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2.
PLoS Genet ; 17(7): e1009639, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-34232960

RESUMEN

ARHGAP42 encodes Rho GTPase activating protein 42 that belongs to a member of the GTPase Regulator Associated with Focal Adhesion Kinase (GRAF) family. ARHGAP42 is involved in blood pressure control by regulating vascular tone. Despite these findings, disorders of human variants in the coding part of ARHGAP42 have not been reported. Here, we describe an 8-year-old girl with childhood interstitial lung disease (chILD), systemic hypertension, and immunological findings who carries a homozygous stop-gain variant (c.469G>T, p.(Glu157Ter)) in the ARHGAP42 gene. The family history is notable for both parents with hypertension. Histopathological examination of the proband lung biopsy showed increased mural smooth muscle in small airways and alveolar septa, and concentric medial hypertrophy in pulmonary arteries. ARHGAP42 stop-gain variant in the proband leads to exon 5 skipping, and reduced ARHGAP42 levels, which was associated with enhanced RhoA and Cdc42 expression. This is the first report linking a homozygous stop-gain variant in ARHGAP42 with a chILD disorder, systemic hypertension, and immunological findings in human patient. Evidence of smooth muscle hypertrophy on lung biopsy and an increase in RhoA/ROCK signaling in patient cells suggests the potential mechanistic link between ARHGAP42 deficiency and the development of chILD disorder.


Asunto(s)
Proteínas Activadoras de GTPasa/genética , Hipertensión/genética , Enfermedades Pulmonares Intersticiales/genética , Animales , Niño , Femenino , Homocigoto , Humanos , Leucocitosis/genética , Leucocitosis/inmunología , Enfermedades Pulmonares Intersticiales/patología , Linfocitosis/genética , Linfocitosis/inmunología , Masculino , Ratones , Linaje , Secuenciación del Exoma , Proteína de Unión al GTP rhoA/genética , Proteína de Unión al GTP rhoA/metabolismo
3.
Hum Mol Genet ; 29(24): 3882-3891, 2021 02 25.
Artículo en Inglés | MEDLINE | ID: mdl-33355670

RESUMEN

Striated preferentially expressed gene (SPEG), a member of the myosin light chain kinase family, is localized at the level of triad surrounding myofibrils in skeletal muscles. In humans, SPEG mutations are associated with centronuclear myopathy and cardiomyopathy. Using a striated muscle-specific Speg-knockout (KO) mouse model, we have previously shown that SPEG is critical for triad maintenance and calcium handling. Here, we further examined the molecular function of SPEG and characterized the effects of SPEG deficiency on triad and focal adhesion proteins. We used yeast two-hybrid assay, and identified desmin, an intermediate filament protein, to interact with SPEG and confirmed this interaction by co-immunoprecipitation. Using domain-mapping assay, we defined that Ig-like and fibronectin III domains of SPEG interact with rod domain of desmin. In skeletal muscles, SPEG depletion leads to desmin aggregates in vivo and a shift in desmin equilibrium from soluble to insoluble fraction. We also profiled the expression and localization of triadic proteins in Speg-KO mice using western blot and immunofluorescence. The amount of RyR1 and triadin were markedly reduced, whereas DHPRα1, SERCA1 and triadin were abnormally accumulated in discrete areas of Speg-KO myofibers. In addition, Speg-KO muscles exhibited internalized vinculin and ß1 integrin, both of which are critical components of the focal adhesion complex. Further, ß1 integrin was abnormally accumulated in early endosomes of Speg-KO myofibers. These results demonstrate that SPEG-deficient skeletal muscles exhibit several pathological features similar to those seen in MTM1 deficiency. Defects of shared cellular pathways may underlie these structural and functional abnormalities in both types of diseases.


