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1.
Annu Rev Cell Dev Biol ; 31: 553-73, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26359777

RESUMO

The respiratory endoderm develops from a small cluster of cells located on the ventral anterior foregut. This population of progenitors generates the myriad epithelial lineages required for proper lung function in adults through a complex and delicately balanced series of developmental events controlled by many critical signaling and transcription factor pathways. In the past decade, understanding of this process has grown enormously, helped in part by cell lineage fate analysis and deep sequencing of the transcriptomes of various progenitors and differentiated cell types. This review explores how these new techniques, coupled with more traditional approaches, have provided a detailed picture of development of the epithelial lineages in the lung and insight into how aberrant development can lead to lung disease.


Assuntos
Endoderma/fisiologia , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Pulmão/fisiologia , Morfogênese/fisiologia , Animais , Linhagem da Célula/fisiologia , Humanos , Organogênese/fisiologia
2.
Genes Dev ; 33(11-12): 656-668, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30923168

RESUMO

Transcription factors (TFs) are dosage-sensitive master regulators of gene expression, with haploinsufficiency frequently leading to life-threatening disease. Numerous mechanisms have evolved to tightly regulate the expression and activity of TFs at the transcriptional, translational, and posttranslational levels. A subset of long noncoding RNAs (lncRNAs) is spatially correlated with transcription factors in the genome, but the regulatory relationship between these lncRNAs and their neighboring TFs is unclear. We identified a regulatory feedback loop between the TF Foxa2 and a downstream lncRNA, Falcor (Foxa2-adjacent long noncoding RNA). Foxa2 directly represses Falcor expression by binding to its promoter, while Falcor functions in cis to positively regulate the expression of Foxa2. In the lung, loss of Falcor is sufficient to lead to chronic inflammatory changes and defective repair after airway epithelial injury. Moreover, disruption of the Falcor-Foxa2 regulatory feedback loop leads to altered cell adhesion and migration, in turn resulting in chronic peribronchial airway inflammation and goblet cell metaplasia. These data reveal that the lncRNA Falcor functions within a regulatory feedback loop to fine-tune the expression of Foxa2, maintain airway epithelial homeostasis, and promote regeneration.


Assuntos
Células Epiteliais/metabolismo , Fator 3-beta Nuclear de Hepatócito/genética , Pulmão/citologia , Pulmão/metabolismo , RNA Longo não Codificante/genética , Animais , Adesão Celular , Linhagem Celular , Movimento Celular , Feminino , Regulação da Expressão Gênica , Fator 3-beta Nuclear de Hepatócito/metabolismo , Homeostase , Humanos , Masculino , Camundongos , Regiões Promotoras Genéticas , Regeneração , Transcrição Gênica
3.
Prenat Diagn ; 43(8): 1092-1095, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37309085

RESUMO

We report a case of a twin-twin transfusion syndrome (TTTS) recipient who, after successful fetoscopic surgery, developed a large pericardial effusion and calcifications of the aorta and main pulmonary artery. The donor fetus never had cardiac strain and never developed cardiac calcifications. A heterozygous likely pathogenic variant in ABCC6 (c.2018T > C, p.Leu673Pro) was identified in the recipient twin. While TTTS recipient twins are at risk of arterial calcifications and right heart failure secondary to the disease, calcifications of the great vessels are also observed in generalized arterial calcification of infancy, a Mendelian genetic disorder with associated biallelic pathogenic variations in ABCC6 or ENPP1, which can result in significant pediatric morbidity or mortality. The recipient twin in this case had some degree of cardiac strain prior to TTTS surgery; however, the progressive calcification of the aorta and pulmonary trunk occurred weeks after TTTS resolution. This case raises the possibility of a gene-environment interaction and emphasizes the need for genetic evaluation in the setting of TTTS and calcifications.


