RESUMEN
To gain insight into the aetiology of posterior subcapsular congenital cataract from the perspective of transcriptional changes, we conducted an mRNA sequencing analysis of the lenses in posterior subcapsular congenital cataract patients and in normal children. There were 1533 differentially expressed genes from 19,072 genes in the lens epithelial cells of the posterior subcapsular congenital cataract patients compared to in the normal controls at a cut-off criteria of |log2 fold change| of >1 and a p-value of <0.05, including 847 downregulated genes and 686 upregulated genes. To further narrow down the DEGs, we utilised the stricter criteria of |log2 fold change| of >1 and an FDR value of <0.05, and we identified 551 DEGs, including 97 upregulated genes and 454 downregulated genes. This study also identified 1263 differentially expressed genes of the 18,755 genes in lens cortex and nuclear fibres, including 646 downregulated genes and 617 upregulated genes. The downregulated genes in epithelial cells were significantly enriched in the structural constituent of lenses, lens development and lens fibre cell differentiation. After filtering the DEGs using the databases iSyTE and Cat-Map, several high-priority candidate genes related to posterior subcapsular congenital cataract such as GRIFIN, HTRA1 and DAPL1 were identified. The findings of our study may provide a deeper understanding of the mechanisms of posterior subcapsular congenital cataract and help in the prevention and treatment of this disease.
Asunto(s)
Catarata/patología , Anomalías Congénitas/patología , Regulación de la Expresión Génica , Serina Peptidasa A1 que Requiere Temperaturas Altas/metabolismo , Cristalino/metabolismo , Proteínas de la Membrana/metabolismo , Transcriptoma , Catarata/genética , Catarata/metabolismo , Diferenciación Celular , Niño , Preescolar , Anomalías Congénitas/genética , Anomalías Congénitas/metabolismo , Perfilación de la Expresión Génica/métodos , Serina Peptidasa A1 que Requiere Temperaturas Altas/genética , Humanos , Lactante , Proteínas de la Membrana/genéticaRESUMEN
The SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) protein syntaxin-5 (Stx5) is essential for Golgi transport. In humans, the STX5 mRNA encodes two protein isoforms, Stx5 Long (Stx5L) from the first starting methionine and Stx5 Short (Stx5S) from an alternative starting methionine at position 55. In this study, we identify a human disorder caused by a single missense substitution in the second starting methionine (p.M55V), resulting in complete loss of the short isoform. Patients suffer from an early fatal multisystem disease, including severe liver disease, skeletal abnormalities and abnormal glycosylation. Primary human dermal fibroblasts isolated from these patients show defective glycosylation, altered Golgi morphology as measured by electron microscopy, mislocalization of glycosyltransferases, and compromised ER-Golgi trafficking. Measurements of cognate binding SNAREs, based on biotin-synchronizable forms of Stx5 (the RUSH system) and Förster resonance energy transfer (FRET), revealed that the short isoform of Stx5 is essential for intra-Golgi transport. Alternative starting codons of Stx5 are thus linked to human disease, demonstrating that the site of translation initiation is an important new layer of regulating protein trafficking.
Asunto(s)
Anomalías Congénitas/metabolismo , Proteínas Qa-SNARE/metabolismo , Secuencias de Aminoácidos , Anomalías Congénitas/genética , Fibroblastos/metabolismo , Glicosilación , Aparato de Golgi/metabolismo , Humanos , Mutación , Biosíntesis de Proteínas , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Transporte de Proteínas , Proteínas Qa-SNARE/química , Proteínas Qa-SNARE/genéticaRESUMEN
The Eyes Absent (EYA) transactivator-phosphatase proteins are important contributors to cell-fate determination processes and to the development of multiple organs. The transcriptional regulatory activity as well as the protein tyrosine phosphatase activities of the EYA proteins can independently contribute to proliferation, differentiation, morphogenesis and tissue homeostasis in different contexts. Aberrant EYA levels or activity are associated with numerous syndromic and non-syndromic developmental disorders, as well as cancers. Commensurate with the multiplicity of biochemical activities carried out by the EYA proteins, they impact upon a range of cellular signaling pathways. Here, we provide a broad overview of the roles played by EYA proteins in development, and highlight the molecular signaling pathways known to be linked with EYA-associated organ development and developmental disorders.