Asunto(s)
Moléculas de Adhesión Celular/metabolismo , Desmina/metabolismo , Adhesiones Focales/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Proteínas Musculares/metabolismo , Proteínas Musculares/fisiología , Músculo Esquelético/patología , Miopatías Estructurales Congénitas/patología , Quinasa de Cadena Ligera de Miosina/fisiología , Animales , Calcio/metabolismo , Moléculas de Adhesión Celular/genética , Desmina/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Masculino , Ratones , Ratones Noqueados , Ratones Transgénicos , Proteínas Musculares/genética , Músculo Esquelético/metabolismo , Mutación , Miopatías Estructurales Congénitas/etiología , Miopatías Estructurales Congénitas/metabolismo
4.
J Sep Sci ; 46(19): e2300172, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-37528737

RESUMEN

Chrysanthemum morifolium cv. Fubaiju is rich in phenolic compounds with various benefits such as anti-inflammatory, antioxidant, and cardiovascular protection. In this study, 12 phenolic compounds, including five flavonoid glycosides and seven quinic acid derivatives, were successfully separated from the flowers of Chrysanthemum morifolium cv. Fubaiju by high-speed counter-current chromatography and preparative high-performance liquid chromatography. Ethyl acetate-n-butanol-acetonitrile-water-acetic acid (5:0.5:2.5:5:0.25, v/v/v/v/v) was selected as solvent system to separate six fractions from the flowers of Chrysanthemum morifolium cv. Fubaiju, and 20% aqueous acetonitrile (containing 0.1% formic acid) was chosen to be the elution solvent in preparative high-performance liquid chromatography for purifying the fractions above. Luteolin-7-O-ß-D-glucoside (1), luteolin-7-O-ß-D-glucuronide (2), apigenin-7-O-ß-D-glucoside (3), luteolin-7-O-ß-D-rutinoside (4), diosmetin-7-O-ß-D-glucoside (5), chlorogenic acid (6), 1,5-dicaffeoylquinic acid (7), 1,4-dicaffeoylquinic acid (8), 3,4-dicaffeoylquinic acid (9), 3,4-dicaffeoyl-epi-quinic acid (10), 3,5-dicaffeoylquinic acid (11), and 4,5-dicaffeoylquinic acid (12) were isolated with purities all above 95%, respectively. In addition, all isolates were evaluated for their protective effects on H2 O2 -induced oxidative damage in adult retinal pigment epithelial cells.

5.
J Environ Manage ; 348: 119206, 2023 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-37898049

RESUMEN

Improving environmental performance of energy- and carbon-intensive sectors represented by the iron and steel (IS) industry is of utmost importance to address the challenges of resource depletion and climate change worldwide. This article adopts a global-super-Epsilon-Based Measure (EBM) model with undesirable output for IS energy efficiency estimation, identifies efficiency determinants based on Technology-Organization-Environment (TOE) framework, and analyzes various pathways for efficiency improvement by grouping Necessary Condition Analysis (NCA) and fuzzy-set Qualitative Comparative Analysis (fsQCA). Empirical testing using statistical data of the G20 economies during 2010-2020 demonstrates that: 1) energy efficiency in the IS industry in G20 countries has risen amidst fluctuations, with developed countries performing more efficiently than developing countries; 2) individual factors do not constitute a compulsory condition to achieve high energy efficiency in the IS industry; 3) three different paths to achieve high energy performance are found, that is, technology-structure driven, regulation-economy-technology driven, and regulation-technology-production driven. Heterogenous policy recommendations for efficiency gains in the IS sector of different countries with divergent features are proposed accordingly.


Asunto(s)
Carbono , Conservación de los Recursos Energéticos , Carbono/análisis , Acero , Hierro , Cambio Climático , Eficiencia , China , Desarrollo Económico , Dióxido de Carbono/análisis
6.
J Environ Manage ; 345: 118766, 2023 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-37579601

RESUMEN

Soil deficiency, cyclic erosion, and heavy metal pollution have led to fertility loss and ecological function decline in mining areas. Fertilization is an important way to rapidly replenish soil nutrients, which have a major influence on the soil nitrogen cycling process, but different fertilization regimes have different impacts on soil properties and microbial functional potentials. Here, metagenomic sequencing was used to investigate the different responses of key functional genes of microbial nitrogen cycling to fertilization regimes and explore the potential effects of soil physicochemical properties on the key functional genes. The results indicated that AC-HH (ammonium chloride-high frequency and concentration) treatment significantly increased the gene abundance of norC (13.40-fold), nirK (5.46-fold), and napA (5.37-fold). U-HH (urea-high frequency and concentration) treatment significantly increased the gene abundance of hao (6.24-fold), pmoA-amoA (4.32-fold) norC (7.00-fold), nosZ (3.69-fold), and nirK (6.88-fold). Functional genes were distributed differently among the 10 dominant phyla. The nifH and nifK genes were distributed only in Proteobacteria. The hao gene was distributed in Gemmatimonadetes, Nitrospirae and Proteobacteria. Fertilization regimes caused changes in functional redundancy in soil, and nirK and nirB, which are involved in denitrification, were present in different genera. Fertilization regimes with high frequency and high concentration were more likely to increase the gene abundance at the genus level. In summary, this study provides insights into the taxon-specific response of soil nitrogen cycling under different fertilization regimes, where changes in fertilization regimes affect microbial nitrogen cycling by altering soil physicochemical properties in a complex dynamic environment.


