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Developmental Biology Jul 2015Ventricular septal defects (VSDs) are the most commonly occurring congenital heart defect. They are regularly associated with complex syndromes, including DiGeorge...
Ventricular septal defects (VSDs) are the most commonly occurring congenital heart defect. They are regularly associated with complex syndromes, including DiGeorge syndrome and Holt-Oram syndrome, which are characterised by haploinsufficiency for the T-box transcription factors TBX1 and TBX5, respectively. The histone acetyltransferase monocytic leukaemia zinc finger protein, MOZ (MYST3/KAT6A), is required for the expression of the Tbx1 and Tbx5 genes. Homozygous loss of MOZ results in DiGeorge syndrome-like defects including VSD. The Moz gene is expressed in the ectodermal, mesodermal and endodermal aspects of the developing pharyngeal apparatus and heart; however it is unclear in which of these tissues MOZ is required for heart development. The role of MOZ in the activation of Tbx1 would suggest a requirement for MOZ in the mesoderm, because deletion of Tbx1 in the mesoderm causes VSDs. Here, we investigated the tissue-specific requirements for MOZ in the mesoderm. We demonstrate that Mesp1-cre-mediated deletion of Moz results in high penetrance of VSDs and overriding aorta and a significant decrease in MOZ-dependant Tbx1 and Tbx5 expression. Together, our data suggest that the molecular pathogenesis of VSDs in Moz germline mutant mice is due to loss of MOZ-dependant activation of mesodermal Tbx1 and Tbx5 expression.
Topics: Animals; DiGeorge Syndrome; Gene Expression Regulation, Developmental; Heart; Heart Septal Defects, Ventricular; Heart Septum; Histone Acetyltransferases; Mesoderm; Mice; Mice, Inbred C57BL; Mice, Knockout; Organogenesis; T-Box Domain Proteins
PubMed: 25912687
DOI: 10.1016/j.ydbio.2015.04.011 -
Taiwanese Journal of Obstetrics &... Dec 2014Trisomy 9 is a rare chromosomal abnormality usually associated with first-trimester miscarriage; few fetuses survive until the second trimester. We report two new cases...
OBJECTIVE
Trisomy 9 is a rare chromosomal abnormality usually associated with first-trimester miscarriage; few fetuses survive until the second trimester. We report two new cases of complete trisomy 9 that both present unusual phenotypic associations, and we analyze the genetic pathway involved in this chromosomal abnormality.
CASE REPORT
The first fetus investigated showed Dandy-Walker malformation, cleft lip, and cleft palate) at the second trimester scan. Cardiovascular abnormalities were characterized by a right-sided, U-shaped aortic arch associated with a ventricular septal defect (VSD). Symmetrical intrauterine growth restriction and multicystic dysplastic kidney disease were associated findings. The second fetus showed a dysmorphic face, bilateral cleft lip, hypoplastic corpus callosum, and a Dandy-Walker malformation. Postmortem examination revealed cardiovascular abnormalities such as persistent left superior vena cava draining into the coronary sinus, membranous ventricular septal defect, overriding aorta, pulmonary valve with two cusps and three sinuses, and the origin of the left subclavian artery distal to the junction of ductus arteriosus and aortic arch.
CONCLUSION
Complete trisomy 9 may result in a wide spectrum of congenital abnormalities, and the presented case series contributes further details on the phenotype of this rare aneuploidy.
Topics: Abnormalities, Multiple; Abortion, Eugenic; Adult; Cardiovascular Abnormalities; Chromosomes, Human, Pair 9; Cleft Lip; Cleft Palate; Dandy-Walker Syndrome; Female; Humans; Phenotype; Pregnancy; Pregnancy Trimester, Second; Prenatal Diagnosis; Trisomy
PubMed: 25510707
DOI: 10.1016/j.tjog.2014.01.005 -
Taiwanese Journal of Obstetrics &... Jun 2014To report prenatal diagnosis of 22q11.2 deletion syndrome in a pregnancy with congenital heart defects in the fetus.
OBJECTIVE
To report prenatal diagnosis of 22q11.2 deletion syndrome in a pregnancy with congenital heart defects in the fetus.
