Calcification of the aortic valve is the third leading cause of heart disease in adults. The incidence increases with age, and it is often associated with a bicuspid aortic valve present in 1-2% of ...the population. Despite the frequency, neither the mechanisms of valve calcification nor the developmental origin of a two, rather than three, leaflet aortic valve is known. Here, we show that mutations in the signalling and transcriptional regulator NOTCH1 cause a spectrum of developmental aortic valve anomalies and severe valve calcification in non-syndromic autosomal-dominant human pedigrees. Consistent with the valve calcification phenotype, Notch1 transcripts were most abundant in the developing aortic valve of mice, and Notch1 repressed the activity of Runx2, a central transcriptional regulator of osteoblast cell fate. The hairy-related family of transcriptional repressors (Hrt), which are activated by Notch1 signalling, physically interacted with Runx2 and repressed Runx2 transcriptional activity independent of histone deacetylase activity. These results suggest that NOTCH1 mutations cause an early developmental defect in the aortic valve and a later de-repression of calcium deposition that causes progressive aortic valve disease.
All 4 children had a positive rapid influenza enzyme immunoassay test result from a nasopharyngeal swab sample that was subsequently confirmed as H1N1 by reverse-transcriptase polymerase chain ...reaction performed at the San Diego County Department of Health (Fig. 1A). Two children required extracorporeal membrane oxygenation support with gradual improvement of the ventricular systolic function over a 1-week period (Figs. 1E and 1F), which is typically observed in patients with fulminant myocarditis (2).
Jacobsen syndrome, also called the 11q terminal deletion disorder, is a contiguous gene disorder caused by the deletion of the end of the long arm of chromosome 11. Intellectual skills range from low ...average to severe/profound intellectual disability and usually correlate with deletion size. Comprehensive genotype/phenotype evaluations are limited, and little is known about specific behavioral characteristics associated with 11q terminal deletion disorder.
In this prospective study, 17 patients with 11q terminal deletion disorder underwent cognitive and behavioral assessments. Deletion sizes were determined by array comparative genomic hybridization.
Deletion sizes ranged from 8.7 to 14.5 Mb across the patients. We found that 8 of 17 patients (47%) exhibited behavioral characteristics consistent with an autism spectrum disorder diagnosis. There was no correlation between deletion size and the presence of autism spectrum disorder, implicating at least one predisposing gene in the distal 8.7 Mb of 11q. The findings from three additional patients with autistic features and "atypical" distal 11q deletions led to the identification of an autism "critical region" in distal 11q containing four annotated genes including ARHGAP32 (also known as RICS), a gene encoding rho GTPase activating protein.
Results from this study support early autism spectrum disorder screening for patients with 11q terminal deletion disorder and provide further molecular insights into the pathogenesis of autism spectrum disorder.
Ets1 deletion in some mouse strains causes septal defects and has been implicated in human congenital heart defects in Jacobsen syndrome, in which one copy of the Ets1 gene is missing. Here, we ...demonstrate that loss of Ets1 in mice results in a decrease in neural crest (NC) cells migrating into the proximal outflow tract cushions during early heart development, with subsequent malalignment of the cushions relative to the muscular ventricular septum, resembling double outlet right ventricle (DORV) defects in humans. Consistent with this, we find that cultured cardiac NC cells from Ets1 mutant mice or derived from iPS cells from Jacobsen patients exhibit decreased migration speed and impaired cell-to-cell interactions. Together, our studies demonstrate a critical role for ETS1 for cell migration in cardiac NC cells that are required for proper formation of the proximal outflow tracts. These data provide further insights into the molecular and cellular basis for development of the outflow tracts, and how perturbation of NC cells can lead to DORV.