Asunto(s)
Metagenómica , Suelo , Suelo/química , Microbiología del Suelo , Bacterias/genética , Fertilización , Nitrógeno
7.
J Cardiovasc Pharmacol ; 80(4): 574-582, 2022 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-35881905

RESUMEN

ABSTRACT: Inositol 1, 4, 5-trisphosphate (IP3) signaling-mediated calcium release drives the contraction of vascular smooth muscles and hence regulates blood vessel volume and blood pressure. Melatonin supplementation has been suggested to be beneficial for hypertension. To determine whether the blood pressure-lowering effect of melatonin was accounted for by IP3 signaling, we evaluated the vasoconstriction response and IP3 signaling in isolated mouse thoracic aortic rings during melatonin incubation. C57BL/6 mice were given intraperitoneal injections daily with melatonin, and the systolic blood pressure and contractility of aortic rings from melatonin-treated mice were decreased, and the contraction suppression effect of melatonin was attributed to the impaired expression of contractile proteins in vascular smooth muscle cells rather than IP3 signaling. Our results further showed that melatonin increased the expression of γ-secretase, which could cleave and release the notch intracellular domain, and the notch intracellular domain prevented the transcription of contractile genes by interfering with the interaction between serum response factor and myocardin, the master regulator of contractile protein. In this article, we report a novel mechanism by which melatonin regulates smooth muscle contractility that does not depend on IP3 signaling.


Asunto(s)
Melatonina , Vasoconstricción , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Secretasas de la Proteína Precursora del Amiloide/farmacología , Animales , Calcio/metabolismo , Proteínas Contráctiles/metabolismo , Proteínas Contráctiles/farmacología , Inositol/metabolismo , Inositol/farmacología , Melatonina/farmacología , Ratones , Ratones Endogámicos C57BL , Contracción Muscular , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/metabolismo , Proteínas Nucleares , Factor de Respuesta Sérica/metabolismo , Factor de Respuesta Sérica/farmacología , Transactivadores
8.
Nature ; 540(7632): 270-275, 2016 12 08.
Artículo en Inglés | MEDLINE | ID: mdl-27919073

RESUMEN

Maternally inherited mitochondrial (mt)DNA mutations can cause fatal or severely debilitating syndromes in children, with disease severity dependent on the specific gene mutation and the ratio of mutant to wild-type mtDNA (heteroplasmy) in each cell and tissue. Pathogenic mtDNA mutations are relatively common, with an estimated 778 affected children born each year in the United States. Mitochondrial replacement therapies or techniques (MRT) circumventing mother-to-child mtDNA disease transmission involve replacement of oocyte maternal mtDNA. Here we report MRT outcomes in several families with common mtDNA syndromes. The mother's oocytes were of normal quality and mutation levels correlated with those in existing children. Efficient replacement of oocyte mutant mtDNA was performed by spindle transfer, resulting in embryos containing >99% donor mtDNA. Donor mtDNA was stably maintained in embryonic stem cells (ES cells) derived from most embryos. However, some ES cell lines demonstrated gradual loss of donor mtDNA and reversal to the maternal haplotype. In evaluating donor-to-maternal mtDNA interactions, it seems that compatibility relates to mtDNA replication efficiency rather than to mismatch or oxidative phosphorylation dysfunction. We identify a polymorphism within the conserved sequence box II region of the D-loop as a plausible cause of preferential replication of specific mtDNA haplotypes. In addition, some haplotypes confer proliferative and growth advantages to cells. Hence, we propose a matching paradigm for selecting compatible donor mtDNA for MRT.