Assuntos
Transfusão Feto-Fetal , Feminino , Humanos , Gravidez , Transfusão Feto-Fetal/complicações , Fetoscopia , Feto/patologia , Interação Gene-Ambiente , Proteínas Associadas à Resistência a Múltiplos Medicamentos , Gêmeos
4.
J Pediatr ; 247: 116-123.e5, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35452657

RESUMO

OBJECTIVES: To identify factors associated with prenatal, perinatal, and postnatal outcomes, and determine medical care use for fetuses and infants with trisomy 13 (T13) and trisomy 18 (T18). STUDY DESIGN: This population-based retrospective cohort study included all prenatal and postnatal diagnoses of T13 or T18 in the greater Cincinnati area from January 1, 2012, to December 31, 2018. Overall survival, survival to hospital discharge, medical management, and maternal, fetal, and neonatal characteristics are analyzed. RESULTS: There were 124 pregnancies (125 fetuses) that were identified, which resulted in 72 liveborn infants. Male fetal sex and hydrops were associated with a higher rate of spontaneous loss. The median length of survival was 7 and 29 days, for infants with T13 and T18, respectively. Of the 27 infants alive at 1 month of age, 13 (48%) were alive at 1 year of age. Only trisomy type (T13), goals of care (comfort care), and extremely low birthweight were associated with a shorter length of survival. A high degree of variability existed in the use of medical services, with 28% of infants undergoing at least 1 surgical procedure and some children requiring repeated (≤29) or prolonged (>1 year) hospitalizations. CONCLUSIONS: Although many infants with T13 or T18 did not survive past the first week of life, nearly 20% lived for more than 1 year with varying degrees of medical support. The length of survival for an infant cannot be easily predicted, and surviving infants have high health care use throughout their lifespans.


Assuntos
Feto , Trissomia , Adolescente , Criança , Cromossomos Humanos Par 18/genética , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Gravidez , Diagnóstico Pré-Natal/métodos , Estudos Retrospectivos , Trissomia/diagnóstico , Síndrome da Trissomia do Cromossomo 13/diagnóstico , Síndrome da Trissomía do Cromossomo 18/diagnóstico
5.
Genes Dev ; 28(12): 1363-79, 2014 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-24939938

RESUMO

Long noncoding RNAs (lncRNAs) are thought to play important roles in regulating gene transcription, but few have well-defined expression patterns or known biological functions during mammalian development. Using a conservative pipeline to identify lncRNAs that have important biological functions, we identified 363 lncRNAs in the lung and foregut endoderm. Importantly, we show that these lncRNAs are spatially correlated with transcription factors across the genome. In-depth expression analyses of lncRNAs with genomic loci adjacent to the critical transcription factors Nkx2.1, Gata6, Foxa2 (forkhead box a2), and Foxf1 mimic the expression patterns of their protein-coding neighbor. Loss-of-function analysis demonstrates that two lncRNAs, LL18/NANCI (Nkx2.1-associated noncoding intergenic RNA) and LL34, play distinct roles in endoderm development by controlling expression of critical developmental transcription factors and pathways, including retinoic acid signaling. In particular, we show that LL18/NANCI acts upstream of Nkx2.1 and downstream from Wnt signaling to regulate lung endoderm gene expression. These studies reveal that lncRNAs play an important role in foregut and lung endoderm development by regulating multiple aspects of gene transcription, often through regulation of transcription factor expression.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Pulmão/crescimento & desenvolvimento , RNA Longo não Codificante/metabolismo , Fatores de Transcrição/metabolismo , Animais , Diferenciação Celular/genética , Linhagem Celular , Endoderma/citologia , Endoderma/metabolismo , Perfilação da Expressão Gênica , Técnicas de Silenciamento de Genes , Genoma , Células HEK293 , Humanos , Pulmão/embriologia , Camundongos , Proteínas Nucleares/genética , RNA Longo não Codificante/genética , Fator Nuclear 1 de Tireoide , Fatores de Transcrição/genética , Via de Sinalização Wnt
6.
Genet Med ; 23(5): 909-917, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33442022

