Publications by authors named "Kate G Ackerman"

25 Publications

  • Page 1 of 1

Perspectives from the Society for Pediatric Research: advice on sustaining science and mentoring during COVID-19.

Pediatr Res 2021 Jan 19. Epub 2021 Jan 19.

Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA.

The COVID-19 pandemic will leave an indelible mark on the careers of current medical trainees. Given the disruptions to medical education, economic impact on institutions, and the uncertainties around future job prospects, trainees are facing unprecedented challenges. This situation is especially concerning for futures of pediatric physician-scientist trainees, where concerns regarding maintaining the pipeline were well documented prior to the emergence of COVID-19. In this Perspectives article, we leverage the unique expertise of our workgroup to address concerns of physician-scientist trainees and to provide suggestions on how to navigate career trajectories in the post-COVID-19 era. We identified and addressed four major areas of concern: lack of in-person conferences and the associated decrease access to mentors and networking activities, decreased academic productivity, diminished job prospects, and mental health challenges. We also suggest actions for trainees, mentors and educational leaders, and institutions to help support trainees during the pandemic, with a goal of maintaining the pediatric physician-scientist pipeline.
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http://dx.doi.org/10.1038/s41390-020-01321-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814517PMC
January 2021

Siblings with lethal primary pulmonary hypoplasia and compound heterozygous variants in the gene: further delineation of the phenotypic spectrum.

Cold Spring Harb Mol Case Stud 2019 06 3;5(3). Epub 2019 Jun 3.

Pediatric Genomics Discovery Program, Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut 06437, USA.

Variants in the mitochondrial alanyl-tRNA synthetase 2 gene (OMIM 612035) are associated with infantile mitochondrial cardiomyopathy or later-onset leukoencephalopathy with premature ovarian insufficiency. Here, we report two newborn siblings who died soon after birth with primary pulmonary hypoplasia without evidence of cardiomyopathy. Whole-exome sequencing detected the same compound heterozygous variants in both siblings (c.1774C>T, p.Arg592Trp and c.647dup, p.Cys218Leufs*6) that have previously been associated with infantile mitochondrial cardiomyopathy. Segregation analysis in the family confirmed carrier status of the parents and an unaffected sibling. To our knowledge, this is the first report of primary pulmonary hypoplasia in the absence of cardiomyopathy associated with recessive variants and further defines the phenotypic spectrum associated with this gene.
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http://dx.doi.org/10.1101/mcs.a003699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6549552PMC
June 2019

Vancomycin Monotherapy May Be Insufficient to Treat Methicillin-resistant Staphylococcus aureus Coinfection in Children With Influenza-related Critical Illness.

Clin Infect Dis 2019 01;68(3):365-372

Department of Pediatrics, Harvard Medical School, Boston, Massachusetts.

Background: Coinfection with influenza virus and methicillin-resistant Staphylococcus aureus (MRSA) causes life-threatening necrotizing pneumonia in children. Sporadic incidence precludes evaluation of antimicrobial efficacy. We assessed the clinical characteristics and outcomes of critically ill children with influenza-MRSA pneumonia and evaluated antibiotic use.

Methods: We enrolled children (<18 years) with influenza infection and respiratory failure across 34 pediatric intensive care units 11/2008-5/2016. We compared baseline characteristics, clinical courses, and therapies in children with MRSA coinfection, non-MRSA bacterial coinfection, and no bacterial coinfection.

Results: We enrolled 170 children (127 influenza A, 43 influenza B). Children with influenza-MRSA pneumonia (N = 30, 87% previously healthy) were older than those with non-MRSA (N = 61) or no (N = 79) bacterial coinfections. Influenza-MRSA was associated with increased leukopenia, acute lung injury, vasopressor use, extracorporeal life support, and mortality than either group (P ≤ .0001). Influenza-related mortality was 40% with MRSA compared to 4.3% without (relative risk [RR], 9.3; 95% confidence interval [CI], 3.8-22.9). Of 29/30 children with MRSA who received vancomycin within the first 24 hours of hospitalization, mortality was 12.5% (N = 2/16) if treatment also included a second anti-MRSA antibiotic compared to 69.2% (N = 9/13) with vancomycin monotherapy (RR, 5.5; 95% CI, 1.4, 21.3; P = .003). Vancomycin dosing did not influence initial trough levels; 78% were <10 µg/mL.