Asunto(s)
ADN Mitocondrial/genética , ADN Mitocondrial/uso terapéutico , Herencia Materna/genética , Enfermedades Mitocondriales/genética , Enfermedades Mitocondriales/patología , Terapia de Reemplazo Mitocondrial/métodos , Mutación , Oocitos/metabolismo , Blastocisto/citología , Blastocisto/metabolismo , Línea Celular , Secuencia Conservada/genética , ADN Mitocondrial/biosíntesis , Células Madre Embrionarias/citología , Células Madre Embrionarias/metabolismo , Femenino , Haplotipos/genética , Humanos , Masculino , Meiosis , Enfermedades Mitocondriales/metabolismo , Enfermedades Mitocondriales/prevención & control , Donación de Oocito , Oocitos/citología , Oocitos/patología , Fosforilación Oxidativa , Linaje , Polimorfismo Genético
9.
Am J Pathol ; 190(12): 2453-2463, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-32919980

RESUMEN

Centronuclear myopathies (CNMs) are a subtype of congenital myopathies characterized by skeletal muscle weakness and an increase in the number of central myonuclei. SPEG (striated preferentially expressed protein kinase) has been identified as the sixth gene associated with CNM, and it has been shown that striated muscle-specific Speg-knockout (KO) mice have defective triad formation, abnormal excitation-contraction coupling, and calcium mishandling. The impact of SPEG deficiency on the survival and function of myogenic cells remains to be deciphered. In this study, the authors examined the overall population, proliferation, and differentiation of myogenic cells obtained from striated muscle-specific Speg-KO mice and compared them with wild-type (WT) controls. SPEG-deficient skeletal muscles contained fewer myogenic cells, which on further study demonstrated reduced proliferation and delayed differentiation compared with those from WT muscles. Regenerative response to skeletal muscle injury in Speg-KO mice was compared with that of WT mice, leading to the identification of similar abnormalities including fewer satellite cells, fewer dividing cells, and an increase in apoptotic cells in KO mice. Overall, these results reveal specific abnormalities in myogenic cell number and behavior associated with SPEG deficiency. Similar satellite cell defects have been reported in mouse models of MTM1- and DNM2-associated CNM, suggestive of shared underlying pathways.


Asunto(s)
Calcio/metabolismo , Diferenciación Celular/fisiología , Proliferación Celular/fisiología , Proteínas Musculares/metabolismo , Músculo Esquelético/metabolismo , Quinasa de Cadena Ligera de Miosina/metabolismo , Animales , Ratones , Proteínas Musculares/genética , Mioblastos/metabolismo , Miopatías Estructurales Congénitas/genética , Proteínas Serina-Treonina Quinasas/metabolismo
10.
Proc Natl Acad Sci U S A ; 115(51): 13039-13044, 2018 12 18.
Artículo en Inglés | MEDLINE | ID: mdl-30478036

RESUMEN

Although there has been considerable debate about whether paternal mitochondrial DNA (mtDNA) transmission may coexist with maternal transmission of mtDNA, it is generally believed that mitochondria and mtDNA are exclusively maternally inherited in humans. Here, we identified three unrelated multigeneration families with a high level of mtDNA heteroplasmy (ranging from 24 to 76%) in a total of 17 individuals. Heteroplasmy of mtDNA was independently examined by high-depth whole mtDNA sequencing analysis in our research laboratory and in two Clinical Laboratory Improvement Amendments and College of American Pathologists-accredited laboratories using multiple approaches. A comprehensive exploration of mtDNA segregation in these families shows biparental mtDNA transmission with an autosomal dominantlike inheritance mode. Our results suggest that, although the central dogma of maternal inheritance of mtDNA remains valid, there are some exceptional cases where paternal mtDNA could be passed to the offspring. Elucidating the molecular mechanism for this unusual mode of inheritance will provide new insights into how mtDNA is passed on from parent to offspring and may even lead to the development of new avenues for the therapeutic treatment for pathogenic mtDNA transmission.