RESUMO

PURPOSE: Previous studies have reported that prenatal exome sequencing (pES) can detect monogenic diseases in fetuses with congenital anomalies with diagnostic yields ranging from 6% to 81%, but there are few reports of its clinical utility. METHODS: We conducted a retrospective chart review of patients who had pES to determine whether results led to clinical management changes. RESULTS: Of 20 patients, 8 (40%) received a definitive diagnosis. Seven patients (35%) had medical management changes based on the pES results, including alterations to their delivery plan and neonatal management (such as use of targeted medications, subspecialty referrals, additional imaging and/or procedures). All patients who received a definitive diagnosis and one who received a likely pathogenic variant (n = 9; 45%) received specific counseling about recurrence risk and the medical/developmental prognosis for the baby. In five (25%) cases, the result facilitated a diagnosis in parents and/or siblings. CONCLUSION: pES results can have significant impacts on clinical management, some of which would not be possible if testing is deferred until after birth. To maximize the clinical utility, pES should be prioritized in cases where multiple care options are available and the imaging findings alone are not sufficient to guide parental decision-making, or where postnatal testing will not be feasible.


Assuntos
Exoma , Diagnóstico Pré-Natal , Exoma/genética , Feminino , Feto , Humanos , Recém-Nascido , Gravidez , Estudos Retrospectivos , Sequenciamento do Exoma
7.
J Pediatr ; 213: 211-217.e4, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31255390

RESUMO

OBJECTIVE: To investigate the prevalence of genetic disease and its economic impact in a level IV neonatal intensive care unit (NICU) by identifying and describing diseases diagnosed, genetic testing methodologies used, timing of diagnosis, length of NICU stay, and charges for NICU care. STUDY DESIGN: A retrospective chart review of patients admitted to a level IV NICU from 2013 to 2014 (n = 1327) was undertaken and data collected up to 2 years of age from the electronic medical record. RESULTS: In total, 117 patients (9%) received 120 genetic diagnoses using a variety of methodologies. A significant minority of diagnoses, 36%, were made after NICU discharge and 41% were made after 28 days of age. Patients receiving a genetic diagnosis had significantly longer mean lengths of stay (46 days vs 29.1 days; P < .01) and costlier mean charges ($598 712 vs $352 102; P < .01) for their NICU care. The NICU stay charge difference to care for a newborn with a genetic condition was on average $246 610 in excess of that for a patient without a genetic diagnosis, resulting in more than $28 000 000 in excess charges to care for all patients with genetic conditions in a single NICU over a 2-year period. CONCLUSIONS: Given the high prevalence of genetic disease in this population and the documented higher cost of care, shortening the time to diagnosis and targeting therapeutic interventions for this population could make a significant impact on neonatal care in level IV NICUs.


Assuntos
Doenças Genéticas Inatas/economia , Doenças Genéticas Inatas/genética , Testes Genéticos/economia , Testes Genéticos/métodos , Unidades de Terapia Intensiva Neonatal , Terapia Intensiva Neonatal/economia , Metilação de DNA , Registros Eletrônicos de Saúde , Exoma , Feminino , Doenças Genéticas Inatas/diagnóstico , Humanos , Hibridização in Situ Fluorescente , Lactente , Mortalidade Infantil , Recém-Nascido , Tempo de Internação , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Alta do Paciente , Prevalência , Estudos Retrospectivos , Análise de Sequência de DNA
8.
Am J Respir Crit Care Med ; 197(10): 1328-1339, 2018 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-29328793

