostic rate for our cohort was 41% (n = 32 of 78 patients). Nineteen patients had a single autosomal dominant (AD) disorder, 11 had a single autosomal recessive (AR) disorder, 1 had an X-linked dominant disorder, and 1 had both an AD and an AR disorder. The 32 patients with pathogenic or likely pathogenic variants exhibited various neurobehavioral and neuroimaging abnormalities, including intellectual disability/developmental delay (n = 28), cerebral palsy-like encephalopathy (n = 11), autism spectrum disorder (n = 5), delayed/hypomyelination (n = 7), and cerebellar abnormalities (n = 9). The results of WES affected management for all patients with a presumptive diagnosis, triggering reproductive planning (n = 27), disease monitoring initiation (n = 4), investigation of systemic involvement of the disorder(s) (n = 6), alteration of presumed disease inheritance pattern (n = 7), changing of prognosis (n = 10), medication discontinuation (n = 5) or initiation (n = 2), and clinical trial education (n = 3). INTERPRETATION: The high diagnostic yield of WES supports its use in pediatric neurology practices. It may also lead to earlier diagnosis, impacting medical management, prognostication, and family planning. WES therefore serves as a critical tool for the child neurologist.


Assuntos
Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/genética , Exoma/genética , Doenças do Sistema Nervoso/diagnóstico , Doenças do Sistema Nervoso/genética , Análise de Sequência de DNA/métodos , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Predisposição Genética para Doença/genética , Humanos , Lactente , Masculino , Pediatria , Adulto Jovem
14.
Mol Genet Metab ; 112(2): 143-7, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24751896

RESUMO

Barth Syndrome is a rare X-linked disorder characterized principally by dilated cardiomyopathy, skeletal myopathy and neutropenia and caused by defects in tafazzin, an enzyme responsible for modifying the acyl chain moieties of cardiolipin. While several comprehensive clinical studies of Barth Syndrome have been published detailing cardiac and hematologic features, descriptions of its biochemical characteristics are limited. To gain a better understanding of the clinical biochemistry of this rare disease, we measured hematologic and biochemical values in a cohort of Barth Syndrome patients. We characterized multiple biochemical parameters, including plasma amino acids, plasma 3-methylglutaconic acid, cholesterol, cholesterol synthetic intermediates, and red blood cell membrane fatty acid profiles in 28 individuals with Barth Syndrome from ages 10 months to 30 years. We describe a unique biochemical profile for these patients, including decreased plasma arginine levels. We further studied the plasma amino acid profiles, cholesterol, cholesterol synthetic intermediates, and plasma 3-methylglutaconic acid levels in 8 female carriers and showed that they do not share any of the distinct, Barth Syndrome-specific biochemical laboratory abnormalities. Our studies augment and expand the biochemical profiles of individuals with Barth Syndrome, describe a unique biochemical profile for these patients, and provide insight into the possible underlying biochemical pathology in this disorder.


Assuntos
Arginina/sangue , Síndrome de Barth/sangue , Síndrome de Barth/fisiopatologia , Biomarcadores/sangue , Adolescente , Adulto , Síndrome de Barth/patologia , Estudos de Casos e Controles , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Adulto Jovem
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