Conclusions: Influenza-MRSA coinfection is associated with high fatality in critically ill children. These data support early addition of a second anti-MRSA antibiotic to vancomycin in suspected severe cases.
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http://dx.doi.org/10.1093/cid/ciy495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6336914PMC
January 2019

Congenital Diaphragmatic Hernia with Liver Herniation into the Pericardial Sac in a 30-Week Gestation Infant.

Pediatr Dev Pathol 2017 Sep-Oct;20(5):421-425. Epub 2017 Jan 25.

1 Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York, USA.

Anterior diaphragmatic defects with pericardial involvement are extremely rare and diagnostically challenging entities encountered perinatally. While a majority of diaphragmatic defects occur in isolation, others are associated with multiple defects forming a complex of syndromes such as Pentalogy of Cantrell. Liver herniation into the pericardial sac poses a particular challenge and can mimic a pericardial tumor on prenatal ultrasound, yielding a different management course. The following case is an unusual presentation of a 30-week gestation female with an anterior midline diaphragmatic defect with liver herniation mimicking as a pericardial tumor, diagnosed at time of autopsy. Postmortem studies also found multiple congenital anomalies including an atrioventricular septal defect and midline gumline defect suggesting at least a partial Pentalogy of Cantrell or variant. Early recognition and screening for associated anomalies are essential for management in this subset of patients.
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http://dx.doi.org/10.1177/1093526616686446DOI Listing
May 2019

Congenital diaphragmatic hernias: from genes to mechanisms to therapies.

Dis Model Mech 2017 08;10(8):955-970

Department of Human Genetics, University of Utah, Salt Lake City, UT 84112, USA

Congenital diaphragmatic hernias (CDHs) and structural anomalies of the diaphragm are a common class of congenital birth defects that are associated with significant morbidity and mortality due to associated pulmonary hypoplasia, pulmonary hypertension and heart failure. In ∼30% of CDH patients, genomic analyses have identified a range of genetic defects, including chromosomal anomalies, copy number variants and sequence variants. The affected genes identified in CDH patients include transcription factors, such as , , and , and signaling pathway components, including members of the retinoic acid pathway. Mutations in these genes affect diaphragm development and can have pleiotropic effects on pulmonary and cardiac development. New therapies, including fetal endoscopic tracheal occlusion and prenatal transplacental fetal treatments, aim to normalize lung development and pulmonary vascular tone to prevent and treat lung hypoplasia and pulmonary hypertension, respectively. Studies of the association between particular genetic mutations and clinical outcomes should allow us to better understand the origin of this birth defect and to improve our ability to predict and identify patients most likely to benefit from specialized treatment strategies.
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http://dx.doi.org/10.1242/dmm.028365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5560060PMC
August 2017

Staphylococcus aureus α-Toxin Response Distinguishes Respiratory Virus-Methicillin-Resistant S. aureus Coinfection in Children.

J Infect Dis 2016 Dec 20;214(11):1638-1646. Epub 2016 Sep 20.

Department of Pediatrics.

Background:  Development of methicillin-resistant Staphylococcus aureus (MRSA) pneumonia after a respiratory viral infection is frequently fatal in children. In mice, S. aureus α-toxin directly injures pneumocytes and increases mortality, whereas α-toxin blockade mitigates disease. The role of α-toxin in pediatric staphylococcal-viral coinfection is unclear.

Methods:  We enrolled children across 34 North American pediatric intensive care units with acute respiratory failure and suspected influenza virus infection. Serial serum anti-α-toxin antibody titers and functional α-toxin neutralization capacity were compared across children coinfected with MRSA or methicillin-susceptible S. aureus (MSSA) and control children infected with influenza virus only. MRSA isolates were tested for α-toxin production and lethality in a murine pneumonia model.

Results:  Influenza virus was identified in 22 of 25 children with MRSA coinfection (9 died) and 22 patients with MSSA coinfection (all survived). Initial α-toxin-specific antibody titers were similar, compared with those in the 13 controls. In patients with serial samples, only MRSA-coinfected patients showed time-dependent increases in anti-α-toxin titer and functional neutralization capacity. MRSA α-toxin production from patient isolates correlated with initial serologic titers and with mortality in murine pneumonia.

