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1.
Int J Mol Sci ; 22(17)2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34502207

RESUMO

The complexity of skeletal pathologies makes use of in vivo models essential to elucidate the pathogenesis of the diseases; nevertheless, chondrocyte and osteoblast cell lines provide relevant information on the underlying disease mechanisms. Due to the limitations of primary chondrocytes, immortalized cells represent a unique tool to overcome this problem since they grow very easily for several passages. However, in the immortalization procedure the cells might lose the original phenotype; thus, these cell lines should be deeply characterized before their use. We immortalized primary chondrocytes from a Cant1 knock-out mouse, an animal model of Desbuquois dysplasia type 1, with a plasmid expressing the SV40 large and small T antigen. This cell line, based on morphological and biochemical parameters, showed preservation of the chondrocyte phenotype. In addition reduced proteoglycan synthesis and oversulfation of glycosaminoglycan chains were demonstrated, as already observed in primary chondrocytes from the Cant1 knock-out mouse. In conclusion, immortalized Cant1 knock-out chondrocytes maintained the disease phenotype observed in primary cells validating the in vitro model and providing an additional tool to further study the proteoglycan biosynthesis defect. The same approach might be extended to other cartilage disorders.


Assuntos
Hidrolases Anidrido Ácido/fisiologia , Condrócitos/patologia , Anormalidades Craniofaciais/patologia , Nanismo/patologia , Glicosaminoglicanos/metabolismo , Instabilidade Articular/patologia , Ossificação Heterotópica/patologia , Fenótipo , Polidactilia/patologia , Animais , Linhagem Celular Transformada , Condrócitos/metabolismo , Anormalidades Craniofaciais/etiologia , Anormalidades Craniofaciais/metabolismo , Nanismo/etiologia , Nanismo/metabolismo , Instabilidade Articular/etiologia , Instabilidade Articular/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ossificação Heterotópica/etiologia , Ossificação Heterotópica/metabolismo , Polidactilia/etiologia , Polidactilia/metabolismo
3.
Am J Hum Genet ; 108(10): 1964-1980, 2021 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-34547244

RESUMO

Congenital diaphragmatic hernia (CDH) is a severe congenital anomaly that is often accompanied by other anomalies. Although the role of genetics in the pathogenesis of CDH has been established, only a small number of disease-associated genes have been identified. To further investigate the genetics of CDH, we analyzed de novo coding variants in 827 proband-parent trios and confirmed an overall significant enrichment of damaging de novo variants, especially in constrained genes. We identified LONP1 (lon peptidase 1, mitochondrial) and ALYREF (Aly/REF export factor) as candidate CDH-associated genes on the basis of de novo variants at a false discovery rate below 0.05. We also performed ultra-rare variant association analyses in 748 affected individuals and 11,220 ancestry-matched population control individuals and identified LONP1 as a risk gene contributing to CDH through both de novo and ultra-rare inherited largely heterozygous variants clustered in the core of the domains and segregating with CDH in affected familial individuals. Approximately 3% of our CDH cohort who are heterozygous with ultra-rare predicted damaging variants in LONP1 have a range of clinical phenotypes, including other anomalies in some individuals and higher mortality and requirement for extracorporeal membrane oxygenation. Mice with lung epithelium-specific deletion of Lonp1 die immediately after birth, most likely because of the observed severe reduction of lung growth, a known contributor to the high mortality in humans. Our findings of both de novo and inherited rare variants in the same gene may have implications in the design and analysis for other genetic studies of congenital anomalies.


Assuntos
Proteases Dependentes de ATP/genética , Proteases Dependentes de ATP/fisiologia , Anormalidades Craniofaciais/genética , Variações do Número de Cópias de DNA , Anormalidades do Olho/genética , Transtornos do Crescimento/genética , Hérnias Diafragmáticas Congênitas/genética , Luxação Congênita de Quadril/genética , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/fisiologia , Mutação de Sentido Incorreto , Osteocondrodisplasias/genética , Anormalidades Dentárias/genética , Animais , Estudos de Casos e Controles , Estudos de Coortes , Anormalidades Craniofaciais/patologia , Anormalidades do Olho/patologia , Feminino , Transtornos do Crescimento/patologia , Hérnias Diafragmáticas Congênitas/patologia , Luxação Congênita de Quadril/patologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Osteocondrodisplasias/patologia , Linhagem , Anormalidades Dentárias/patologia
5.
Int J Mol Sci ; 22(15)2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34360864