Asunto(s)
Anomalías Congénitas/genética , Ojo/metabolismo , Regulación del Desarrollo de la Expresión Génica , Riñón/metabolismo , Proteínas Tirosina Fosfatasas/genética , Transactivadores/genética , Animales , Anomalías Congénitas/embriología , Anomalías Congénitas/metabolismo , Ojo/embriología , Ojo/crecimiento & desarrollo , Predisposición Genética a la Enfermedad/genética , Humanos , Riñón/embriología , Riñón/crecimiento & desarrollo , Mutación , Proteínas Tirosina Fosfatasas/metabolismo , Transactivadores/metabolismoRESUMEN
The fish abnormal embryonic development has attracted public attention in the recent few years. In this study, an iTRAQ proteomic analysis of mosquitofish between conjoined twins and normal fishes is applied for the first time by using the genome database of mosquitofish. Three thousand four hundred ninety proteins were identified with 304 differentially expressed proteins (DEPs). One hundred six differentially upregulated proteins (DUPs) and 198 differentially downregulated proteins (DDPs) were identified between the conjoined twins and normal mosquitofish groups. Notably, the proteins related to lipid and proteolysis were the important GO terms for the DUPs while response to light stimulus and response to radiation were the most enriched GO terms for the DDPs. The proteins related to lysosome, apoptosis, autophagy, and phagosome were the functional KEGG pathway for the DUPs while most of the pathways were related to cardiovascular for the DDPs. This study expatiated a pivotal protein profile between the conjoined twins and normal mosquitofish which can provide a conference for fish embryonic development.
Asunto(s)
Anomalías Congénitas/metabolismo , Ciprinodontiformes/anomalías , Ciprinodontiformes/metabolismo , Proteínas de Peces/metabolismo , Animales , ProteómicaRESUMEN
A father's lifestyle impacts offspring health; yet, the underlying molecular mechanisms remain elusive. We hypothesized that a diet that changes methyl donor availability will alter the sperm and embryo epigenomes to impact embryonic gene expression and development. Here, we demonstrate that a folate-deficient (FD) diet alters histone H3 lysine 4 trimethylation (H3K4me3) in sperm at developmental genes and putative enhancers. A subset of H3K4me3 alterations in sperm are retained in the pre-implantation embryo and associated with deregulated embryonic gene expression. Using a genetic mouse model in which sires have pre-existing altered H3K4me2/3 in sperm, we show that a FD diet exacerbates alterations in sperm H3K4me3 and embryonic gene expression, leading to an increase in developmental defect severity. These findings imply that paternal H3K4me3 is transmitted to the embryo and influences gene expression and development. It further suggests that epigenetic errors can accumulate in sperm to worsen offspring developmental outcomes.
Asunto(s)
Anomalías Congénitas/patología , Metilación de ADN , Dieta , Embrión de Mamíferos/citología , Regulación del Desarrollo de la Expresión Génica , Histonas/química , Espermatozoides/metabolismo , Animales , Animales Recién Nacidos , Cromatina/química , Cromatina/genética , Anomalías Congénitas/etiología , Anomalías Congénitas/metabolismo , Embrión de Mamíferos/metabolismo , Epigénesis Genética , Femenino , Histonas/genética , Masculino , Ratones , Ratones Endogámicos C57BL , FenotipoRESUMEN
OBJECTIVE: To study whether markers of prenatal exposure to reproductive hormones are related to Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome, polycystic ovary syndrome (PCOS), and endometriosis. DESIGN: Case-control study. Comparison of sex hormone-related external genital and digital characteristics in cases and controls. SETTING: University hospital. PATIENT(S): We enrolled 172 women in four groups-women with MKRH, women with PCOS, women with endometriosis, and controls (43 in each group). INTERVENTION(S): Measurement of two anthropometric biomarkers: anogenital distance and digit ratio. MAIN OUTCOME MEASURE(S): Anogenital distance was measured from the anus to the anterior clitoral surface (AGDac) and from the anus to the posterior fourchette (AGDaf). For the digit ratio we used a direct, as well as a computer-assisted graphic measurement to measure the length of the second and fourth digit. RESULT(S): After adjustment for body mass index and age, AGDac was the shortest in endometriosis and the longest in PCOS groups, with a mean difference of 10 mm (95% confidence interval 3.1-16.8). AGDaf but not AGDac measures were found to be significantly larger in the MRKH group, with a mean difference compared with controls of 2.6 mm (95% confidence interval 0.1-5.2). The digit ratio was not significantly different between the groups. CONCLUSION(S): In this study we did find limited evidence for androgen exposure during the development of MRKH. This is compatible with the hypothesis that the uterovaginal agenesis may have been the result of temporary prenatal exposure to altered gonadal hormone concentrations. For endometriosis and PCOS we confirm previously observed associations for anogenital distance reflecting possible estrogen-based and androgen-based intrauterine origins, respectively. DUTCH TRIAL REGISTRATION NUMBER: NTR7492.