Conclusions:  These data implicate α-toxin as a relevant antigen in severe pediatric MRSA pneumonia associated with respiratory viral infection, supporting a potential role for toxin-neutralizing therapy.
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http://dx.doi.org/10.1093/infdis/jiw441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5144732PMC
December 2016

KIF7 Controls the Proliferation of Cells of the Respiratory Airway through Distinct Microtubule Dependent Mechanisms.

PLoS Genet 2015 Oct 6;11(10):e1005525. Epub 2015 Oct 6.

Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, New York, United States of America; Department of Pediatrics, University of Rochester Medical Center, Rochester, New York, United States of America; Center for Pediatric Biomedical Research, University of Rochester Medical Center, Rochester, New York, United States of America.

The cell cycle must be tightly coordinated for proper control of embryonic development and for the long-term maintenance of organs such as the lung. There is emerging evidence that Kinesin family member 7 (Kif7) promotes Hedgehog (Hh) signaling during embryonic development, and its misregulation contributes to diseases such as ciliopathies and cancer. Kif7 encodes a microtubule interacting protein that controls Hh signaling through regulation of microtubule dynamics within the primary cilium. However, whether Kif7 has a function in nonciliated cells remains largely unknown. The role Kif7 plays in basic cell biological processes like cell proliferation or cell cycle progression also remains to be elucidated. Here, we show that Kif7 is required for coordination of the cell cycle, and inactivation of this gene leads to increased cell proliferation in vivo and in vitro. Immunostaining and transmission electron microscopy experiments show that Kif7dda/dda mutant lungs are hyperproliferative and exhibit reduced alveolar epithelial cell differentiation. KIF7 depleted C3H10T1/2 fibroblasts and Kif7dda/dda mutant mouse embryonic fibroblasts have increased growth rates at high cellular densities, suggesting that Kif7 may function as a general regulator of cellular proliferation. We ascertained that in G1, Kif7 and microtubule dynamics regulate the expression and activity of several components of the cell cycle machinery known to control entry into S phase. Our data suggest that Kif7 may function to regulate the maintenance of the respiratory airway architecture by controlling cellular density, cell proliferation, and cycle exit through its role as a microtubule associated protein.
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http://dx.doi.org/10.1371/journal.pgen.1005525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4595342PMC
October 2015

Dissatisfaction with maintenance of certification in academic pediatrics.

Pediatr Res 2016 Feb 30;79(2):240-2. Epub 2015 Sep 30.

McNair Medical Institute, Pediatric Diabetes and Endocrinology, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas.

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http://dx.doi.org/10.1038/pr.2015.189DOI Listing
February 2016

Wt1 and β-catenin cooperatively regulate diaphragm development in the mouse.

Dev Biol 2015 Nov 14;407(1):40-56. Epub 2015 Aug 14.

Department of Biomedical Genetics, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA; Department of Pediatrics, Center for Pediatric Biomedical Research, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA. Electronic address:

The developing diaphragm consists of various differentiating cell types, many of which are not well characterized during organogenesis. One important but incompletely understood tissue, the diaphragmatic mesothelium, is distinctively present from early stages of development. Congenital Diaphragmatic Hernia (CDH) occurs in humans when diaphragm tissue is lost during development, resulting in high morbidity and mortality postnatally. We utilized a Wilms Tumor 1 (Wt1) mutant mouse model to investigate the involvement of the mesothelium in normal diaphragm signaling and development. Additionally, we developed and characterized a Wt1(CreERT2)-driven β-catenin loss-of-function model of CDH after finding that canonical Wnt signaling and β-catenin are reduced in Wt1 mutant mesothelium. Mice with β-catenin loss or constitutive activation induced in the Wt1 lineage are only affected when tamoxifen injection occurs between E10.5 and E11.5, revealing a critical time-frame for Wt1/ β-catenin activity. Conditional β-catenin loss phenocopies the Wt1 mutant diaphragm defect, while constitutive activation of β-catenin on the Wt1 mutant background is sufficient to close the diaphragm defect. Proliferation and apoptosis are affected, but primarily these genetic manipulations appear to lead to a change in normal diaphragm differentiation. Our data suggest a fundamental role for mesothelial signaling in proper formation of the diaphragm.
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http://dx.doi.org/10.1016/j.ydbio.2015.08.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4641796PMC
November 2015

Molecular pathogenesis of congenital diaphragmatic hernia revealed by exome sequencing, developmental data, and bioinformatics.