RESUMO

This study evaluated the new bone formation potential of micro-macro biphasic calcium phosphate (MBCP) and Bio-Oss grafting materials with and without dental pulp-derived mesenchymal stem cells (DPSCs) and bone marrow-derived mesenchymal stem cells (BMSCs) in a rabbit calvarial bone defect model. The surface structure of the grafting materials was evaluated using a scanning electron microscope (SEM). The multipotent differentiation characteristics of the DPSCs and BMSCs were assessed. Four circular bone defects were created in the calvarium of 24 rabbits and randomly allocated to eight experimental groups: empty control, MBCP, MBCP+DPSCs, MBCP+BMSCs, Bio-Oss+DPSCs, Bio-Oss+BMSCs, and autogenous bone. A three-dimensional analysis of the new bone formation was performed using micro-computed tomography (micro-CT) and a histological study after 2, 4, and 8 weeks of healing. Homogenously porous structures were observed in both grafting materials. The BMSCs revealed higher osteogenic differentiation capacities, whereas the DPSCs exhibited higher colony-forming units. The micro-CT and histological analysis findings for the new bone formation were consistent. In general, the empty control showed the lowest bone regeneration capacity throughout the experimental period. By contrast, the percentage of new bone formation was the highest in the autogenous bone group after 2 (39.4% ± 4.7%) and 4 weeks (49.7% ± 1.5%) of healing (p < 0.05). MBCP and Bio-Oss could provide osteoconductive support and prevent the collapse of the defect space for new bone formation. In addition, more osteoblastic cells lining the surface of the newly formed bone and bone grafting materials were observed after incorporating the DPSCs and BMSCs. After 8 weeks of healing, the autogenous bone group (54.9% ± 6.1%) showed a higher percentage of new bone formation than the empty control (35.3% ± 0.5%), MBCP (38.3% ± 6.0%), MBCP+DPSC (39.8% ± 5.7%), Bio-Oss (41.3% ± 3.5%), and Bio-Oss+DPSC (42.1% ± 2.7%) groups. Nevertheless, the percentage of new bone formation did not significantly differ between the MBCP+BMSC (47.2% ± 8.3%) and Bio-Oss+BMSC (51.2% ± 9.9%) groups and the autogenous bone group. Our study results demonstrated that autogenous bone is the gold standard. Both the DPSCs and BMSCs enhanced the osteoconductive capacities of MBCP and Bio-Oss. In addition, the efficiency of the BMSCs combined with MBCP and Bio-Oss was comparable to that of the autogenous bone after 8 weeks of healing. These findings provide effective strategies for the improvement of biomaterials and MSC-based bone tissue regeneration.


Assuntos
Regeneração Óssea , Substitutos Ósseos/uso terapêutico , Anormalidades Craniofaciais/cirurgia , Minerais/uso terapêutico , Engenharia Tecidual/métodos , Tecidos Suporte , Animais , Transplante Ósseo , Masculino , Osteogênese , Coelhos , Cicatrização
6.
Eur J Med Genet ; 64(10): 104295, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34371190

RESUMO

Defects in the PIEZO1 gene cause lymphatic dysplasia in an autosomal recessive manner, mostly by loss-of-function variants. Moreover, since 2019, the role of PIEZO1 in bone formation has been established, but there have been no PIEZO1-related cases presenting definite skeletal involvement to date. A 21-year-old male with primary lymphatic dysplasia had some other distinctive clinical features, including multiple fracture history during infancy, thoracolumbar scoliosis, short stature, and left-sided facial bone hypoplasia. We analyzed the whole exome of the patient and found two novel pathogenic variants of PIEZO1 in trans: a 93.7 kb heterozygous deletion (chr16:88,782,477-88,876,207; exon 1-50) and c.2858G>A (p.Arg953His). Sanger sequencing validated the deletion with breakpoints, and each variant was inherited from a different parent. This study presented an extremely rare case of a patient with lymphatic dysplasia caused by compound heterozygous variants of PIEZO1, along with additional clinical manifestations including several skeletal phenotypes.


Assuntos
Anormalidades Craniofaciais/genética , Fraturas Ósseas/genética , Canais Iônicos/genética , Linfangiectasia Intestinal/genética , Linfedema/genética , Mutação , Fenótipo , Escoliose/genética , Anormalidades Craniofaciais/patologia , Fraturas Ósseas/patologia , Heterozigoto , Humanos , Linfangiectasia Intestinal/patologia , Linfedema/patologia , Masculino , Escoliose/patologia , Adulto Jovem
7.
Development ; 148(17)2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34383890