RESUMO

RATIONALE: Disruption of normal pulmonary development is a leading cause of morbidity and mortality in infants. Congenital lung malformations are a unique model to study the molecular pathogenesis of isolated structural birth defects, as they are often surgically resected. OBJECTIVES: To provide insight into the molecular pathogenesis of congenital lung malformations through analysis of cell-type and gene expression changes in these lesions. METHODS: Clinical data, and lung tissue for DNA, RNA, and histology, were obtained from 58 infants undergoing surgical resection of a congenital lung lesion. Transcriptome-wide gene expression analysis was performed on paired affected and unaffected samples from a subset of infants (n = 14). A three-dimensional organoid culture model was used to assess isolated congenital lung malformation epithelium (n = 3). MEASUREMENTS AND MAIN RESULTS: Congenital lung lesions express higher levels of airway epithelial related genes, and dysregulated expression of genes related to the Ras and PI3K-AKT-mTOR (phosphatidylinositol 3-kinase-AKT-mammalian target of rapamycin) signaling pathways. Immunofluorescence confirmed differentiated airway epithelial cell types throughout all major subtypes of congenital lung lesions, and three-dimensional cell culture demonstrated a cell-autonomous defect in the epithelium of these lesions. CONCLUSIONS: This study provides the first comprehensive analysis of the congenital lung malformation transcriptome and suggests that disruptions in Ras or PI3K-AKT-mTOR signaling may contribute to the pathology through an epithelial cell-autonomous defect.


Assuntos
Malformação Adenomatoide Cística Congênita do Pulmão/genética , Malformação Adenomatoide Cística Congênita do Pulmão/cirurgia , Predisposição Genética para Doença , Pulmão/fisiopatologia , Anormalidades do Sistema Respiratório/genética , Anormalidades do Sistema Respiratório/cirurgia , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pennsylvania , Fenótipo
9.
Am J Perinatol ; 34(7): 684-692, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-27960200

RESUMO

Background Association studies of various gene variants in neonatal sepsis show conflicting results. Objective We performed a systematic review of candidate gene association studies in neonatal sepsis to provide pooled estimates of risk for selected gene variants. Methods We performed a search using MeSH terms "infection," "sepsis," "infant," "genetic variation," "polymorphism," and "genetic association studies." We included studies evaluating associations between neonatal sepsis and genetic variants (2000-2015). We excluded case reports/series, commentaries, narrative reviews, and nonhuman research. We assessed quality of studies using STREGA guidelines. Following estimation of odds ratios (ORs), data were pooled using random effects models. Results Twenty eight of 1,404 identified studies were included. Meta-analyses were performed for interleukin (IL)-6, tumor necrosis factor-α (TNF-α), and IL-10 as these gene variants were tested in multiple studies. TNF-α 308GG genotype demonstrated trends toward increased sepsis risk in the primary analysis of culture-proven sepsis (OR 1.18, 95% confidence interval [CI] 0.97-1.44). IL-10 1082GG genotype was associated with lower sepsis odds in very low-birth-weight (VLBW) infants (OR 0.51, 95% CI 0.29-0.91). Conclusion We uncovered an association between IL-10 1082 gene variation and sepsis in VLBW infants but did not identify associations between neonatal sepsis and TNF-α 308 or IL-6 gene variation. Larger cohort replication studies are required to validate these findings.


Assuntos
Recém-Nascido de muito Baixo Peso , Interleucina-10/genética , Interleucina-6/genética , Sepse Neonatal/genética , Fator de Necrose Tumoral alfa/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Recém-Nascido , Polimorfismo de Nucleotídeo Único , Fatores de Risco
10.
Am J Med Genet A ; 161A(3): 473-8, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23401257

RESUMO

Loss of function mutations in FREM1 have been demonstrated in Manitoba-oculo-tricho-anal (MOTA) syndrome and Bifid Nose Renal Agenesis and Anorectal malformations (BNAR) syndrome, but the wider phenotypic spectrum that is associated with FREM1 mutations remains to be defined. We screened three probands with phenotypic features of MOTA syndrome. In one severely affected infant who was diagnosed with MOTA syndrome because of bilateral eyelid colobomas, a bifid nasal tip, hydrometrocolpos and vaginal atresia, we found two nonsense mutations that likely result in complete loss of FREM1 function. This infant also had renal dysplasia, a finding more consistent with BNAR syndrome. Another male who was homozygous for a novel stop mutation had an extensive eyelid colobomas, corneopalpebral synechiae, and unilateral renal agenesis. A third male child diagnosed with MOTA syndrome because of corneopalpebral synechiae and eyelid colobomas had a homozygous splice site mutation in FREM1. These cases illustrate that disruption of the FREM1 gene can produce a spectrum of clinical manifestations encompassing the previously described MOTA and BNAR syndromes, and that features of both syndromes may be seen in the same individual. The phenotype of FREM1-related disorders is thus more pleiotropic than for MOTA and BNAR syndrome alone and more closely resembles the widespread clinical involvement seen with Fraser syndrome. Moreover, our first case demonstrates that vaginal atresia may be a feature of FREM1-related disorders.