CASE REPORT
A 26-year-old, primigravid woman was referred for counseling at 24 weeks of gestation because of abnormal ultrasound findings of fetal congenital heart defects. The Level II ultrasound revealed a singleton fetus with heart defects including overriding aorta, small pulmonary artery, and ventricular septal defect. Cordocentesis was performed. The DNA extracted from the cord blood was analyzed by multiplex ligation-dependent amplification (MLPA). The MLPA showed deletion in the DiGeorge syndrome (DGS) critical region of chromosome 22 low copy number repeat (LCR) 22-A∼C. Conventional cytogenetic analysis revealed a normal male karyotype. Repeated amniocentesis and cordocentesis were performed. Whole-genome array comparative genomic hybridization (aCGH) on cord blood was performed. aCGH detected a 3.07-Mb deletion at 22q11.21. Conventional cytogenetic analysis of cultured amniocytes revealed a karyotype 46,XY. Metaphase fluorescence in situ hybridization (FISH) analysis on cultured amniocytes confirmed an interstitial 22q11.2 deletion.
CONCLUSION
Prenatal ultrasound findings of congenital heart defects indicate that the fetuses are at increased risk for chromosome abnormalities. Studies for 22q11.2 deletion syndrome should be considered adjunct to conventional karyotyping. Although FISH has become a standard procedure for diagnosis of 22q11.2 deletion syndrome, MLPA can potentially diagnose a broader spectrum of abnormalities, and aCGH analysis has the advantage of refining the 22q11.2 deletion breakpoints and detecting uncharacterized chromosome rearrangements or genomic imbalances.
Topics: Abnormalities, Multiple; Adult; Chromosome Deletion; Chromosomes, Human, Pair 22; Comparative Genomic Hybridization; DiGeorge Syndrome; Female; Fetal Diseases; Heart Defects, Congenital; Humans; In Situ Hybridization; Karyotype; Male; Multiplex Polymerase Chain Reaction; Pregnancy; Prenatal Diagnosis; Ultrasonography
PubMed: 25017279
DOI: 10.1016/j.tjog.2014.04.021 -
Circulation Research Aug 2014The E3 ubiquitin ligase inducible degrader of the low-density lipoprotein receptor (IDOL) triggers lysosomal degradation of the low-density lipoprotein receptor. The...
RATIONALE
The E3 ubiquitin ligase inducible degrader of the low-density lipoprotein receptor (IDOL) triggers lysosomal degradation of the low-density lipoprotein receptor. The tissue-specific effects of the IDOL pathway on plasma cholesterol and atherosclerosis have not been examined.
OBJECTIVE
Given that the liver is the primary determinant of plasma cholesterol levels, we sought to examine the consequence of effect of chronic liver-specific expression of a dominant-active form of IDOL in mice.
METHODS AND RESULTS
We expressed a degradation-resistant, dominant-active form of IDOL (super IDOL [sIDOL]) in C57Bl/6J mice from the liver-specific albumin promoter (L-sIDOL transgenics). L-sIDOL mice were fed a Western diet for 20 or 30 weeks and then analyzed for plasma lipid levels and atherosclerotic lesion formation. L-sIDOL mice showed dramatic reductions in hepatic low-density lipoprotein receptor protein and increased plasma low-density lipoprotein cholesterol levels on both chow and Western diets. Moreover, L-sIDOL mice developed marked atherosclerotic lesions when fed a Western diet. Lesion formation in L-sIDOL mice was more robust than in apolipoprotein E*3 Leiden mice and did not require the addition of cholate to the diet. Western diet-fed L-sIDOL mice had elevated expression of liver X receptor target genes and proinflammatory genes in their aortas.
CONCLUSIONS
Liver-specific expression of dominant-active IDOL is associated with hypercholesterolemia and a marked elevation in atherosclerotic lesions. Our results show that increased activity of the IDOL pathway in the liver can override other low-density lipoprotein receptor regulatory pathways leading to cardiovascular disease. L-sIDOL mice are a robust, dominantly inherited, diet-inducible model for the study of atherosclerosis.
Topics: Albumins; Animals; Aorta; Aortic Diseases; Apolipoprotein E3; Atherosclerosis; Cholesterol, LDL; Diet, High-Fat; Diet, Western; Disease Models, Animal; Humans; Hypercholesterolemia; Inflammation Mediators; Liver; Liver X Receptors; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Orphan Nuclear Receptors; Plaque, Atherosclerotic; Promoter Regions, Genetic; Receptors, LDL; Time Factors; Ubiquitin-Protein Ligases
PubMed: 24935961
DOI: 10.1161/CIRCRESAHA.115.304440 -
BMJ Case Reports May 2014A 17-year-old male patient presented with cyanosis, repeated squatting since childhood and haemoptysis since the past 1 month. He had central cyanosis with clubbing....