RESUMO

Neural crest cells (NCCs) within the mandibular and maxillary prominences of the first pharyngeal arch are initially competent to respond to signals from either region. However, mechanisms that are only partially understood establish developmental tissue boundaries to ensure spatially correct patterning. In the 'hinge and caps' model of facial development, signals from both ventral prominences (the caps) pattern the adjacent tissues whereas the intervening region, referred to as the maxillomandibular junction (the hinge), maintains separation of the mandibular and maxillary domains. One cap signal is GATA3, a member of the GATA family of zinc-finger transcription factors with a distinct expression pattern in the ventral-most part of the mandibular and maxillary portions of the first arch. Here, we show that disruption of Gata3 in mouse embryos leads to craniofacial microsomia and syngnathia (bony fusion of the upper and lower jaws) that results from changes in BMP4 and FGF8 gene regulatory networks within NCCs near the maxillomandibular junction. GATA3 is thus a crucial component in establishing the network of factors that functionally separate the upper and lower jaws during development.


Assuntos
Padronização Corporal , Face/embriologia , Fator de Transcrição GATA3/metabolismo , Animais , Região Branquial/citologia , Região Branquial/embriologia , Região Branquial/metabolismo , Morte Celular , Proliferação de Células , Anormalidades Craniofaciais/embriologia , Anormalidades Craniofaciais/genética , Anormalidades Craniofaciais/metabolismo , Embrião de Mamíferos , Fator de Transcrição GATA3/genética , Regulação da Expressão Gênica no Desenvolvimento , Mandíbula/citologia , Mandíbula/embriologia , Maxila/citologia , Maxila/embriologia , Camundongos , Morfogênese , Crista Neural/citologia , Crista Neural/embriologia , Crista Neural/metabolismo
8.
J Neurosurg Pediatr ; 28(4): 425-431, 2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34388723

RESUMO

OBJECTIVE: Crouzon syndrome with acanthosis nigricans (CAN) is a rare and clinically complex subtype of Crouzon syndrome. At three craniofacial centers, this multicenter study was undertaken to assess clinical signs in relation to the required interventions and treatment course in patients with CAN. METHODS: A retrospective cohort study of CAN was performed to obtain information about the clinical treatment course of these patients. Three centers participated: Erasmus Medical Centre, Rotterdam, the Netherlands; John Radcliffe Hospital, Oxford, United Kingdom; and Hôpital Necker-Enfants Malades, Paris, France. RESULTS: Nineteen patients (5 males, 14 females) were included in the study. All children were operated on, with a mean of 2.2 surgeries per patient (range 1-6). Overall, the following procedures were performed: 23 vault expansions, 10 monobloc corrections, 6 midface surgeries, 11 foramen magnum decompressions, 29 CSF-diverting surgeries, 23 shunt-related interventions, and 6 endoscopic third ventriculostomies, 3 of which subsequently required a shunt. CONCLUSIONS: This study demonstrates that patients with the mutation c.1172C>A (p.Ala391Glu) in the FGFR3 gene have a severe disease trajectory, requiring multiple surgical procedures. The timing and order of interventions have changed among patients and centers. It was not possible to differentiate the effect of a more severe clinical presentation from the effect of treatment order on outcome.


Assuntos
Acantose Nigricans/cirurgia , Disostose Craniofacial/cirurgia , Acantose Nigricans/complicações , Acantose Nigricans/genética , Encéfalo/diagnóstico por imagem , Criança , Pré-Escolar , Protocolos Clínicos , Estudos de Coortes , Anormalidades Craniofaciais/cirurgia , Disostose Craniofacial/complicações , Disostose Craniofacial/genética , Descompressão Cirúrgica , Feminino , Forame Magno/cirurgia , França , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Mutação/genética , Países Baixos , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Reino Unido , Ventriculostomia
9.
Rev. ecuat. pediatr ; 22(2): 1-7, 31 de agosto del 2021.
Artigo em Espanhol | LILACS | ID: biblio-1284497