Assuntos
Anormalidades Múltiplas/diagnóstico , Coloboma/diagnóstico , Hipertelorismo/diagnóstico , Nefropatias/diagnóstico , Receptores de Interleucina/genética , Doenças Retais/diagnóstico , Anormalidades Múltiplas/genética , Canal Anal/anormalidades , Coloboma/genética , Consanguinidade , Evolução Fatal , Feminino , Estudos de Associação Genética , Humanos , Hipertelorismo/genética , Lactente , Recém-Nascido , Nefropatias/genética , Masculino , Técnicas de Diagnóstico Molecular , Mutação , Nariz/anormalidades , Fenótipo , Doenças Retais/genética , Análise de Sequência de DNA
11.
Am J Med Genet A ; 161A(8): 1929-39, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23804593

RESUMO

Here we describe three subjects with mosaic genome-wide paternal uniparental isodisomy (GWpUPD) each of whom presented initially with overgrowth, hemihyperplasia (HH), and hyperinsulinism (HI). Due to the severity of findings and the presence of additional features, SNP array testing was performed, which demonstrated mosaic GWpUPD. Comparing these individuals to 10 other live-born subjects reported in the literature, the predominant phenotype is that of pUPD11 and notable for a very high incidence of tumor development. Our subjects developed non-metastatic tumors of the adrenal gland, kidney, and/or liver. All three subjects had pancreatic hyperplasia resulting in HI. Notably, our subjects to date display minimal features of other diseases associated with paternal UPD loci. Both children who survived the neonatal period have displayed near-normal cognitive development, likely due to a favorable tissue distribution of the mosaicism. To understand the range of UPD mosaicism levels, we studied multiple tissues using SNP array analysis and detected levels of 5-95%, roughly correlating with the extent of tissue involvement. Given the rapidity of tumor growth and the difficulty distinguishing malignant and benign tumors in these GWpUPD subjects, we have utilized increased frequency of ultrasound (US) and alpha-fetoprotein (AFP) screening in the first years of life. Because of a later age of onset of additional tumors, continued tumor surveillance into adolescence may need to be considered in these rare patients.


Assuntos
Cromossomos Humanos Par 11/genética , Genoma Humano , Hiperbilirrubinemia Hereditária/genética , Hiperinsulinismo/genética , Hiperplasia/genética , Mosaicismo , Neoplasias/genética , Dissomia Uniparental/genética , Adulto , Células Cultivadas , Pré-Escolar , Aberrações Cromossômicas , Hibridização Genômica Comparativa , Feminino , Genótipo , Humanos , Hiperbilirrubinemia Hereditária/patologia , Hiperinsulinismo/patologia , Hiperplasia/patologia , Lactente , Imageamento por Ressonância Magnética , Neoplasias/patologia , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Dissomia Uniparental/patologia , alfa-Fetoproteínas/metabolismo
12.
bioRxiv ; 2023 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-38187557