Proc Natl Acad Sci U S A 2014 Aug 8;111(34):12450-5. Epub 2014 Aug 8.

The Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA 02114; Department of Surgery, Harvard Medical School, Boston, MA 02115; Broad Institute, Cambridge, MA 02141;

Congenital diaphragmatic hernia (CDH) is a common and severe birth defect. Despite its clinical significance, the genetic and developmental pathways underlying this disorder are incompletely understood. In this study, we report a catalog of variants detected by a whole exome sequencing study on 275 individuals with CDH. Predicted pathogenic variants in genes previously identified in either humans or mice with diaphragm defects are enriched in our CDH cohort compared with 120 size-matched random gene sets. This enrichment was absent in control populations. Variants in these critical genes can be found in up to 30.9% of individuals with CDH. In addition, we filtered variants by using genes derived from regions of recurrent copy number variations in CDH, expression profiles of the developing diaphragm, protein interaction networks expanded from the known CDH-causing genes, and prioritized genes with ultrarare and highly disruptive variants, in 11.3% of CDH patients. These strategies have identified several high priority genes and developmental pathways that likely contribute to the CDH phenotype. These data are valuable for comparison of candidate genes generated from whole exome sequencing of other CDH cohorts or multiplex kindreds and provide ideal candidates for further functional studies. Furthermore, we propose that these genes and pathways will enhance our understanding of the heterogeneous molecular etiology of CDH.
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http://dx.doi.org/10.1073/pnas.1412509111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4151769PMC
August 2014

Kif7 is required for the patterning and differentiation of the diaphragm in a model of syndromic congenital diaphragmatic hernia.

Proc Natl Acad Sci U S A 2013 May 6;110(21):E1898-905. Epub 2013 May 6.

Department of Biomedical Genetics, Center for Pediatric Biomedical Research, University of Rochester Medical Center, Rochester, NY 14642, USA.

Congenital diaphragmatic hernia (CDH) is a common birth defect that results in a high degree of neonatal morbidity and mortality, but its pathological mechanisms are largely unknown. Therefore, we performed a forward genetic screen in mice to identify unique genes, models, and mechanisms of abnormal diaphragm development. We identified a mutant allele of kinesin family member 7 (Kif7), the disorganized diaphragm (dd). Embryos homozygous for the dd allele possess communicating diaphragmatic hernias, central tendon patterning defects, and increased cell proliferation with diaphragmatic tissue hyperplasia. Because the patterning of the central tendon is undescribed, we analyzed the expression of genes regulating tendonogenesis in dd/dd mutant embryos, and we determined that retinoic acid (RA) signaling was misregulautted. To further investigate the role of Kif7 and RA signaling in the development of the embryonic diaphragm, we established primary mesenchymal cultures of WT embryonic day 13.5 diaphragmatic cells. We determined that RA signaling is necessary for the expression of tendon markers as well as the expression of other CDH-associated genes. Knockdown of Kif7, and retinoic acid receptors alpha (Rara), beta (Rarb), and gamma (Rarg) indicated that RA signaling is dependent on these genes to promote tendonogenesis within the embryonic diaphragm. Taken together, our results provide evidence for a model in which inhibition of RA receptor signaling promotes CDH pathogenesis through a complex gene network.
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http://dx.doi.org/10.1073/pnas.1222797110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3666741PMC
May 2013

Congenital diaphragmatic hernia candidate genes derived from embryonic transcriptomes.

Proc Natl Acad Sci U S A 2012 Feb 6;109(8):2978-83. Epub 2012 Feb 6.

Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA 02114, USA.

Congenital diaphragmatic hernia (CDH) is a common (1 in 3,000 live births) major congenital malformation that results in significant morbidity and mortality. The discovery of CDH loci using standard genetic approaches has been hindered by its genetic heterogeneity. We hypothesized that gene expression profiling of developing embryonic diaphragms would help identify genes likely to be associated with diaphragm defects. We generated a time series of whole-transcriptome expression profiles from laser captured embryonic mouse diaphragms at embryonic day (E)11.5 and E12.5 when experimental perturbations lead to CDH phenotypes, and E16.5 when the diaphragm is fully formed. Gene sets defining biologically relevant pathways and temporal expression trends were identified by using a series of bioinformatic algorithms. These developmental sets were then compared with a manually curated list of genes previously shown to cause diaphragm defects in humans and in mouse models. Our integrative filtering strategy identified 27 candidates for CDH. We examined the diaphragms of knockout mice for one of the candidate genes, pre-B-cell leukemia transcription factor 1 (Pbx1), and identified a range of previously undetected diaphragmatic defects. Our study demonstrates the utility of genetic characterization of normal development as an integral part of a disease gene identification and prioritization strategy for CDH, an approach that can be extended to other diseases and developmental anomalies.
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http://dx.doi.org/10.1073/pnas.1121621109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3286948PMC
February 2012

Congenital diaphragmatic defects: proposal for a new classification based on observations in 234 patients.