RESUMO

Introducción: El síndrome de Rubinstein ­ Taybi es una patología de origen genético que afecta a 1 de cada 100.000 a 125.000 nacidos vivos, se caracteriza por presentar: retraso en el crecimiento, retraso en el desarrollo psicomotriz y anomalías morfológicas que incluyen: rasgos faciales peculiares (cejas arqueadas y gruesas, fisuras palpebrales inclinadas hacia abajo, puente nasal convexo con punta de la nariz por debajo de las alas), pulgares y hallux anchos. Su origen epigenético en el 60% de los casos se debe a una alteración en el gen CREBBP (codificador de la proteína CPB), en el 10% a un cambio en el gen EP300 (codificador de la proteína p300) y en el 30% no se han logrado identificar su causa. Caso clínico: Niño de 8 años de edad con retardo en el desarrollo psicomotriz, con dificultades para la adaptación escolar. Al examen físico con rasgos faciales: cejas superpobladas y arqueadas, hirsutismo en frente y región de labio superior, fisuras palpebrales inclinadas hacia abajo, hipertelorismo con estrabismo convergente, puente nasal ancho, nariz achatada, la punta se extiende levemente por debajo de las alas nasales. Con hirsutismo en región cervical e interescapular. En las manos se identifica dedos pulgares anchos, en el resto de dedos se evidencian falanges distales ensanchadas, de igual forma en la región de los pies se identifican hallux anchos y falanges distales ensanchadas. Evolución: El paciente sigue en observación por consulta externa, fue enviado a programas de terapia de lenguaje, lectura y psicomotriz. No ha desarrollado infecciones pulmonares hasta el cierre del seguimiento, 6 meses posteriores al diagnóstico. Conclusión: En presente caso reporta las alteraciones fenotípicas características faciales y de extremidades de un niño con síndrome de Rubinstein-Taybi, las cuales ayudaron al diagnóstico clínico.


Introduction: Rubinstein-Taybi syndrome is a pathology of genetic origin that affects 1 out of every 100,000 to 125,000 live births, it is characterized by: growth retardation, delay in psy-chomotor development and morphological abnormalities that include: peculiar facial features (thick arched eyebrows, downward sloping palpebral fissures, convex nasal bridge with tip of nose below wings), broad thumbs and hallux. Its epigenetic origin in 60% of cases is due to an alteration in the CREBBP gene (coding for CPB protein), in 10% to a change in the EP300 gene (coding for p300 protein) and in the 30% have not been able to identify its cause. Clinical case: 8-year-old boy with a delay in psychomotor development, with difficulties in adapting to school. On physical examination with facial features: overpopulated and arched eyebrows, hirsutism in the forehead and upper lip region, downward sloping palpebral fissures, hypertelorism with convergent strabismus, wide nasal bridge, flattened nose, the tip extends slightly below the nasal wings. With hirsutism in the cervical and interscapular region. In the hands, broad thumbs are identified, in the rest of the fingers there are widened distal phalanges, in the same way in the region of the feet, wide hallux and widened distal phalanges are identified. Evolution: The patient continues to be observed by outpatient consultation, he was sent to speech, reading and psychomotor therapy programs. He has not developed pulmonary infections until the close of follow-up, 6 months after diagnosis. Conclusion: In this case, it reports the phenotypic alterations of the facial and limb characteristics of a child with Rubinstein-Taybi syndrome, which helped the clinical diagnosis.


Introdução: A síndrome de Rubinstein-Taybi é uma patologia de origem genética que afeta 1 em cada 100.000 a 125.000 nascidos vivos, é caracterizada por: retardo de crescimento, atraso no desenvolvimento psicomotor e anormalidades morfológicas que incluem: características faciais peculiares (sobrancelhas arqueadas e grossas, descendente fissuras palpebrais, ponte nasal convexa com a ponta do nariz abaixo das asas), polegares largos e hálux. Sua origem epigenética em 60% dos casos deve-se a uma alteração no gene CREBBP (que codifica a proteína CPB), em 10% a uma alteração no gene EP300 (que codifica a proteína p300) e em 30% sua causa não foi identificada . Caso clínico: Menino de 8 anos com atraso no desenvolvimento psicomotor, com dificuldade de adaptação à escola. No exame físico com características faciais: sobrancelhas superpovoadas e arqueadas, hirsutismo na testa e região do lábio superior, fissuras palpebrais inclinadas para baixo, hipertelorismo com estrabismo convergente, ponte nasal larga, nariz achatado, a ponta se estende ligeiramente abaixo das asas nasais. Com hirsutismo na região cervical e interescapular. Nas mãos identificam-se os polegares largos, nos restantes dedos são identificadas falanges distais alargadas, da mesma forma que na região dos pés, hálux largo e falanges distais alargadas. Evolução: O paciente ainda está em acompanhamento ambulatorial, foi encaminhado para programas de fonoaudiologia. Ele não desenvolveu infecções pulmonares até o fechamento do acompanhamento, 6 meses após o diagnóstico. Conclusão: Nesse caso, relata as alterações fenotípicas das características faciais e de membros de uma criança com síndrome de Rubinstein-Taybi, o que auxiliou no diagnóstico clínico.