Correct cardiac development is essential for fetal and adult life. Disruptions in a variety of signaling pathways result in congenital heart defects, including outflow and inflow tract defects. We ...previously found that WNT11 regulates outflow tract development. However, tissue specific requirements for WNT11 in this process remain unknown and whether WNT11 is required for inflow tract development has not been addressed. Here we find that germline Wnt11 null mice also show hypoplasia of the dorsal mesenchymal protrusion (DMP), which is required for atrioventricular septation. Ablation of Wnt11 with myocardial cTnTCre recapitulated outflow tract defects observed in germline Wnt11 null mice, but DMP development was unaffected. In contrast, ablation of Wnt11 with Isl1Cre fully recapitulated both outflow tract and DMP defects of Wnt11 germline nulls. DMP hypoplasia in Wnt11 mutants was associated with reduced proliferation within the DMP, but no evident defects in myocardial differentiation of the DMP. Examination of Pitx2-, Axin2-, or Patched-lacZ reporter mice revealed no alterations in reporter expression, suggesting that WNT11 was required downstream of, or in parallel to, these signaling pathways to regulate DMP formation. These studies revealed a previously unappreciated role for WNT11 for DMP formation and distinct tissue-specific requirements for WNT11 in outflow tract and DMP development.
•WNT11 is required for outflow tract and DMP development.•Outflow tract development requires myocardial WNT11 expression.•DMP development requires expression of WNT11 in Isl1Cre lineages.•DMP hypoplasia in Wnt11 mutants is correlated with reduced proliferation.
Jacobsen syndrome (JBS) is a rare congenital disorder caused by a terminal deletion of the long arm of chromosome 11. A subset of patients exhibit social behavioural problems that meet the diagnostic ...criteria for autism spectrum disorder (ASD); however, the underlying molecular pathogenesis remains poorly understood. PX-RICS is located in the chromosomal region commonly deleted in JBS patients with autistic-like behaviour. Here we report that PX-RICS-deficient mice exhibit ASD-like social behaviours and ASD-related comorbidities. PX-RICS-deficient neurons show reduced surface γ-aminobutyric acid type A receptor (GABAAR) levels and impaired GABAAR-mediated synaptic transmission. PX-RICS, GABARAP and 14-3-3ζ/θ form an adaptor complex that interconnects GABAAR and dynein/dynactin, thereby facilitating GABAAR surface expression. ASD-like behavioural abnormalities in PX-RICS-deficient mice are ameliorated by enhancing inhibitory synaptic transmission with a GABAAR agonist. Our findings demonstrate a critical role of PX-RICS in cognition and suggest a causal link between PX-RICS deletion and ASD-like behaviour in JBS patients.
The aim of this study was to characterize the cardiovascular and musculoskeletal systems of elite volleyball players, including aortic dimensions. Previous studies have shown that the upper limit of ...normal aortic sinus diameter for male and female athletes is 4 and 3.4 cm, respectively.
Cross-sectional analysis.
United States Olympic Volleyball Training Facility and Rady Children's Hospital San Diego.
Seventy (37 male) members of the US national volleyball team.
Athletes underwent evaluation that included medical and family histories, targeted physical examinations specifically focusing on abnormalities present in Marfan syndrome (MFS), and transthoracic echocardiograms. Cardiac chamber and great artery size, valve function, and coronary artery origins were assessed.
Three male athletes (8%) had an aortic sinus diameter ≥4 cm, one of whom also had an ascending aorta >4 cm. Two female athletes (6%) had aortic sinus diameter ≥3.4 cm, and another had an ascending aorta of 3.4 cm. There were no other intracardiac or arterial abnormalities. Individual musculoskeletal characteristics of MFS were common among the athletes but not more frequent or numerous in those with aortic dilation.
The prevalence of aortic root dilation in this population of athletes was higher than what has previously been reported in other similar populations. Further study is needed to determine whether these represent pathological changes or normal variations in tall athletes.
This study adds to the existing knowledge base of athlete's heart, with specific attention to aortic dimensions in elite volleyball players. The data are relevant to similar athletes' medical care and to preparticipation cardiac screening in general.
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