RESUMO

Differential chromatin accessibility accompanies and mediates transcriptional control of diverse cell fates and their differentiation during embryogenesis. While the critical role of NKX2-1 and its transcriptional targets in lung morphogenesis and pulmonary epithelial cell differentiation is increasingly known, mechanisms by which chromatin accessibility alters the epigenetic landscape and how NKX2-1 interacts with other co-activators required for alveolar epithelial cell differentiation and function are not well understood. Here, we demonstrate that the paired domain zinc finger transcriptional regulators PRDM3 and PRDM16 regulate chromatin accessibility to mediate cell differentiation decisions during lung morphogenesis. Combined deletion of Prdm3 and Prdm16 in early lung endoderm caused perinatal lethality due to respiratory failure from loss of AT2 cell function. Prdm3/16 deletion led to the accumulation of partially differentiated AT1 cells and loss of AT2 cells. Combination of single cell RNA-seq, bulk ATAC-seq, and CUT&RUN demonstrated that PRDM3 and PRDM16 enhanced chromatin accessibility at NKX2-1 transcriptional targets in peripheral epithelial cells, all three factors binding together at a multitude of cell-type specific cis-active DNA elements. Network analysis demonstrated that PRDM3/16 regulated genes critical for perinatal AT2 cell differentiation, surfactant homeostasis, and innate host defense. Lineage specific deletion of PRDM3/16 in AT2 cells led to lineage infidelity, with PRDM3/16 null cells acquiring partial AT1 fate. Together, these data demonstrate that NKX2-1-dependent regulation of alveolar epithelial cell differentiation is mediated by epigenomic modulation via PRDM3/16.

13.
J Perinatol ; 42(5): 580-588, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35181764

RESUMO

OBJECTIVE: To determine detection rates of genetic disease in a level IV neonatal intensive care unit (NICU) and cost of care. STUDY DESIGN: We divided 2703 neonates, admitted between 2013 and 2016 to a level IV NICU, into two epochs and determined how genetic testing utilization, genetic diagnoses identified, and cost of NICU care changed over time. RESULT: The increasing use of multi-gene panels 104 vs 184 (P = 0.02) and whole exome sequencing (WES) 9 vs 28 (P = 0.03) improved detection of genetic disease, 9% vs 12% (P < 0.01). Individuals with genetic diagnoses had higher mean NICU charges, $723,422 vs $417,013 (P < 0.01) secondary to longer lengths of stay, not genetic services. CONCLUSION: The increased utilization of broad genetic testing improved the detection of genetic disease but contributed minimally to the cost of care while bolstering understanding of the patient's condition and prognosis.


Assuntos
Testes Genéticos , Unidades de Terapia Intensiva Neonatal , Hospitalização , Humanos , Recém-Nascido , Sequenciamento do Exoma
14.
Elife ; 112022 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-35976093

RESUMO

The tips of the developing respiratory buds are home to important progenitor cells marked by the expression of SOX9 and ID2. Early in embryonic development (prior to E13.5), SOX9+progenitors are multipotent, generating both airway and alveolar epithelium, but are selective progenitors of alveolar epithelial cells later in development. Transcription factors, including Sox9, Etv5, Irx, Mycn, and Foxp1/2 interact in complex gene regulatory networks to control proliferation and differentiation of SOX9+progenitors. Molecular mechanisms by which these transcription factors and other signaling pathways control chromatin state to establish and maintain cell-type identity are not well-defined. Herein, we analyze paired gene expression (RNA-Seq) and chromatin accessibility (ATAC-Seq) data from SOX9+ epithelial progenitor cells (EPCs) during embryonic development in Mus musculus. Widespread changes in chromatin accessibility were observed between E11.5 and E16.5, particularly at distal cis-regulatory elements (e.g. enhancers). Gene regulatory network (GRN) inference identified a common SOX9+ progenitor GRN, implicating phosphoinositide 3-kinase (PI3K) signaling in the developmental regulation of SOX9+ progenitor cells. Consistent with this model, conditional ablation of PI3K signaling in the developing lung epithelium in mouse resulted in an expansion of the SOX9+ EPC population and impaired airway epithelial cell differentiation. These data demonstrate that PI3K signaling is required for epithelial patterning during lung organogenesis, and emphasize the combinatorial power of paired RNA and ATAC seq in defining regulatory networks in development.