Asunto(s)
Trastornos del Desarrollo Sexual 46, XX/metabolismo , Antropometría , Anomalías Congénitas/metabolismo , Endometriosis/metabolismo , Hormonas Gonadales/metabolismo , Conductos Paramesonéfricos/anomalías , Síndrome del Ovario Poliquístico/metabolismo , Trastornos del Desarrollo Sexual 46, XX/diagnóstico , Trastornos del Desarrollo Sexual 46, XX/patología , Adulto , Canal Anal/patología , Estudios de Casos y Controles , Clítoris/patología , Anomalías Congénitas/diagnóstico , Anomalías Congénitas/patología , Endometriosis/diagnóstico , Endometriosis/patología , Femenino , Dedos/patología , Humanos , Persona de Mediana Edad , Conductos Paramesonéfricos/metabolismo , Conductos Paramesonéfricos/patología , Síndrome del Ovario Poliquístico/diagnóstico , Síndrome del Ovario Poliquístico/patología , Valor Predictivo de las Pruebas , Reproducibilidad de los ResultadosRESUMEN
The pathophysiological mechanism underlying pregnancy complications such as congenital malformations, miscarriage, preeclampsia, or fetal growth restriction is not entirely known. However, the negative impact of the mother's body oxidative imbalance on the fetus and the course of gestation is increasingly discussed. This article is an integrative review of some original studies and review papers on the effects of oxidative stress on the adverse pregnancy outcomes mainly birth defects in fetuses. A systematic search for English language articles published from 2010 until 2020 was made, using MEDLINE data. Additionally, we analyzed the Cochrane and Scopus databases, discussions with experts, and a review of bibliography of articles from scientifically relevant and valuable sources. The main purposes are to assess the contribution of the existing literature of associations of oxidative stress on the etiology of the abovementioned conditions and to identify relevant information and outline existing knowledge. Furthermore, the authors aim to find any gaps in the research, thereby providing grounds for our own research. The key search terms were "oxidative stress in pregnancy," "oxidative stress and congenital malformations," and "oxidative stress and adverse pregnancy outcomes." Studies have confirmed that oxidative stress has a significant impact on pregnancy and is involved in the pathomechanism of adverse pregnancy outcomes.
Asunto(s)
Estrés Oxidativo , Complicaciones del Embarazo , Anomalías Congénitas/metabolismo , Anomalías Congénitas/patología , Femenino , Humanos , Hipertensión Inducida en el Embarazo/metabolismo , Hipertensión Inducida en el Embarazo/patología , Oxidorreductasas/metabolismo , Preeclampsia/metabolismo , Preeclampsia/patología , Embarazo , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Preexisting/pregestational diabetes enhances the risk of birth defects. Several factors have been involved during the implantation process, such as cytokines (granulocyte-macrophage-colony-stimulating factor [GM-CSF]). The objective was to evaluate the effects of two levels of diabetes on the redox status of preimplantation embryos during the implantation process to comprehend how both are involved in embryo and fetal viability against maternal diabetes. Female Sprague-Dawley rats received streptozotocin at birth (mild diabetes [MD]) or at adulthood (severe diabetes [SD]) to obtain two experimental diabetes intensities. After confirming the diabetic status, the nondiabetic and diabetic groups were mated around day 110 of life. At gestational day (GD) 21, fetuses were assessed for viability and malformations and ovaries for embryo loss before implantation. Other pregnant nondiabetic and diabetic rats were sacrificed at GD2-4 for maternal and preimplantation embryo oxidative stress markers, maternal serum insulin, uterine fluid GM-CSF, and preimplantation embryo morphological analysis. MD and SD caused abnormal redox levels, lower GM-CSF and insulin levels during the preimplantation period, and embryonic loss before implantation. SD caused lower fetal viability and higher fetal malformation percentages at GD21. The SD dam-derived preimplantation embryos presented lower glutathione levels and higher thiobarbituric acid reactive substances concentration at GD3 and an increased frequency of abnormal preimplantation embryos at GD4. In conclusion, preexisting diabetes leads to complications in the implantation process. Furthermore, maternal oxidative stress and other metabolic changes alter the redox state and morphological structure of preimplantation embryos, contributing to damaged growth and development in late pregnancy.