Asunto(s)
ADN Mitocondrial/genética , Genes Mitocondriales , Herencia Materna , Mitocondrias/genética , Enfermedades Mitocondriales/genética , Herencia Paterna , Adulto , Preescolar , Bases de Datos Genéticas , Femenino , Genoma Mitocondrial , Humanos , Patrón de Herencia , Masculino , Persona de Mediana Edad , Linaje
11.
Int J Mol Sci ; 22(11)2021 May 27.
Artículo en Inglés | MEDLINE | ID: mdl-34072258

RESUMEN

Mutations in striated preferentially expressed protein kinase (SPEG), a member of the myosin light chain kinase protein family, are associated with centronuclear myopathy (CNM), cardiomyopathy, or a combination of both. Burgeoning evidence suggests that SPEG plays critical roles in the development, maintenance, and function of skeletal and cardiac muscles. Here we review the genotype-phenotype relationships and the molecular mechanisms of SPEG-related diseases. This review will focus on the progress made toward characterizing SPEG and its interacting partners, and its multifaceted functions in muscle regeneration, triad development and maintenance, and excitation-contraction coupling. We will also discuss future directions that are yet to be investigated including understanding of its tissue-specific roles, finding additional interacting proteins and their relationships. Understanding the basic mechanisms by which SPEG regulates muscle development and function will provide critical insights into these essential processes and help identify therapeutic targets in SPEG-related disorders.


Asunto(s)
Susceptibilidad a Enfermedades , Expresión Génica , Desarrollo de Músculos , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Animales , Proteínas Portadoras/metabolismo , Acoplamiento Excitación-Contracción/genética , Regulación de la Expresión Génica , Humanos , Desarrollo de Músculos/genética , Proteínas Musculares/química , Músculo Esquelético/metabolismo , Mutación , Miocardio/metabolismo , Unión Proteica , Dominios y Motivos de Interacción de Proteínas , Isoformas de Proteínas , Proteínas Serina-Treonina Quinasas/química , Regeneración/genética , Transducción de Señal , Relación Estructura-Actividad
12.
Neurobiol Dis ; 143: 105013, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32653676

RESUMEN

Fragile X associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder caused by expansion of CGG repeats in the 5' UTR of the fragile X mental retardation 1 (FMR1) gene. Using the well-established FXTAS Drosophila model, we performed a high-throughput chemical screen using 3200 small molecules. NSC363998 was identified to suppress the neurodegeneration caused by riboCGG (rCGG) repeats. Three predicted targets of a NSC363998 derivative are isopeptidases in the neddylation pathway and could modulate the neurotoxicity caused by the rCGG repeats. Decreasing levels of neddylation resulted in enhancing neurodegeneration phenotypes, while up-regulation could rescue the phenotypes. Furthermore, known neddylation substrates, Cul3 and Vhl, and their downstream target, Sima, were found to modulate rCGG90-dependent neurotoxicity. Our results suggest that altered neddylation activity can modulate the rCGG repeat-mediated toxicity by regulating Sima protein levels, which could serve as a potential therapeutic target for FXTAS.


Asunto(s)
Ataxia/metabolismo , Síndrome del Cromosoma X Frágil/metabolismo , Regulación de la Expresión Génica/fisiología , Subunidad alfa del Factor 1 Inducible por Hipoxia/biosíntesis , Degeneración Nerviosa/metabolismo , Procesamiento Proteico-Postraduccional/fisiología , Temblor/metabolismo , Animales , Ataxia/patología , Drosophila , Proteínas de Drosophila/biosíntesis , Síndrome del Cromosoma X Frágil/patología , Humanos , Proteína NEDD8 , Degeneración Nerviosa/patología , Fármacos Neuroprotectores/farmacología , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Temblor/patología , Expansión de Repetición de Trinucleótido
13.
Int J Mol Sci ; 21(15)2020 07 30.
Artículo en Inglés | MEDLINE | ID: mdl-32825207

RESUMEN

The author wishes to make the following correction to this paper [...].