Studying how lungs develop has helped us understand and treat often-devastating lung diseases. This includes diseases like cystic fibrosis which result from spelling mistakes known as mutations in a person's genetic code. However, not all lung diseases involve mutations. Many other diseases, in both adults and children, are caused by genes failing to switch on or off at some point during lung development. DNA is surrounded by various proteins which package it into a compressed structure known as chromatin. Cells can control which genes are turned on or off by modifying how tightly packed parts of the genetic code are within chromatin. Changes in chromatin accessibility, also known as 'epigenetic' changes, are a normal part of development, and guide cells towards specific jobs or identities as an organ matures. However, how this happens in the developing lung is poorly understood. Here, Khattar, Fernandes et al. set out to determine how chromatin accessibility shapes development of the tissue lining the lungs, focusing on a group of progenitor cells which produce the protein SOX9. These cells are initially found at the tips of the early lung, where they go on to develop into the cells that line the whole of the mature organ. Initial experiments used large-scale genetic techniques to measure gene activity and chromatin accessibility simultaneously in progenitor cells extracted from the lungs of mice. Khattar, Fernandes et al. were then able to predict the signaling pathways that shape the lung lining based on which genes were surrounded by unpacked chromatin, and determine the proteins responsible for these epigenetic changes. This included the signaling pathway Phosphatidylinositol 3 kinase (PI3K) which is involved in a number of cellular processes. Additional experiments in mice confirmed that the PI3K pathway became active very early in lung development and remained so until adulthood. In contrast, mice lacking a gene that codes for a key part of the PI3K pathway had defective lungs which failed to develop a proper lining. The data generated in this study will provide an important resource for future studies investigating how epigenetic changes drive normal lung development. Khattar, Fernandes et al. hope that this knowledge will help researchers to better understand the cause of human lung diseases, and identify already available 'epigenetic drugs' which could be repurposed to treat them.


Assuntos
Redes Reguladoras de Genes , Fosfatidilinositol 3-Quinases , Animais , Diferenciação Celular/genética , Cromatina , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Pulmão , Camundongos , Fosfatidilinositol 3-Quinase/genética , Fosfatidilinositol 3-Quinases/genética , Gravidez
15.
JCI Insight ; 7(18)2022 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-35980752

RESUMO

Accurate estimate of fetal maturity could provide individualized guidance for delivery of complicated pregnancies. However, current methods are invasive, have low accuracy, and are limited to fetal lung maturation. To identify diagnostic gestational biomarkers, we performed transcriptomic profiling of lung and brain, as well as cell-free RNA from amniotic fluid of preterm and term rhesus macaque fetuses. These data identify potentially new and prior-associated gestational age differences in distinct lung and neuronal cell populations when compared with existing single-cell and bulk RNA-Seq data. Comparative analyses found hundreds of genes coincidently induced in lung and amniotic fluid, along with dozens in brain and amniotic fluid. These data enable creation of computational models that accurately predict lung compliance from amniotic fluid and lung transcriptome of preterm fetuses treated with antenatal corticosteroids. Importantly, antenatal steroids induced off-target gene expression changes in the brain, impinging upon synaptic transmission and neuronal and glial maturation, as this could have long-term consequences on brain development. Cell-free RNA in amniotic fluid may provide a substrate of global fetal maturation markers for personalized management of at-risk pregnancies.


Assuntos
Líquido Amniótico , Ácidos Nucleicos Livres , Líquido Amniótico/metabolismo , Animais , Ácidos Nucleicos Livres/metabolismo , Feminino , Desenvolvimento Fetal , Macaca mulatta , Gravidez , Transcriptoma
16.
Clin Case Rep ; 9(12): e05163, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34987809

RESUMO

Diprosopus is an extremely rare congenital anomaly involving craniofacial duplication. The etiology and pathophysiology remain unknown, and no genetic mutations have been definitively associated with the condition. This case describes an infant born at 27-weeks completed gestation with multiple congenital anomalies including diprosopus and discusses the implications of prenatal diagnosis.