Asunto(s)
Anomalías Congénitas/etiología , Diabetes Mellitus Experimental/complicaciones , Desarrollo Embrionario/fisiología , Animales , Anomalías Congénitas/metabolismo , Diabetes Mellitus Experimental/metabolismo , Implantación del Embrión/fisiología , Femenino , Estrés Oxidativo/fisiología , Ratas , Ratas Sprague-DawleyRESUMEN
Human oncoproteins promote transformation of cells into tumours by dysregulating the signalling pathways that are involved in cell growth, proliferation and death. Although oncoproteins were discovered many years ago and have been widely studied in the context of cancer, the recent use of high-throughput sequencing techniques has led to the identification of cancer-associated mutations in other conditions, including many congenital disorders. These syndromes offer an opportunity to study oncoprotein signalling and its biology in the absence of additional driver or passenger mutations, as a result of their monogenic nature. Moreover, their expression in multiple tissue lineages provides insight into the biology of the proto-oncoprotein at the physiological level, in both transformed and unaffected tissues. Given the recent paradigm shift in regard to how oncoproteins promote transformation, we review the fundamentals of genetics, signalling and pathogenesis underlying oncoprotein duality.
Asunto(s)
Transformación Celular Neoplásica/metabolismo , Anomalías Congénitas/genética , Enfermedades Genéticas Congénitas/genética , Neoplasias/genética , Neoplasias/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Animales , Transformación Celular Neoplásica/genética , Anomalías Congénitas/metabolismo , Modelos Animales de Enfermedad , Interacción Gen-Ambiente , Enfermedades Genéticas Congénitas/metabolismo , Humanos , Ratones , Mutación/genética , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/fisiología , Transducción de SeñalRESUMEN
Causes for miscarriages and congenital malformations can be genetic, environmental, or a combination of both. Genetic variants, hypoxia, malnutrition, or other factors individually may not affect embryo development, however, they may do so collectively. Biallelic loss-of-function variants in HAAO or KYNU, two genes of the nicotinamide adenine dinucleotide (NAD) synthesis pathway, are causative of congenital malformation and miscarriage in humans and mice. The variants affect normal embryonic development by disrupting the synthesis of NAD, a key factor in multiple biological processes, from its dietary precursor tryptophan, resulting in NAD deficiency. This study demonstrates that congenital malformations caused by NAD deficiency can occur independent of genetic disruption of NAD biosynthesis. C57BL/6J wild-type mice had offspring exhibiting similar malformations when their supply of the NAD precursors tryptophan and vitamin B3 in the diet was restricted during pregnancy. When the dietary undersupply was combined with a maternal heterozygous variant in Haao, which alone does not cause NAD deficiency or malformations, the incidence of embryo loss and malformations was significantly higher, suggesting a gene-environment interaction. Maternal and embryonic NAD levels were deficient. Mild hypoxia as an additional factor exacerbated the embryo outcome. Our data show that NAD deficiency as a cause of embryo loss and congenital malformation is not restricted to the rare cases of biallelic mutations in NAD synthesis pathway genes. Instead, monoallelic genetic variants and environmental factors can result in similar outcomes. The results expand our understanding of the causes of congenital malformations and the importance of sufficient NAD precursor consumption during pregnancy.