Pediatr Dev Pathol 2012 Jul-Aug;15(4):265-74. Epub 2012 Mar 7.

Center for Pediatric Biomedical Research, University of Rochester, Rochester, NY, USA.

Congenital diaphragmatic defects (CDDs) are a common group of birth defects, yet we presently know little about their pathogenesis. No systematic study documenting the detailed morphology of CDD has been performed, and current classification schemata of diaphragm phenotypes incompletely capture the location and extent of diaphragmatic involvement. To define the range of CDD anatomy, diaphragmatic pathology was reviewed from an examination of 181 autopsy records of children with CDDs at Children's Hospital Boston between 1927 and 2006. Defects were classified according to several parameters, including type (communicating versus noncommunicating) and location (anterior, posterior, etc.). The information permitted development of a phenotyping worksheet for prospective use on patients undergoing diaphragmatic repair at Children's Hospital Boston or MassGeneral Hospital for Children. Fifty-three patients who died between 1990 and 2006 had a total of 63 defects. Thirty-nine had a "classic" CDD phenotype (64% posterolateral, 18% hemidiaphragmatic aplasia, and 18% anterior). The remaining 19 defects, not fitting classical descriptions, were located in the posteromedial, anterolateral, or lateral regions of the diaphragm. Prospective data collected during surgical repair revealed posterolateral defects in 34 of 41 cases that demonstrated wide phenotypic variability in size, location, shape, type, and extent of organ displacement. Congenital diaphragmatic defects display significant phenotypic variation. Because rigorous anatomic evaluation and documentation are important steps towards elucidating the developmental biology of these disorders, we suggest establishment of a new and more precise classification using the model presented herein.
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http://dx.doi.org/10.2350/11-05-1041-OA.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3761363PMC
November 2012

The naive airway hyperresponsiveness of the A/J mouse is Kit-mediated.

Proc Natl Acad Sci U S A 2011 Aug 18;108(31):12787-92. Epub 2011 Jul 18.

Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.

There is a wide variation among humans and mice in airway hyperresponsiveness (AHR) in the absence of allergen sensitization, i.e., naïve AHR. Because mast cell (MC) activation is thought to mediate AHR in atopic asthmatic subjects, we asked whether MCs mediate naïve AHR in A/J mice. We generated an A/J congenic strain lacking c-Kit by introgression of the Wv mutation, which resulted in the elimination of MCs and the abrogation of naïve AHR. Imatinib, which disrupts Kit signaling, also abrogated AHR in A/J mice. Remarkably, introduction of the Vga9 Mitf mutation into the A/J background resulted in the ablation of MCs but did not ameliorate AHR. These results indicate that c-Kit is required for development of AHR in an MC-independent fashion.
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http://dx.doi.org/10.1073/pnas.1106582108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3150901PMC
August 2011

Characterization of the chromosome 1q41q42.12 region, and the candidate gene DISP1, in patients with CDH.

Am J Med Genet A 2010 Oct;152A(10):2493-504

Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.