17.
Am J Med Genet A ; 152A(3): 565-72, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20140962

RESUMO

Potocki-Shaffer syndrome is a rare contiguous gene deletion syndrome due to haploinsufficiency of the 11p11.2p12 region and is characterized by craniofacial abnormalities, developmental delay, intellectual disability, multiple exostoses, and biparietal foramina. In this study, six patients with the Potocki-Shaffer syndrome were identified and evaluated using a multidisciplinary protocol that included assessments by a geneticist, ophthalmologist, otolaryngologist, orthopedist, nephrologist, audiologist, and neuropsychologist. Diagnostic studies included skeletal survey, magnetic resonance imaging of the brain, renal ultrasound, complete blood count, comprehensive metabolic panel, thyroid studies, and urinalysis. Using array comparative genomic hybridization, we further characterized the deletion in five of these patients. The results of these evaluations were combined with a comprehensive review of reported cases. Our data highlight the characteristic facial features, biparietal foramina, moderate-to-severe developmental delay and intellectual disability, myopia and strabismus, and multiple exostoses seen with this disorder. We also identify for the first time an association of Potocki-Shaffer syndrome with sensorineural hearing loss and autistic behaviors. Finally, we provide recommendations for the health maintenance of patients with Potocki-Shaffer syndrome.


Assuntos
Anormalidades Múltiplas/genética , Anormalidades Craniofaciais/genética , Deficiências do Desenvolvimento/genética , Exostose Múltipla Hereditária/genética , Anormalidades Múltiplas/patologia , Anormalidades Múltiplas/terapia , Adolescente , Transtorno Autístico/genética , Criança , Pré-Escolar , Deleção Cromossômica , Cromossomos Humanos Par 11 , Anormalidades Craniofaciais/patologia , Deficiências do Desenvolvimento/psicologia , Deficiências do Desenvolvimento/terapia , Intervenção Educacional Precoce , Exostose Múltipla Hereditária/patologia , Feminino , Perda Auditiva Neurossensorial/genética , Humanos , Lactente , Masculino , Fenótipo , Síndrome
19.
Ann Am Thorac Soc ; 13(12): 385-393, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27925785

RESUMO

Pediatric rare lung disease (PRLD) is a term that refers to a heterogeneous group of rare disorders in children. In recent years, this field has experienced significant progress marked by scientific discoveries, multicenter and interdisciplinary collaborations, and efforts of patient advocates. Although genetic mechanisms underlie many PRLDs, pathogenesis remains uncertain for many of these disorders. Furthermore, epidemiology and natural history are insufficiently defined, and therapies are limited. To develop strategies to accelerate scientific advancement for PRLD research, the NHLBI of the National Institutes of Health convened a strategic planning workshop on September 3 and 4, 2015. The workshop brought together a group of scientific experts, intramural and extramural investigators, and advocacy groups with the following objectives: (1) to discuss the current state of PRLD research; (2) to identify scientific gaps and barriers to increasing research and improving outcomes for PRLDs; (3) to identify technologies, tools, and reagents that could be leveraged to accelerate advancement of research in this field; and (4) to develop priorities for research aimed at improving patient outcomes and quality of life. This report summarizes the workshop discussion and provides specific recommendations to guide future research in PRLD.


Assuntos
Pesquisa Biomédica/tendências , Pneumopatias/terapia , Doenças Raras/terapia , Criança , Humanos , Pneumopatias/etiologia , National Heart, Lung, and Blood Institute (U.S.) , Pediatria , Guias de Prática Clínica como Assunto , Qualidade de Vida , Doenças Raras/etiologia , Estados Unidos
20.
JIMD Rep ; 5: 17-20, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23430912

RESUMO

Glycogen storage disease type II (OMIM #232300), or Pompe disease, may present in the newborn period with moderate-to-severe biventricular hypertrophy with or without left ventricular outflow tract obstruction that typically leads to death from cardiorespiratory failure in the first year of life. Glycogen deposition tends to be uniform, and is only occasionally accompanied by patchy areas of fibrosis. Here, we present an infant identified with biventricular hypertrophy and cardiac masses by prenatal ultrasound. Postnatal molecular studies did not support the diagnosis of tuberous sclerosis in this case. Additional evaluation for infantile hypertrophic cardiomyopathy confirmed the diagnosis of Pompe disease. We discuss whether the "cardiac masses," which brought this infant to medical attention and facilitated an early diagnosis of Pompe disease, may represent an unusual manifestation of GSD type II or the coincidental occurrence of an unrelated disease process.

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