14.
J Anim Physiol Anim Nutr (Berl) ; 104(1): 269-279, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31553089

RESUMEN

This study was conducted to determine the effects of oral administration with glutamate on metabolism of suckling piglets based on 1 H-Nuclear magnetic resonance (1 H NMR) spectroscopy through the level of metabolism. Forty-eight healthy [(Yorkshire × Landrace) × Duroc] piglets born on the same day with a similar birth bodyweight (1.55 ± 0.20 kg) were obtained from six sows (8 piglets per sow). The piglets from each sow were randomly assigned into four treatments (2 piglets per treatment). The piglets were given 0.09 g/kg body weight (BW) of sodium chloride (CN group), 0.03 g/kg BW monosodium glutamate (LMG group), 0.25 g/kg BW monosodium glutamate (MMG group) and 0.50 g/kg BW monosodium glutamate (HMG group) twice a day respectively. An 1 H NMR-based metabolomics' study found that the addition of monosodium glutamate (MSG) significantly reduced serum citrate content in 7-day-old piglets, while HMG significantly increased serum trimethylamine content and significantly reduced unsaturated fat content in 7-day-old piglets (p < .05). The content of glutamine, trimethylamine, albumin, choline and urea nitrogen was significantly increased and the creatinine content decreased significantly in the 21-day-old HMG (p < .05). Analysis of serum hormones revealed that glucagon-like peptide-1 (GLP-1) content in the 21-day-old HMG was highest (p < .05). The cholecystokinin (CCK) content in the HMG of 7-day-old piglets was lower than that in the LMG (p < .05), and the CCK content in the serum of the 21-day-old MMG was highest (p < .05). The serum leptin levels in the 21-day-old HMG were the lowest (p < .05). The serum insulin content in the 7-day-old MMG was highest (p < .05). This study suggests that MSG plays an important role in the metabolism of sugar, fat and protein (amino acids). These results provide a theoretical basis for designing piglet feed formulations.


Asunto(s)
Animales Lactantes , Metaboloma/efectos de los fármacos , Metabolómica , Glutamato de Sodio/farmacología , Porcinos/fisiología , Administración Oral , Alimentación Animal , Fenómenos Fisiológicos Nutricionales de los Animales , Animales , Dieta/veterinaria , Suplementos Dietéticos , Porcinos/sangre
15.
Int J Mol Sci ; 20(15)2019 Jul 24.
Artículo en Inglés | MEDLINE | ID: mdl-31344855

RESUMEN

Breast cancer, the most prevalent cancer type among women worldwide, remains incurable once metastatic. Long noncoding RNA (lncRNA) and microRNA (miRNA) play important roles in breast cancer by regulating specific genes or proteins. In this study, we found miR-133b was silenced in breast cancer cell lines and in breast cancer tissues, which predicted poor prognosis in breast cancer patients. We also confirmed that lncRNA NEAT1 was up-regulated in breast cancer and inhibited the expression of miR-133b, and identified the mitochondrial protein translocase of inner mitochondrial membrane 17 homolog A (TIMM17A) that serves as the target of miR-133b. Both miR-133b knockdown and TIMM17A overexpression in breast cancer cells promoted cell migration and invasion both in vitro and in vivo. In summary, our findings reveal that miR-133b plays a critical role in breast cancer cell metastasis by targeting TIMM17A. These findings may provide new insights into novel molecular therapeutic targets for breast cancer.


Asunto(s)
Neoplasias de la Mama/genética , MicroARNs/genética , Proteínas de Transporte de Membrana Mitocondrial/genética , ARN Largo no Codificante/genética , Anciano , Animales , Neoplasias de la Mama/patología , Movimiento Celular/genética , Proliferación Celular/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Xenoinjertos , Humanos , Células MCF-7 , Ratones , Persona de Mediana Edad , Proteínas del Complejo de Importación de Proteínas Precursoras Mitocondriales , Invasividad Neoplásica/genética , Invasividad Neoplásica/patología
16.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(4): 306-309, 2019 Apr 10.
Artículo en Zh | MEDLINE | ID: mdl-30950013

RESUMEN

OBJECTIVE: To explore the genetic basis and pregnancy outcome of fetuses with urinary system anomalies. METHODS: Ultrasonographic features, genetic testing and pregnancy outcomes of 337 fetuses with urinary system anomalies identified by prenatal ultrasonograhy were collected for analysis. RESULTS: Ultrasonographic features of the fetuses were mainly characterized by hydronephrosis or hydronephrosis, polycystic kidney disease, and renal dysplasia. Thirty four fetuses (10.1%) were found to harbor a genetic defect, including 14 numerical chromosomal disorders, 10 structural chromosomal aberrations, and 10 pathogenic copy number variations (CNVs). In 31 cases, the parents elected induced labor. For the 303 fetuses with negative findings, 142 were born by spontaneous delivery or Caesarean section, 48 cases underwent induced labor, 1 case had miscarriage, and the remaining 112 cases had unknown or missed pregnancy outcomes. CONCLUSION: Hydronephrosis or hydronephrosis, polycystic kidney disease, and renal dysplasia are the most common findings among fetuses with urinary system anomalies. Approximately 10.1% of such fetuses are positive by genetic testing.