Cytogenetic and molecular cytogenetic studies demonstrate association between congenital diaphragmatic hernia (CDH) and chromosome 1q41q42 deletions. In this study, we screened a large CDH cohort (N=179) for microdeletions in this interval by the multiplex ligation-dependent probe amplification (MLPA) technique, and also sequenced two candidate genes located therein, dispatched 1 (DISP1) and homo sapiens H2.0-like homeobox (HLX). MLPA analysis verified deletions of this region in two cases, an unreported patient with a 46,XY,del(1)(q41q42.13) karyotype and a previously reported patient with a Fryns syndrome phenotype [Kantarci et al., 2006]. HLX sequencing showed a novel but maternally inherited single nucleotide variant (c.27C>G) in a patient with isolated CDH, while DISP1 sequencing revealed a mosaic de novo heterozygous substitution (c.4412C>G; p.Ala1471Gly) in a male with a left-sided Bochdalek hernia plus multiple other anomalies. Pyrosequencing demonstrated the mutant allele was present in 43%, 12%, and 4.5% of the patient's lymphoblastoid, peripheral blood lymphocytes, and saliva cells, respectively. We examined Disp1 expression at day E11.5 of mouse diaphragm formation and confirmed its presence in the pleuroperitoneal fold, as well as the nearby lung which also expresses Sonic hedgehog (Shh). Our report describes the first de novo DISP1 point mutation in a patient with complex CDH. Combining this finding with Disp1 embryonic mouse diaphragm and lung tissue expression, as well as previously reported human chromosome 1q41q42 aberrations in patients with CDH, suggests that DISP1 may warrant further consideration as a CDH candidate gene.
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http://dx.doi.org/10.1002/ajmg.a.33618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3797530PMC
October 2010

Fog2 is critical for cardiac function and maintenance of coronary vasculature in the adult mouse heart.

J Clin Invest 2009 Jun;119(6):1462-76

Department of Cardiology, Children's Hospital Boston and Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.

Aberrant transcriptional regulation contributes to the pathogenesis of both congenital and adult forms of heart disease. While the transcriptional regulator friend of Gata 2 (FOG2) is known to be essential for heart morphogenesis and coronary development, its tissue-specific function has not been previously investigated. Additionally, little is known about the role of FOG2 in the adult heart. Here we used spatiotemporally regulated inactivation of Fog2 to delineate its function in both the embryonic and adult mouse heart. Early cardiomyocyte- restricted loss of Fog2 recapitulated the cardiac and coronary defects of the Fog2 germline murine knockouts. Later cardiomyocyte-restricted loss of Fog2 (Fog2MC) did not result in defects in cardiac structure or coronary vessel formation. However, Fog2MC adult mice had severely depressed ventricular function and died at 8-14 weeks. Fog2MC adult hearts displayed a paucity of coronary vessels, associated with myocardial hypoxia, increased cardiomyocyte apoptosis, and cardiac fibrosis. Induced inactivation of Fog2 in the adult mouse heart resulted in similar phenotypes, as did ablation of the FOG2 interaction with the transcription factor GATA4. Loss of the FOG2 or FOG2-GATA4 interaction altered the expression of a panel of angiogenesis-related genes. Collectively, our data indicate that FOG2 regulates adult heart function and coronary angiogenesis.
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http://dx.doi.org/10.1172/JCI38723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2689123PMC
June 2009

Timing of delivery and survival rates for infants with prenatal diagnoses of congenital diaphragmatic hernia.

Pediatrics 2009 Feb;123(2):494-502

Department of Pediatrics, Division of Neonatology,University of Rochester, Rochester, New York, USA.

Objectives: The goal of the study was to test the hypothesis that infants with known congenital diaphragmatic hernias born at early term gestation (37-38 weeks) rather than later (39-41 weeks) had greater survival rates and less extracorporeal membrane oxygenation use. Primary outcomes were survival to hospital discharge or transfer and extracorporeal membrane oxygenation use. METHODS; A retrospective cohort study of term infants with prenatal diagnoses of congenital diaphragmatic hernia was performed with the Congenital Diaphragmatic Hernia Study Group Registry of patients with congenital diaphragmatic hernias who were treated between January 1995 and December 2006.

Results: Among 628 term infants at 37 to 41 weeks of gestation who had prenatal diagnoses of congenital diaphragmatic hernia and were free of major associated anomalies, early term birth (37 vs 39-41 weeks) and greater birth weight were associated independently with survival, whereas black race was related inversely to survival. Infants born at early term with birth weights at or above the group mean (3.1 kg) had the greatest survival rate (80%). Among infants born through elective cesarean delivery, infants born at 37 to 38 weeks of gestation, compared with 39 to 41 weeks, had less use of extracorporeal membrane oxygenation (22.0% vs 35.5%) and a trend toward a greater survival rate (75.0% vs 65.8%).