Asunto(s)
Aborto Espontáneo/genética , Anomalías Congénitas/genética , Interacción Gen-Ambiente , NAD/deficiencia , Aborto Espontáneo/metabolismo , Animales , Anomalías Congénitas/metabolismo , Embrión de Mamíferos/metabolismo , Femenino , Humanos , Masculino , Fenómenos Fisiologicos Nutricionales Maternos , Ratones , Ratones Endogámicos C57BL , EmbarazoRESUMEN
BACKGROUND Inositol is an essential nutrient for cell growth, survival and embryonic development. Myo-inositol is the predominant form in natural. To investigate the correlation between inositol metabolism and embryonic development, we assessed the metabolic characteristics of myo-inositol, phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) and phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3) of pregnant women in the North China (Yangquan and Weihai) and South China (Nanchang and Haikou) China. MATERIAL AND METHODS All data were collected by face-to-face interview during pregnant women health visits using a questionnaire. Plasma levels of myo-inositol, PI(4,5)P2 and PI(3,4,5)P3 from 89 randomly collected pregnant women were detected by gas chromatography-mass spectrometry and enzyme linked immunosorbent assay. RESULTS A total of 400 pregnant women were included in this survey. The plasma levels of myo-inositol and PI(4,5)P2 in the North China group of pregnant women were significantly higher than that in the South China group (P<0.01). The birth weight of fetuses in the North China group was heavier than that in the South China group (P<0.01). The birth length of fetuses in Yangquan was the longest among the 4 cities (P<0.01). The incidence rate of birth defects was 3.05% in the North China group, and 0.0% in the South China group. In bivariate linear correlation analysis, the body weight correlated with myo-inositol (r=0.5044, P<0.0001), PI(4,5)P2 (r=0.5950, P<0.0001) and PI(3,4,5)P3 (r=0.4710, P<0.0001), the body length was correlated with PI(4,5)P2 (r=0.3114, P=0.0035) and PI(3,4,5)P3 (r=0.2638, P<0.0130). CONCLUSIONS The plasma levels of myo-inositol and PI(4,5)P2 in pregnant women had significant difference between the North and the South of China, which might be correlated with fetal development and birth defects.
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Anomalías Congénitas/epidemiología , Desarrollo Fetal/fisiología , Inositol/metabolismo , Fosfatidilinositol 4,5-Difosfato/metabolismo , Adulto , China/epidemiología , Anomalías Congénitas/metabolismo , Femenino , Geografía , Humanos , Incidencia , Recién Nacido , Inositol/sangre , Fosfatidilinositol 4,5-Difosfato/sangre , Fosfatos de Fosfatidilinositol/sangre , Fosfatos de Fosfatidilinositol/metabolismo , EmbarazoRESUMEN
How genes and environment interact to cause birth defects is not well understood, but key to developing new strategies to modify risk. The threshold model has been proposed to represent this complex interaction. This model stipulates that while environmental exposure or genetic mutation alone may not result in a defect, factors in combination increase phenotypic variability resulting in more individuals crossing the disease threshold where birth defects manifest. Many environmental factors that contribute to birth defects induce widespread cellular stress and misfolding of proteins. Yet, the impact of the stress response on the threshold model is not typically considered in discephering the etiology of birth defects. This mini-review will explore a potential mechanism for gene-environment interactions co-opted from studies of evolution. This model stipulates that heat shock proteins that mediate the stress response induced by environmental factors can influence the number of individuals that cross disease thresholds resulting in increased incidence of birth defects. Studies in the field of evolutionary biology have demonstrated that heat shock proteins and Hsp90 in particular provide a link between environmental stress, genotype and phenotype. Hsp90 is a highly expressed molecular chaperone that assists a wide variety of protein clients with folding and conformational changes needed for proper function. Hsp90 also chaperones client proteins with potentially deleterious amino acid changes to suppress variation caused by genetic mutations. However, upon exposure to stress, Hsp90 abandons its normal physiological clients and is diverted to assist with the misfolded protein response. This can impact the activity of signaling pathways that involve Hsp90 clients as well as unmask suppressed protein variation, essentially creating complex traits in a single step. In this capacity Hsp90 acts as an evolutionary capacitor allowing stored variation to accumulate and then become expressed in times of stress. This mechanism provides a substrate which natural selection can act upon at the population level allowing survival of the species with selective pressure. However, at the level of the individual, this mechanism can result in simultaneous expression of deleterious variants as well as reduced activity of a variety of Hsp90 chaperoned pathways, potentially shifting phenotypic variability over the disease threshold resulting in birth defects.