Asunto(s)
Variaciones en el Número de Copia de ADN , Resultado del Embarazo , Cesárea , Aberraciones Cromosómicas , Femenino , Feto , Pruebas Genéticas , Humanos , Embarazo , Diagnóstico Prenatal , Ultrasonografía Prenatal
17.
Reprod Biomed Online ; 34(4): 361-368, 2017 04.
Artículo en Inglés | MEDLINE | ID: mdl-28385334

RESUMEN

Mutations in mitochondrial DNA (mtDNA) are maternally inherited and can cause fatal or debilitating mitochondrial disorders. The severity of clinical symptoms is often associated with the level of mtDNA mutation load or degree of heteroplasmy. Current clinical options to prevent transmission of mtDNA mutations to offspring are limited. Experimental spindle transfer in metaphase II oocytes, also called mitochondrial replacement therapy, is a novel technology for preventing mtDNA transmission from oocytes to pre-implantation embryos. Here, we report a female carrier of Leigh syndrome (mtDNA mutation 8993T > G), with a long history of multiple undiagnosed pregnancy losses and deaths of offspring as a result of this disease, who underwent IVF after reconstitution of her oocytes by spindle transfer into the cytoplasm of enucleated donor oocytes. A male euploid blastocyst wasobtained from the reconstituted oocytes, which had only a 5.7% mtDNA mutation load. Transfer of the embryo resulted in a pregnancy with delivery of a boy with neonatal mtDNA mutation load of 2.36-9.23% in his tested tissues. The boy is currently healthy at 7 months of age, although long-term follow-up of the child's longitudinal development remains crucial.


Asunto(s)
Heterocigoto , Enfermedad de Leigh/prevención & control , Terapia de Reemplazo Mitocondrial , Oocitos/ultraestructura , ADN Mitocondrial/química , Femenino , Fertilización In Vitro , Humanos , Enfermedad de Leigh/genética , Nacimiento Vivo , Herencia Materna , Mitocondrias , Donación de Oocito , Linaje , Embarazo , Diagnóstico Preimplantación , Análisis de Secuencia de ADN
20.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 34(3): 321-326, 2017 Jun 10.
Artículo en Zh | MEDLINE | ID: mdl-28604947

RESUMEN

OBJECTIVE: To explore the value of single nucleotide polymorphism array (SNP-array) for the analysis of pediatric patients with growth retardation. METHODS: One hundred eighty one children with growth retardation were enrolled. DNA was extracted from peripheral samples from the patients, and whole genome copy number variations (CNVs) were detected using Illumina Human Cyto SNP-12. All identified CNVs were further analyzed with reference to databases including ClinGen, ClinVar, DECIPHER, OMIM and DGV as well as comprehensive review of literature from PubMed to determine their pathogenicity. RESULTS: Forty seven patients (26%) with abnormal CNVs were detected, which included 12 known microdeletions/microduplications syndrome (26%), 10 pathogenic non-syndromic CNVs (21%), 3 numerical chromosome aberrations (6%), 3 unbalanced translocations (6%), 4 pathogenic mosaicisms (9%) and 15 cases with unknown clinical significance (32%). After excluding obvious numerical and/or structural chromosomal abnormalities, this study has detected 15 pathogenic microdeletions/microduplications sized 5 Mb or less, which may be missed by routine chromosomal karyotyping. In addition, there were 3 cases with loss of heterozygoisty (LOH) containing known or predicted imprinting genes as well as 2 cases with suspected parental consanguinity. CONCLUSION: SNP-array technology is a powerful tool for the genetic diagnosis of children with growth disorders with advantages of high resolution and improved accuracy.


Asunto(s)
Discapacidades del Desarrollo/diagnóstico , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Polimorfismo de Nucleótido Simple , Adolescente , Niño , Preescolar , Aberraciones Cromosómicas , Variaciones en el Número de Copia de ADN , Discapacidades del Desarrollo/genética , Femenino , Humanos , Lactante , Cariotipificación , Masculino
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