Assuntos
Humanos , Criança , Síndrome de Rubinstein-Taybi , Relatos de Casos , Polegar , Anormalidades Craniofaciais , Transtornos Cromossômicos
10.
Genes (Basel) ; 12(6)2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34200686

RESUMO

Since 2011, eight males with an X-linked recessive disorder (Ogden syndrome, MIM #300855) associated with the same missense variant p.(Ser37Pro) in the NAA10 gene have been described. After the advent of whole exome sequencing, many NAA10 variants have been reported as causative of syndromic or non-syndromic intellectual disability in both males and females. The NAA10 gene lies in the Xq28 region and encodes the catalytic subunit of the major N-terminal acetyltransferase complex NatA, which acetylates almost half the human proteome. Here, we present a young female carrying a de novo NAA10 [NM_003491:c.247C > T, p.(Arg83Cys)] variant. The 18-year-old girl has severely delayed motor and language development, autistic traits, postnatal growth failure, facial dysmorphisms, interventricular septal defect, neuroimaging anomalies and epilepsy. Our attempt is to expand and compare genotype-phenotype correlation in females with NAA10-related syndrome. A detailed clinical description could have relevant consequences for the clinical management of known and newly identified individuals.


Assuntos
Anormalidades Craniofaciais/genética , Deficiências do Desenvolvimento/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Deficiência Intelectual/genética , Acetiltransferase N-Terminal A/genética , Acetiltransferase N-Terminal E/genética , Fenótipo , Adolescente , Anormalidades Craniofaciais/patologia , Deficiências do Desenvolvimento/patologia , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Genótipo , Humanos , Deficiência Intelectual/patologia , Mutação de Sentido Incorreto , Síndrome
12.
Arch Biochem Biophys ; 710: 108983, 2021 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-34228963

RESUMO

Lon is an ATP-dependent protease belonging to the "ATPase associated with diverse cellular activities" (AAA+) protein family. In humans, Lon is translated as a precursor and imported into the mitochondria matrix through deletion of the first 114 amino acid residues. In mice, embryonic knockout of lon is lethal. In humans, some dysfunctional lon mutations are tolerated but they cause a developmental disorder known as the CODAS syndrome. To gain a better understanding on the enzymology of human mitochondrial Lon, this study compares the structure-function relationship of the WT versus one of the CODAS mutants R721G to identify the mechanistic features in Lon catalysis that are affected. To this end, steady-state kinetics were used to quantify the difference in ATPase and ATP-dependent peptidase activities between WT and R721G. The Km values for the intrinsic as well as protein-stimulated ATPase were increased whereas the kcat value for ATP-dependent peptidase activity was decreased in the R721G mutant. The mutant protease also displayed substrate inhibition kinetics. In vitro studies revealed that R721G did not degrade the endogenous mitochondrial Lon substrate pyruvate dehydrogenase kinase isoform 4 (PDK4) effectively like WT hLon. Furthermore, the pyruvate dehydrogenase complex (PDH) protected PDK4 from hLon degradation. Using hydrogen deuterium exchange/mass spectrometry and negative stain electron microscopy, structural perturbations associated with the R721G mutation were identified. To validate the in vitro findings under a physiologically relevant condition, the intrinsic stability as well as proteolytic activity of WT versus R721G mutant towards PDK 4 were compared in cell lysates prepared from immortalized B lymphocytes expressing the respective protease. The lifetime of PDK4 is longer in the mutant cells, but the lifetime of Lon protein is longer in the WT cells, which corroborate the in vitro structure-functional relationship findings.


Assuntos
Mitocôndrias/enzimologia , Protease La/química , Protease La/genética , Sequência de Aminoácidos , Substituição de Aminoácidos , Animais , Linfócitos B/enzimologia , Biocatálise , Anormalidades Craniofaciais/enzimologia , Anormalidades Craniofaciais/genética , Estabilidade Enzimática/genética , Anormalidades do Olho/enzimologia , Anormalidades do Olho/genética , Transtornos do Crescimento/enzimologia , Transtornos do Crescimento/genética , Luxação Congênita de Quadril/enzimologia , Luxação Congênita de Quadril/genética , Humanos , Cinética , Camundongos , Modelos Moleculares , Simulação de Dinâmica Molecular , Proteínas Mutantes/química , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Mutação de Sentido Incorreto , Osteocondrodisplasias/enzimologia , Osteocondrodisplasias/genética , Protease La/metabolismo , Piruvato Desidrogenase Quinase de Transferência de Acetil/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Relação Estrutura-Atividade , Especificidade por Substrato , Anormalidades Dentárias/enzimologia , Anormalidades Dentárias/genética
13.
Int J Mol Sci ; 22(12)2021 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-34208498