A 17-year-old male patient presented with cyanosis, repeated squatting since childhood and haemoptysis since the past 1 month. He had central cyanosis with clubbing. Cardiovasular examination revealed ejection systolic murmur in the pulmonary area with single S2. ECG showed right ventricular hypertrophy (RVH) with right atrial enlargement and first-degree heart block. Two-dimensional echo showed ventricular septal defect, overriding aorta, RVH, right ventricular enlargement (RVE) and right atrial enlargement with infundibular and valvular pulmonary stenosis and 1.9 cm ostium secondum atrial septal defect. There was no evidence of atrioventricular canal defect. The patient was diagnosed with pentology of Fallots. Follow-up ECG showed complete heart block (CHB) that again reverted to first-degree heart block. A diagnosis of pentology of Fallot with intermittent CHB was made with an awake heart rate of 50/min. This case report shows association of CHB with tetralogy of Fallot.
Topics: Abnormalities, Multiple; Adolescent; Atrioventricular Block; Cyanosis; Diagnosis, Differential; Echocardiography, Doppler, Color; Echocardiography, Three-Dimensional; Electrocardiography; Emergency Service, Hospital; Heart Defects, Congenital; Heart Murmurs; Heart Rate; Heart Septal Defects, Ventricular; Humans; Hypertrophy, Right Ventricular; Male; Monitoring, Physiologic; Prognosis; Radiography, Thoracic; Tetralogy of Fallot; Treatment Refusal; Trilogy of Fallot
PubMed: 24832712
DOI: 10.1136/bcr-2014-204140 -
Acta Radiologica Short Reports Jan 2014Tetralogy of Fallot (TOF) is one of the most common congenital heart malformations comprising a ventricular septal defect, right ventricular outflow tract obstruction,...
Tetralogy of Fallot (TOF) is one of the most common congenital heart malformations comprising a ventricular septal defect, right ventricular outflow tract obstruction, right ventricular hypertrophy, and overriding aorta. A rare variant includes pulmonary atresia and major aortopulmonary collateral arteries. Altered hemodynamics within the functional single-ventricle results in turbulent flow and predisposes to endocardial vegetation formation which may consequently lead to thromboembolic events. We present a rare case of an adult survivor of uncorrected TOF with pulmonary atresia.
PubMed: 24778798
DOI: 10.1177/2047981613515211 -
Acta Veterinaria Scandinavica Mar 2014A 3-week-old female white Bengal Tiger cub (Panthera tigris tigris) presented with acute onset tachypnoea, cyanosis and hypothermia. The cub was severely hypoxaemic with...
A 3-week-old female white Bengal Tiger cub (Panthera tigris tigris) presented with acute onset tachypnoea, cyanosis and hypothermia. The cub was severely hypoxaemic with a mixed acid-base disturbance. Echocardiography revealed severe pulmonic stenosis, right ventricular hypertrophy, high membranous ventricular septal defect and an overriding aorta. Additionally, an atrial septal defect was found on necropsy, resulting in the final diagnosis of Tetralogy of Fallot with an atrial septal defect (a subclass of Pentalogy of Fallot). This report is the first to encompass arterial blood gas analysis, thoracic radiographs, echocardiography and necropsy findings in a white Bengal Tiger cub diagnosed with Tetralogy of Fallot with an atrial septal defect.
Topics: Animals; Animals, Newborn; Blood Gas Analysis; Echocardiography; Fatal Outcome; Female; Heart Septal Defects, Atrial; Radiography; Tetralogy of Fallot; Tigers
PubMed: 24594084
DOI: 10.1186/1751-0147-56-12 -
BMJ Case Reports Jan 2014Tetralogy of Fallot is a cyanotic congenital heart disease characterised by a tetrad of four anomalies including ventricular septal defect, pulmonary stenosis,...
Tetralogy of Fallot is a cyanotic congenital heart disease characterised by a tetrad of four anomalies including ventricular septal defect, pulmonary stenosis, over-riding of aorta and right ventricular hypertrophy with high incidence of infant and early childhood mortality with middle age survival less than 5%. Most cases require treatment in infancy and are symptomatic early on. Rare cases of survival to middle age have been reported especially after the fourth decade. We report an unoperated case of tetralogy of Fallot diagnosed at the age of 67 which is one of the longest time periods of diagnosis of a life-threatening congenital heart disease. Despite tetralogy and having right ventricular dysfunction manifested in the form of congestive symptoms, this patient presented with systemic hypertension along with cyanosis and clubbing which is considered to be a relatively rare presentation in this syndrome. The patient wished to be managed conservatively.
Topics: Aged; Angiography; Blood Pressure; Diagnosis, Differential; Echocardiography; Humans; Hypertension; Male; Tetralogy of Fallot; Tomography, X-Ray Computed; Ventricular Dysfunction, Right; Ventricular Function, Right
PubMed: 24473430
DOI: 10.1136/bcr-2013-202647 -
Cilia Dec 2012The primary cilium is a microtubule-based, plasma membrane-ensheathed protrusion projecting from the basal bodies of almost all cell types in the mammalian body. In the...