Conclusions: The timing of delivery is an independent, potentially important factor in the consideration of elective delivery for infants diagnosed prenatally as having congenital diaphragmatic hernias. Among fetuses with prenatally diagnosed congenital diaphragmatic hernias and without major associated anomalies, early term delivery may confer advantage.
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http://dx.doi.org/10.1542/peds.2008-0528DOI Listing
February 2009

Disruption of striated preferentially expressed gene locus leads to dilated cardiomyopathy in mice.

Circulation 2009 Jan 31;119(2):261-8. Epub 2008 Dec 31.

Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02115, USA.

Background: The striated preferentially expressed gene (Speg) generates 4 different isoforms through alternative promoter use and tissue-specific splicing. Depending on the cell type, Speg isoforms may serve as markers of striated or smooth muscle differentiation.

Methods And Results: To elucidate function of Speg gene isoforms, we disrupted the Speg gene locus in mice by replacing common exons 8, 9, and 10 with a lacZ gene. beta-Galactosidase activity was detected in cardiomyocytes of the developing heart starting at day 11.5 days post coitum (dpc). beta-Galactosidase activity in other cell types, including vascular smooth muscle cells, did not begin until 18.5 dpc. In the developing heart, protein expression of only Spegalpha and Spegbeta isoforms was present in cardiomyocytes. Homozygous Speg mutant hearts began to enlarge by 16.5 dpc, and by 18.5 dpc, they demonstrated dilation of right and left atria and ventricles. These cardiac abnormalities in the absence of Speg were associated with a cellular hypertrophic response, myofibril degeneration, and a marked decrease in cardiac function. Moreover, Speg mutant mice exhibited significant neonatal mortality, with increased death occurring by 2 days after birth.

Conclusions: These findings demonstrate that mutation of the Speg locus leads to cardiac dysfunction and a phenotype consistent with a dilated cardiomyopathy.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.108.799536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2630246PMC
January 2009

Congenital diaphragmatic hernia and pulmonary hypoplasia: new insights from developmental biology and genetics.

Am J Med Genet C Semin Med Genet 2007 May;145C(2):105-8

Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.

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http://dx.doi.org/10.1002/ajmg.c.30133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2891760PMC
May 2007

Development of the diaphragm and genetic mouse models of diaphragmatic defects.

Am J Med Genet C Semin Med Genet 2007 May;145C(2):109-16

Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.

Improving our understanding of diaphragmatic development is essential to making progress in defining the pathogenesis and genetic etiologies of congenital diaphragmatic defects in humans. As mouse genetic technology has given us new tools to manipulate and observe development, a number of mouse models have recently emerged that provide valuable insight to this field. In this article, we review our current understanding of diaphragmatic embryogenesis including the origin of diaphragmatic tissue. We use rodent models to review the muscularization of the diaphragm and review selected genetic models of abnormal muscularization. We also review models of posterior diaphragmatic defects and discuss evidence for the pleuroperitoneal fold (PPF) tissue contributing to the diaphragm. Finally, we discuss models of anterior and central hernias. It may be simplistic to subdivide this review based on anatomic regions of the diaphragm, as evidence is emerging that defects in different regions of the diaphragm in humans and in mice may be etiologically related. However, at this time we do not have enough knowledge to make more mechanistic or genetic classifications though with time, genetic progress in the field of diaphragm development will allow us to do this.
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http://dx.doi.org/10.1002/ajmg.c.30128DOI Listing
May 2007

Gata4 is necessary for normal pulmonary lobar development.

Am J Respir Cell Mol Biol 2007 Apr 1;36(4):391-7. Epub 2006 Dec 1.

Division of Genetics, Brigham and Women's Hospital, Harvard Medical School New Research Building 458, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.

Mutations of Fog2 in mice result in a phenotype that includes pulmonary lobar defects. To determine whether formation of the accessory lobe bronchus is mediated by a Gata family cofactor, we evaluated embryonic lungs from mice carrying missense mutations that cause loss of FOG-GATA protein interaction. Lungs from embryos carrying a missense mutation in Gata6 were structurally normal, while lungs from embryos carrying mutations of either Gata4 or of both Gata4 and Gata6 had a structural phenotype that matched the Fog2 mutant phenotype. Expression analysis showed that Gata4 and Fog2 are expressed in the ventral and medial pulmonary mesenchyme during secondary budding. Although Gata4 has not previously been suspected as playing a role in lung development, we have found that a Fog2-Gata4 interaction is critical for the development of normal pulmonary lobar structure, and this phenotype is not influenced by the additional loss of Gata6 interaction. Fog2 and Gata4 in the early pulmonary mesenchyme participate in patterning the secondary bronchus of the accessory lobe.
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http://dx.doi.org/10.1165/rcmb.2006-0211RCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1899327PMC
April 2007

Fog2 is required for normal diaphragm and lung development in mice and humans.