Asunto(s)
Anomalías Congénitas/genética , Anomalías Congénitas/metabolismo , Interacción Gen-Ambiente , Proteínas HSP90 de Choque Térmico/fisiología , Estrés Oxidativo/fisiología , Animales , HumanosRESUMEN
The offspring of Robo2 mutant mice usually present with variable phenotypes of congenital anomalies of the kidney and urinary tract (CAKUT). An intrauterine low-protein diet can also cause CAKUT in offspring, dominated by the duplicated collecting system phenotype. A single genetic or environment factor can only partially explain the pathogenesis of CAKUT. The present study aimed to establish an intrauterine low-protein diet roundabout 2 (Robo2) mutant mouse model and found that the intrauterine low-protein diet led to significantly increased CAKUT phenotypes in Robo2PB/+ mice offspring, dominant by a duplicated collecting system. At the same time, more ectopic and lower located ureteric buds (UBs) were observed in the intrauterine low-protein diet-fed Robo2 mutant mouse model, and the number of UB branches was reduced in the serum-free culture. During UB protrusion, intrauterine low-protein diet reduced the expression of Slit2/Robo2 in Robo2 mutant mice and affected the expression of glial cell-derived neurotrophic factor/Ret, which is a key molecule for metanephric development, with increasing phospho-Akt and phospho-cAMP responsive element-binding protein 3 activity and a reduction of apoptotic cells in embryonic day 11.5 UB tissues. The mechanism by which an intrauterine low-protein diet aggravates CAKUT in Robo2 mutant mice may be related to the disruption of Akt/cAMP responsive element-binding protein 3 signaling and a reduction in apoptosis in UB tissue.
Asunto(s)
Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Dieta con Restricción de Proteínas , Riñón/anomalías , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptores Inmunológicos/genética , Sistema Urinario/anomalías , Animales , Anomalías Congénitas/metabolismo , Femenino , Riñón/metabolismo , Fenómenos Fisiologicos Nutricionales Maternos/fisiología , Ratones , Ratones Noqueados , Receptores Inmunológicos/metabolismo , Sistema Urinario/metabolismoRESUMEN
Congenital esophageal stenosis (CES) is a type of esophageal stenosis, and three histological subtypes (tracheobronchial remnants, fibromuscular thickening or fibromuscular stenosis, and membranous webbing or esophageal membrane) are described. Symptoms of CES usually appears with the introduction of the semisolid alimentation. Dysphagia is the most common symptom, but esophageal food impaction, respiratory distress or failure to thrive can be clinical manifestations of CES. Wide spectrum of differential diagnoses leads to delayed definitive diagnosis and appropriate treatment. Depends on hystological subtype of CES, some treatment procedures (dilation or segmental esophageal resection) are recommended, but individually approach is still important in terms of frequency and type of dilation procedures or type of the surgical treatment. Dysphagia can persist after the treatment and a long follow-up period is recommended. In 33% of patients with CES, a different malformations in the digestive system, but also in the other systems, are described.
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Trastornos de Deglución/metabolismo , Trastornos de Deglución/patología , Estenosis Esofágica/metabolismo , Estenosis Esofágica/patología , Animales , Anomalías Congénitas/metabolismo , Anomalías Congénitas/patología , Atresia Esofágica/metabolismo , Atresia Esofágica/patología , Humanos , Modelos BiológicosRESUMEN
Congenital anomalies cause ~7% of all neonatal deaths, many of which have no identified pathophysiological cause. Because accurate and robust laboratory tests are unavailable for most birth defects, physicians rely on imaging such as ultrasound and MRI. Biomarkers from human body fluids are considered a powerful diagnostic tool to assess human disease and health as it mirrors an individual's condition. Minimally invasive 'liquid biopsies' from blood samples are highly valuable for diagnosis, prognosis, risk assessment, and treatment of many conditions. Recent large-scale analysis ('omics') have enabled researchers to identify novel biomarkers in different areas. To accurately facilitate the early detection of congenital anomalies, the identification of biomarkers from maternal plasma should be promoted. This approach will uncover new opportunities in prenatal diagnosing and likely lead to a better understanding of the pathogenesis of congenital anomalies.