BACKGROUND
The primary cilium is a microtubule-based, plasma membrane-ensheathed protrusion projecting from the basal bodies of almost all cell types in the mammalian body. In the past several years a plethora of papers has indicated a crucial role for primary cilia in the development of a wide variety of organs. We have investigated heart development in cobblestone, a hypomorphic allele of the gene encoding the intraflagellar transport protein Ift88, and uncovered a number of the most common congenital heart defects seen in newborn humans.
METHODS
We generated serial sections of mutant cobblestone and wild type embryos in the region encompassing the heart and the cardiac outflow tract. The sections were further processed to generate three-dimensional reconstructions of these structures, and immunofluorescence confocal microscopy, transmission electron microscopy, and in situ hybridization were used to examine signal transduction pathways in the relevant areas. Whole mount in situ hybridization was also employed for certain developmental markers.
RESULTS
In addition to an enlarged pericardium and failure of both ventricular and atrial septum formation, the cobblestone mutants displayed manifold defects in outflow tract formation, including persistent truncus arteriosus, an overriding aorta, and abnormal transformation of the aortic arches. To discern the basis of these anomalies we examined both the maintenance of primary cilia as well as endogenous and migratory embryonic cell populations that contribute to the outflow tract and atrioventricular septa. The colonization of the embryonic heart by cardiac neural crest occurred normally in the cobblestone mutant, as did the expression of Sonic hedgehog. However, with the loss of primary cilia in the mutant hearts, there was a loss of both downstream Sonic hedgehog signaling and of Islet 1 expression in the second heart field, a derivative of the pharyngeal mesoderm. In addition, defects were recorded in development of atrial laterality and ventricular myocardiogenesis. Finally, we observed a reduction in expression of Bmp4 in the outflow tract, and complete loss of expression of both Bmp2 and Bmp4 in the atrioventricular endocardial cushions. Loss of BMP2/4 signaling may result in the observed proliferative defect in the endocardial cushions, which give rise to both the atrioventricular septa as well as to the septation of the outflow tract.
CONCLUSIONS
Taken together, our results potentially identify a novel link between Sonic hedgehog signaling at the primary cilium and BMP-dependent effects upon cardiogenesis. Our data further point to a potential linkage of atrioventricular septal defects, the most common congenital heart defects, to genes of the transport machinery or basal body of the cilia.
PubMed: 23351706
DOI: 10.1186/2046-2530-1-23 -
Atherosclerosis Mar 2013In addition to its effects on cholesterol levels, apoE3 has lipid-independent effects that contribute to cardiovascular protection; one of these effects is the ability...
OBJECTIVE
In addition to its effects on cholesterol levels, apoE3 has lipid-independent effects that contribute to cardiovascular protection; one of these effects is the ability to inhibit cell cycling in VSMCs. The goal of this study was to identify and characterize cell cycle-regulatory mechanisms responsible for the anti-mitogenic effect of apoE.
METHODS AND RESULTS
Primary VSMCs were stimulated with serum in the absence or presence of apoE3. apoE3 upregulated expression of the cdk inhibitor, p27(kip1), in primary VSMCs, and this effect required Cox2 and activation of PGI(2)-IP signaling. The microRNA family, miR221/222 has recently been identified as a post-translational regulator of p27, and apoE3 inhibited miR221/222 expression in a Cox2- and PGI(2)/IP-dependent manner. Moreover, reconstituted miR222 expression was sufficient to override the effects of apoE on p27 expression and S phase entry. The ability to repress expression of miR221/222 is shared by apoE3-containing HDL but is absent from apoA-1, LDL and apoE-depleted HDL. All three apoE isoforms regulate miR221/222, and the effect is independent of the C-terminal lipid-binding domain. miR221/222 levels are increased in the aortae of apoE3-null mice and reduced when apoE3 expression is reconstituted by adeno-associated virus infection. Thus, regulation of miR221/222 by apoE3 occurs in vivo as well as in vitro.
CONCLUSIONS
ApoE inhibits VSMC proliferation by regulating p27 through miR221/222. Control of cell cycle-regulatory microRNAs adds a new dimension to the spectrum of cardiovascular protective effects afforded by apoE and apoE-HDL.
Topics: Animals; Apolipoprotein E3; Cell Cycle Checkpoints; Cells, Cultured; Cyclin-Dependent Kinase Inhibitor p27; Cyclooxygenase 2; Male; Mice; MicroRNAs; Muscle, Smooth, Vascular
PubMed: 23294923
DOI: 10.1016/j.atherosclerosis.2012.12.003