RESUMO

CYP1B1 loss of function (LoF) is the main known genetic alteration present in recessive primary congenital glaucoma (PCG), an infrequent disease characterized by delayed embryonic development of the ocular iridocorneal angle; however, the underlying molecular mechanisms are poorly understood. To model CYP1B1 LoF underlying PCG, we developed a cyp1b1 knockout (KO) zebrafish line using CRISPR/Cas9 genome editing. This line carries the c.535_667del frameshift mutation that results in the 72% mRNA reduction with the residual mRNA predicted to produce an inactive truncated protein (p.(His179Glyfs*6)). Microphthalmia and jaw maldevelopment were observed in 23% of F0 somatic mosaic mutant larvae (144 hpf). These early phenotypes were not detected in cyp1b1-KO F3 larvae (144 hpf), but 27% of adult (four months) zebrafish exhibited uni- or bilateral craniofacial alterations, indicating the existence of incomplete penetrance and variable expressivity. These phenotypes increased to 86% in the adult offspring of inbred progenitors with craniofacial defects. No glaucoma-related phenotypes were observed in cyp1b1 mutants. Transcriptomic analyses of the offspring (seven dpf) of cyp1b1-KO progenitors with adult-onset craniofacial defects revealed functionally enriched differentially expressed genes related to extracellular matrix and cell adhesion, cell growth and proliferation, lipid metabolism (retinoids, steroids and fatty acids and oxidation-reduction processes that include several cytochrome P450 genes) and inflammation. In summary, this study shows the complexity of the phenotypes and molecular pathways associated with cyp1b1 LoF, with species dependency, and provides evidence for the dysregulation of extracellular matrix gene expression as one of the mechanisms underlying the pathogenicity associated with cyp1b1 disruption.


Assuntos
Anormalidades Craniofaciais/genética , Anormalidades Craniofaciais/metabolismo , Citocromo P-450 CYP1B1/genética , Citocromo P-450 CYP1B1/metabolismo , Matriz Extracelular/genética , Estudos de Associação Genética , Metabolismo dos Lipídeos/genética , Animais , Matriz Extracelular/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Técnicas de Inativação de Genes , Predisposição Genética para Doença , Camundongos Transgênicos , Peixe-Zebra
14.
Eur J Med Genet ; 64(9): 104289, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34265435

RESUMO

BACKGROUND: Kleefstra syndrome type 1 (KS1, OMIM#610253) is a rare autosomal-dominant Mendelian disorder due to heterozygous mutations in the EHMT1 gene or heterozygous deletion of genomic segment of 9q34.3(9qdel). Neurodevelopmental disorder (NDD), intellectual disability (ID) and childhood-onset hypotonia are the well-known phenotypes of KS1. However, these findings were all investigated based on western patients with KS1. METHODS: KS1 patients were diagnosed by genetic tests. The clinical data was collected and the phenotypes were standardized by compared with patients that previously reported. In silico, conservational and protein structural analysis were performed to assessment the missense variants. RESULTS: Ten patients from unrelated families were diagnosed as KS1, who all had NDD and seven of them had global developmental delay (GDD) with significant personal-social disabilities. Among the ten patients, only one (1/10) patient showed neonatal or infantile obesity. The other nine patients were heterozygous variations, including three missense mutations (p.Glu235Gly, p.Asp903Gly, and p.Leu943Pro), three frameshifting mutations (p.Asn1106Lysfs*71, p.Asn1055Tyrfs*121, and p.Lys288Argfs*20), one nonsense mutation (p.Arg246*), one slice site mutation (c.3540+2T > C) and one 9q34.3 deletion in gene of EHMT1. Furthermore, missense mutations showed potential pathogenicity analyzed by in silico. CONCLUSION: We demonstrated that the clinical features in Chinese patients with KS1 were due to EHMT1 defects. We also reported seven novel variants which enriched the mutation spectrum and provided a good understanding of the pathogenesis of KS1.


Assuntos
Anormalidades Craniofaciais/genética , Cardiopatias Congênitas/genética , Histona-Lisina N-Metiltransferase/genética , Deficiência Intelectual/genética , Pré-Escolar , Deleção Cromossômica , Cromossomos Humanos Par 9/genética , Anormalidades Craniofaciais/patologia , Feminino , Cardiopatias Congênitas/patologia , Heterozigoto , Histona-Lisina N-Metiltransferase/química , Humanos , Lactente , Deficiência Intelectual/patologia , Masculino , Mutação , Fenótipo , Domínios Proteicos
16.
Emerg Med Clin North Am ; 39(3): 493-508, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34215399

RESUMO

Anatomically, the airway is ever changing in size, anteroposterior alignment, and point of most narrow dimension. Special considerations regarding obesity, chronic and acute illness, underlying developmental abnormalities, and age can all affect preparation and intervention toward securing a definitive airway. Mechanical ventilation strategies should focus on limiting peak inspiratory pressures and optimizing lung protective tidal volumes. Emergency physicians should work toward minimizing risk of peri-intubation hypoxemia and arrest. With review of anatomic and physiologic principles in the setting of a practical approach toward evaluating and managing distress and failure, emergency physicians can successfully manage critical pediatric airway encounters.