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Líquidos Corporales/metabolismo , Anomalías Congénitas/diagnóstico , Diagnóstico Prenatal/métodos , Biomarcadores/metabolismo , Anomalías Congénitas/metabolismo , Femenino , Humanos , EmbarazoRESUMEN
Drastic epigenetic reprogramming occurs during human gametogenesis and early embryo development. Advances in low-input and single-cell epigenetic techniques have provided powerful tools to dissect the genome-wide dynamics of different epigenetic molecular layers in these processes. In this review, we focus mainly on the most recent progress in understanding the dynamics of DNA methylation, chromatin accessibility, and histone modifications in human gametogenesis and early embryo development. Deficiencies in remodeling of the epigenomes can cause severe developmental defects, infertility, and long-term health issues in offspring. Aspects of the external environment, including assisted reproductive technology procedures, parental diets, and unhealthy parental habits, may disturb the epigenetic reprogramming processes and lead to an aberrant epigenome in the offspring. Here, we review the current knowledge of the potential risk factors of aberrant epigenomes in humans.
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Anomalías Congénitas/genética , Epigénesis Genética , Gametogénesis , Óvulo/metabolismo , Espermatozoides/metabolismo , Cromatina/química , Cromatina/metabolismo , Anomalías Congénitas/metabolismo , Anomalías Congénitas/patología , Metilación de ADN , Embrión de Mamíferos , Desarrollo Embrionario , Femenino , Histonas/genética , Histonas/metabolismo , Humanos , Infertilidad/genética , Infertilidad/metabolismo , Infertilidad/terapia , Patrón de Herencia , Masculino , Óvulo/crecimiento & desarrollo , Técnicas Reproductivas Asistidas , Factores de Riesgo , Espermatozoides/crecimiento & desarrolloRESUMEN
Congenital birth defects may result in a critical condition affecting the baby, including severe fetal/neonatal handicap and mortality. Several studies have shown that genetic, nutritional, and environmental factors may have an impact on fetal development and neonatal health. The relevance of essential and toxic elements on fetal development has not yet been fully investigated, and the results of recent research indicate that these elements may be crucial in the assessment of the risk of malformations in neonates. We determined the association between essential and toxic elements and the level of folate in maternal serum (MS) and amniotic fluid (AF), along with neonatal abnormalities. A total of 258 pregnant Polish women in the age group of 17â»42 years participated in this study. AF and MS were collected during vaginal delivery or during cesarean section. An inductively coupled plasma mass spectrometry technique was used to determine the levels of various elements in AF and MS. The results of this exploratory study indicate that the levels of essential and toxic elements are associated with fetal and newborn anatomical abnormalities and growth disorders.
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Líquido Amniótico/metabolismo , Anomalías Congénitas/metabolismo , Desarrollo Fetal , Ácido Fólico/metabolismo , Trastornos del Crecimiento/metabolismo , Minerales/metabolismo , Oligoelementos/metabolismo , Adolescente , Adulto , Anomalías Congénitas/sangre , Anomalías Congénitas/etiología , Femenino , Trastornos del Crecimiento/sangre , Trastornos del Crecimiento/etiología , Humanos , Recién Nacido , Minerales/sangre , Embarazo , Oligoelementos/sangre , Adulto JovenRESUMEN
Development of external genitalia and perineum is the subject of developmental biology as well as toxicology and teratology researches. Cloaca forms in the lower (caudal) end of endoderm. Such endodermal epithelia and surrounding mesenchyme interact with various signals to form the external genitalia. External genitalia (the anlage termed as genital tubercle: GT) formation shows prominent sexually dimorphic morphogenesis in late embryonic stages, which is an unexplored developmental research field because of many reasons. External genitalia develop adjacent to the cloaca which develops urethra and corporal bodies. Developmental regulators including growth factor signals are necessary for epithelia-mesenchyme interaction (EMI) in posterior embryos including the cloaca and urethra in the genitalia. In the case of male type urethra, formation of tubular urethra proceeds from the lower (ventral) side of external genitalia as a masculinization process in contrast to the case of female urethra. Mechanisms for its development are not elucidated yet due to the lack of suitable mutant mouse models. Because of the recent progresses of Cre (recombinase)-mediated conditional target gene modification analyses, many developmental regulatory genes become increasingly analyzed. Conditional gene knockout mouse approaches and tissue lineage approaches are expected to offer vital information for such sexually dimorphic developmental processes. This review aims to offer recent updates on the progresses of these emerging developmental processes for the research field of congenital anomalies.