PLoS Genet 2005 Jul 17;1(1):58-65. Epub 2005 Jun 17.

Division of Emergency Medicine, Department of Medicine, Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

Congenital diaphragmatic hernia and other congenital diaphragmatic defects are associated with significant mortality and morbidity in neonates; however, the molecular basis of these developmental anomalies is unknown. In an analysis of E18.5 embryos derived from mice treated with N-ethyl-N-nitrosourea, we identified a mutation that causes pulmonary hypoplasia and abnormal diaphragmatic development. Fog2 (Zfpm2) maps within the recombinant interval carrying the N-ethyl-N-nitrosourea-induced mutation, and DNA sequencing of Fog2 identified a mutation in a splice donor site that generates an abnormal transcript encoding a truncated protein. Human autopsy cases with diaphragmatic defect and pulmonary hypoplasia were evaluated for mutations in FOG2. Sequence analysis revealed a de novo mutation resulting in a premature stop codon in a child who died on the first day of life secondary to severe bilateral pulmonary hypoplasia and an abnormally muscularized diaphragm. Using a phenotype-driven approach, we have established that Fog2 is required for normal diaphragm and lung development, a role that has not been previously appreciated. FOG2 is the first gene implicated in the pathogenesis of nonsyndromic human congenital diaphragmatic defects, and its necessity for pulmonary development validates the hypothesis that neonates with congenital diaphragmatic hernia may also have primary pulmonary developmental abnormalities.
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http://dx.doi.org/10.1371/journal.pgen.0010010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1183529PMC
July 2005

Infants with Bochdalek diaphragmatic hernia: sibling precurrence and monozygotic twin discordance in a hospital-based malformation surveillance program.

Am J Med Genet A 2005 Oct;138A(2):81-8

Genetics and Teratology, MassGeneral Hospital for Children, Boston, Massachusetts, USA.

Congenital diaphragmatic hernia (CDH) is a common and often devastating birth defect. In order to learn more about possible genetic causes, we reviewed and classified 203 cases of the Bochdalek hernia type identified through the Brigham and Women's Hospital (BWH) Active Malformation Surveillance Program over a 28-year period. Phenotypically, 55% of the cases had isolated CDH, and 45% had complex CDH defined as CDH in association with additional major malformations or as part of a syndrome. When classified according to likely etiology, 17% had a Recognized Genetic etiology for their CDH, while the remaining 83% had No Apparent Genetic etiology. Detailed analysis using this largest cohort of consecutively collected cases of CDH showed low precurrence among siblings. Additionally, there was no concordance for CDH among five monozygotic twin pairs. These findings, in conjunction with previous reports of de novo dominant mutations in patients with CDH, suggest that new mutations may be an important mechanism responsible for CDH. The twin data also raise the possibility that epigenetic abnormalities contribute to the development of CDH.
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http://dx.doi.org/10.1002/ajmg.a.30904DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2891716PMC
October 2005

Interacting genetic loci cause airway hyperresponsiveness.

Physiol Genomics 2005 Mar 18;21(1):105-11. Epub 2005 Jan 18.

Division of Genetics, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

Airway hyperresponsiveness (AHR) is a key physiological component of asthma, and the genetic basis of this complex trait has remained elusive. We created recombinant congenic mice with increased naive AHR by serially backcrossing A/J mice (which have elevated naive AHR) with C57BL/6J mice and selecting for mice with an elevated naive AHR phenotype. The seventh backcross-generation hyperresponsive mice retained A/J loci in three regions. Quantitative trait linkage (QTL) analysis of 123 unselected N8 progeny demonstrated that the AHR phenotype was not associated with any single locus but was significantly associated with an interaction of loci on chromosomes 2 and 6. These findings were confirmed in an independent analysis of chromosome substitution strain mice. The identification of genomic regions containing loci causally associated with AHR and the demonstration that this trait requires their interaction have important implications for the dissection of the genetic etiology of asthma in humans.
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http://dx.doi.org/10.1152/physiolgenomics.00267.2004DOI Listing
March 2005