Assuntos
Síndrome do Desconforto Respiratório/terapia , Insuficiência Respiratória/terapia , Manuseio das Vias Aéreas , COVID-19/terapia , Criança , Anormalidades Craniofaciais/complicações , Cuidados Críticos , Desenho de Equipamento , Capacidade Residual Funcional , Parada Cardíaca/terapia , Humanos , Hipnóticos e Sedativos/uso terapêutico , Intubação Intratraqueal/métodos , Laringoscópios , Laringoscopia/métodos , Laringe/anatomia & histologia , Doenças Neuromusculares/terapia , Ventilação não Invasiva , Oxigenoterapia , Medicina de Emergência Pediátrica , Obesidade Pediátrica/complicações , Respiração com Pressão Positiva , Gravação em Vídeo
17.
Environ Toxicol Pharmacol ; 87: 103700, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34237469

RESUMO

Glyphosate [N-(phosphonomethyl)glycine] is the active ingredient in widely used broad-spectrum herbicides. Even though the toxicity mechanism of this herbicide in vertebrates is poorly understood, evidence suggests that glyphosate is an endocrine disruptor capable of producing morphological anomalies as well as cardiotoxic and neurotoxic effects. We used the zebrafish model to assess the effects of early life glyphosate exposure on the development of cartilage and bone tissues and organismal responses. We found functional alterations, including a reduction in the cardiac rate, significant changes in the spontaneous tail movement pattern, and defects in craniofacial development. These effects were concomitant with alterations in the level of the estrogen receptor alpha osteopontin and bone sialoprotein. We also found that embryos exposed to glyphosate presented spine deformities as adults. These developmental alterations are likely induced by changes in protein levels related to bone and cartilage formation.


Assuntos
Osso e Ossos/efeitos dos fármacos , Anormalidades Craniofaciais/induzido quimicamente , Glicina/análogos & derivados , Herbicidas/toxicidade , Teratógenos/toxicidade , Animais , Osso e Ossos/anormalidades , Anormalidades Craniofaciais/metabolismo , Anormalidades Craniofaciais/veterinária , Embrião não Mamífero/anormalidades , Embrião não Mamífero/efeitos dos fármacos , Embrião não Mamífero/metabolismo , Receptor alfa de Estrogênio/metabolismo , Feminino , Proteínas de Peixes/metabolismo , Glicina/toxicidade , Frequência Cardíaca/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Masculino , Osteopontina/metabolismo , Sialoglicoproteínas/metabolismo , Peixe-Zebra/anormalidades , Peixe-Zebra/metabolismo
18.
J Plast Reconstr Aesthet Surg ; 74(9): 2319-2329, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34274246

RESUMO

BACKGROUND: The CLEFT-Q includes 12 independently functioning scales that measure appearance (face, nose, nostrils, teeth, lips, jaws), health-related quality of life (psychological, social, school, speech distress), and speech function, and an eating/drinking checklist. Previous qualitative research revealed that the CLEFT-Q has content validity in noncleft craniofacial conditions. This study aimed to examine the psychometric performance of the CLEFT-Q in an international sample of patients with a broad range of facial conditions. METHODS: Data were collected between October 2016 and December 2019 from 2132 patients aged 8 to 29 years with noncleft facial conditions. Rasch measurement theory (RMT) analysis was used to examine Differential Item Function (DIF) by comparing the original CLEFT-Q sample and the new FACE-Q craniofacial sample. Reliability and validity of the scales in a combined cleft and craniofacial sample (n=4743) were examined. RESULTS: DIF was found for 23 CLEFT-Q items when the datasets for the two samples were compared. When items with DIF were split by sample, correlations between the original and split person locations showed that DIF had negligible impact on scale scoring (correlations ≥0.995). In the combined sample, RMT analysis led to the retention of original content for ten CLEFT-Q scales, modification of the Teeth scale, and the addition of an Eating/Drinking scale. Data obtained fit with the Rasch model for 11 scales (exception School, p=0.04). Person Separation Index and Cronbach alpha values met the criteria. CONCLUSION: The scales described in this study can be used to measure outcomes in children and young adults with cleft and noncleft craniofacial conditions.