Asunto(s)
Anomalías Congénitas/genética , Regulación del Desarrollo de la Expresión Génica , Genitales/embriología , Organogénesis/genética , Perineo/embriología , Animales , Anomalías Congénitas/metabolismo , Anomalías Congénitas/patología , Modelos Animales de Enfermedad , Embrión de Mamíferos , Endodermo/crecimiento & desarrollo , Endodermo/metabolismo , Endodermo/patología , Femenino , Genitales/metabolismo , Genitales/patología , Humanos , Factor de Transcripción MafB/genética , Factor de Transcripción MafB/metabolismo , Masculino , Ratones , Ratones Noqueados , Perineo/patología , Caracteres Sexuales , Factor de Transcripción AP-1/genética , Factor de Transcripción AP-1/metabolismo , Vía de Señalización WntRESUMEN
Mutations in KIF14 have previously been associated with either severe, isolated or syndromic microcephaly with renal hypodysplasia (RHD). Syndromic microcephaly-RHD was strongly reminiscent of clinical ciliopathies, relating to defects of the primary cilium, a signalling organelle present on the surface of many quiescent cells. KIF14 encodes a mitotic kinesin, which plays a key role at the midbody during cytokinesis and has not previously been shown to be involved in cilia-related functions. Here, we analysed four families with fetuses presenting with the syndromic form and harbouring biallelic variants in KIF14. Our functional analyses showed that the identified variants severely impact the activity of KIF14 and likely correspond to loss-of-function mutations. Analysis in human fetal tissues further revealed the accumulation of KIF14-positive midbody remnants in the lumen of ureteric bud tips indicating a shared function of KIF14 during brain and kidney development. Subsequently, analysis of a kif14 mutant zebrafish line showed a conserved role for this mitotic kinesin. Interestingly, ciliopathy-associated phenotypes were also present in mutant embryos, supporting a potential direct or indirect role for KIF14 at cilia. However, our in vitro and in vivo analyses did not provide evidence of a direct role for KIF14 in ciliogenesis and suggested that loss of kif14 causes ciliopathy-like phenotypes through an accumulation of mitotic cells in ciliated tissues. Altogether, our results demonstrate that KIF14 mutations result in a severe syndrome associating microcephaly and RHD through its conserved function in cytokinesis during kidney and brain development.
Asunto(s)
Anomalías Congénitas/genética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Enfermedades Renales/congénito , Riñón/anomalías , Cinesinas/genética , Mutación con Pérdida de Función , Microcefalia/genética , Proteínas Oncogénicas/genética , Animales , Anomalías Congénitas/metabolismo , Citocinesis/genética , Modelos Animales de Enfermedad , Femenino , Técnica del Anticuerpo Fluorescente , Genes Letales , Estudios de Asociación Genética/métodos , Sitios Genéticos , Humanos , Riñón/metabolismo , Enfermedades Renales/genética , Enfermedades Renales/metabolismo , Cinesinas/química , Cinesinas/metabolismo , Masculino , Microcefalia/metabolismo , Microcefalia/patología , Proteínas Oncogénicas/química , Proteínas Oncogénicas/metabolismo , Linaje , Fenotipo , Relación Estructura-Actividad , Pez CebraRESUMEN
OBJECTIVE: To determine if there is a difference in reoperation rates for symptomatic nonunions in atlantoaxial (C1-C2) fusions with or without bone morphogenetic protein (BMP) using data from a national spine registry and to analyze the different types of bone grafts used in the non-BMP group. METHODS: Data from the Kaiser Permanente spine registry were used to identify patients with C1-C2 fusions with >2 years follow-up. Patient characteristics, diagnosis, operative times, length of stay, and reoperations were extracted from the registry. The data set was divided into patients with and without BMP. Further analysis was made of the different types of non-BMP grafts as well as the instrumentation used. RESULTS: In our cohort, we found 58 patients (53.7%) with BMP and 50 patients (46.3%) without with an average follow-up time of 5 years (interquartile range, 2.04-8.49). The BMP versus non-BMP groups differed in admitting diagnosis, operative times, length of stay, and follow-up times. There were no reoperations for symptomatic nonunions in both groups. The non-BMP group included iliac crest graft (with or without allograft [+/-] allograft); lamina (+/- allograft); and allograft alone. CONCLUSIONS: Using one of the largest retrospective studies on C1-C2 fusions with and without BMP, we found no difference in reoperation rates for symptomatic nonunions. For the non-BMP group, we found that lamina (+/- allograft) or allograft alone may also be just as effective as iliac crest graft (+/- allograft) in having no reoperations for symptomatic nonunions.