Assuntos
Anormalidades Craniofaciais/psicologia , Estética , Lábio/cirurgia , Procedimentos Cirúrgicos Ortognáticos , Medidas de Resultados Relatados pelo Paciente , Qualidade de Vida , Rinoplastia , Adolescente , Adulto , Enxerto de Osso Alveolar , Lista de Checagem , Criança , Anormalidades Craniofaciais/cirurgia , Feminino , Humanos , Masculino , Psicometria , Reprodutibilidade dos Testes
19.
Toxicol Appl Pharmacol ; 426: 115653, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34302850

RESUMO

Peroxisome Proliferator Activated Receptors (PPARs) are transcription factors that regulate processes such as lipid and glucose metabolism. Synthetic PPAR ligands, designed as therapeutics for metabolic disease, provide a tool to assess the relationship between PPAR activity and pancreas development in vivo, an area that remains poorly characterized. Here, we aim to assess the effects of PPAR agonists and antagonists on gene expression, embryonic morphology and pancreas development in transgenic zebrafish embryos. To evaluate developmental perturbations, we assessed gross body and pancreas morphology at 4 days post fertilization (dpf) in response to developmental exposures with PPARα, PPARγ, and PPARß/δ agonists and antagonists at 0, 0.01, 0.1, 1, and 10 µM concentrations. All ligand exposures, with the exception of the PPARα agonist, resulted in significantly altered fish length and yolk sac area. PPARγ agonist and antagonist had higher incidence of darkened yolk sac and craniofacial deformities, whereas PPARα antagonist had higher incidence of pericardial edema and death. Significantly reduced endocrine pancreas area was observed in both PPARγ ligands and PPARα agonist exposed embryos, some of which also exhibited aberrant endocrine pancreas morphology. Both PPARß/δ ligands caused reduced exocrine pancreas length and novel aberrant phenotype, and disrupted gene expression of pancreatic targets pdx1, gcga, and try. Lipid staining was performed at 8 dpf and revealed altered lipid accumulation consistent with isoform function. These data indicate chronic exposure to synthetic ligands may induce morphological and pancreatic defects in zebrafish embryos.


Assuntos
Pâncreas/anormalidades , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Receptores Ativados por Proliferador de Peroxissomo/antagonistas & inibidores , Anormalidades Múltiplas , Animais , Animais Geneticamente Modificados , Anormalidades Craniofaciais , Embrião não Mamífero , Desenvolvimento Embrionário , Feminino , Expressão Gênica , Metabolismo dos Lipídeos , Masculino , Transdução de Sinais , Saco Vitelino/anormalidades , Peixe-Zebra/anormalidades , Peixe-Zebra/genética
20.
Taiwan J Obstet Gynecol ; 60(4): 771-774, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34247823

RESUMO

OBJECTIVE: We present prenatal diagnosis of recurrent mosaic ring chromosome 13 [r(13)] of maternal origin. CASE REPORT: A 27-year-old woman underwent amniocentesis at 17 weeks of gestation because of a past history of fetal abnormality caused by mosaic r(13) in the previous fetus associated with fetal intrauterine growth restriction (IUGR), a karyotype of 46,XY,r(13)[23]/45,XY,-13[10]/46,XY,idic r(13)[2] and a maternal origin of abnormal r(13). The parental karyotypes were normal. During this pregnancy, amniocentesis revealed a karyotype of 46,XX,r(13)[12]/45,XX,-13[8] and a 22.80-Mb deletion of chromosome 13q31.3-q34. The pregnancy was subsequently terminated, and a malformed fetus was delivered with craniofacial dysmorphism. Repeat amniocentesis revealed a karyotype of 46,XX,r(13)(p11.1q31)[18]/45,XX,-13[12]. The placenta had a karyotype of 46,XX,r(13)(p11.1q31)[27]/45,XY,-13[13]. Polymorphic DNA marker analysis using the DNA derived from the parental bloods and umbilical cord confirmed a maternal origin of the abnormal r(13). CONCLUSION: Prenatal diagnosis of mosaic r(13) in consecutive pregnancies should raise a suspicion of parental gonadal mosaicism, and polymorphic DNA marker analysis is useful for determination of the parental origin of recurrent aneuploidy under such a circumstance.


Assuntos
Anormalidades Múltiplas/diagnóstico , Amniocentese , Transtornos Cromossômicos/diagnóstico , Anormalidades Craniofaciais/diagnóstico , Anormalidades Múltiplas/embriologia , Aborto Eugênico , Adulto , Deleção Cromossômica , Transtornos Cromossômicos/embriologia , Cromossomos Humanos Par 13/genética , Anormalidades Craniofaciais/embriologia , Feminino , Humanos , Cariótipo , Mosaicismo/embriologia , Gravidez , Cromossomos em Anel
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