The pacemaking activity of specialized tissues in the heart and gut results in lifelong rhythmic contractions. Here we describe a new syndrome characterized by Chronic Atrial and Intestinal Dysrhythmia, termed CAID syndrome, in 16 French Canadians and 1 Swede. We show that a single shared homozygous founder mutation in SGOL1, a component of the cohesin complex, causes CAID syndrome. Cultured dermal fibroblasts from affected individuals showed accelerated cell cycle progression, a higher rate of senescence and enhanced activation of TGF-? signaling. Karyotypes showed the typical railroad appearance of a centromeric cohesion defect. Tissues derived from affected individuals displayed pathological changes in both the enteric nervous system and smooth muscle. Morpholino-induced knockdown of sgol1 in zebrafish recapitulated the abnormalities seen in humans with CAID syndrome. Our findings identify CAID syndrome as a novel generalized dysrhythmia, suggesting a new role for SGOL1 and the cohesin complex in mediating the integrity of human cardiac and gut rhythm.
The genetics of congenital heart disease (CHD) remain incompletely understood. Exome sequencing has been successfully used to identify disease-causing mutations in familial disorders in which candidate gene analyses and linkage mapping have failed.
Heart failure is a major problem in the patient with congenital heart disease. Normally interpreted as a sequela of surgical interventions or abnormal preoperative loading conditions, there is increasing evidence that congenital heart malformations and abnormal ventricular function can have the same underlying genetic cause. With the changing demographic characteristics and increasing complexity of care for patients with congenital heart disease, it can be anticipated that heart failure will be a rapidly growing concern in our field. In this article, we aim to give an overview of recent findings from mouse and human models that highlight shared pathways for the regulation of cardiac development and contractility, and their importance for medical care in the near future.
As a result of technological advances in the field of high-throughput genomics, there has been a remarkable transition in studying the nature of complex genetic disorders. The genetic analysis of prothrombotic risk factors has shifted from candidate gene to genome-wide association studies (GWAS) in adults. GWAS established a framework in which up to 90% of common genetic variation can be analyzed in a single experiment. Given the ubiquity of the GWAS approach in the adult population, it will become essential for clinicians and researchers in the field of pediatrics to interpret results derived from genetic high-throughput studies. Here, we review the current knowledge regarding genetic factors affecting prothrombotic risk in children and adults. Advantages and pitfalls of the GWAS approach are discussed, including the use of intermediate phenotypes, deep resequencing, and the differences between family-based and association studies. Intelligently designed and well-powered studies incorporating stringent phenotype assessment will contribute to decipher the genetic basis of stroke and venous thrombosis in children.
Elevated levels of acute phase proteins (APP) are often found in patients with cardiovascular diseases. In a previous study, we demonstrated the importance of the IL-6-gp130 axis -as a key regulator of inflammatory acute phase signaling in hepatocytes-for the development of atherosclerosis.
The selective serotonin reuptake inhibitor (SSRI) sertraline is widely used as an antidepressant agent during pregnancy and lactation because of its low placental transfer and low level of excretion into breastmilk. Symptoms such as neonatal abstinence syndrome and serotonergic overstimulation have been reported after in utero exposure to SSRIs. These symptoms are self-limiting and usually peak within the first 48 hours after birth. In our case, a preterm infant was exposed to sertraline and its main metabolite desmethylsertraline in utero and via breastmilk. Beyond the first 48 hours after birth, the infant developed increasing clinical signs of serotonergic overstimulation associated with substance intake via breastmilk, until breastfeeding was discontinued on postnatal Day 9. In spite of a low calculated daily substance intake via breastmilk, the serum substance levels of the preterm infant were within the therapeutic range of adults. The serotonergic overstimulation may be explained by the limited metabolic capacity of the infant and the immaturity of the blood-brain barrier.
The distribution of human disease-associated mutations is not random across the human genome. Despite the fact that natural selection continually removes disease-associated mutations, an enrichment of these variants can be observed in regions of low recombination. There are a number of mechanisms by which such a clustering could occur, including genetic perturbations or demographic effects within different populations. Recent genome-wide association studies (GWAS) suggest that single nucleotide polymorphisms (SNPs) associated with complex disease traits are not randomly distributed throughout the genome, but tend to cluster in regions of low recombination.
Related JoVE Video
Journal of Visualized Experiments
What is Visualize?
JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.
How does it work?
We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.
Video X seems to be unrelated to Abstract Y...
In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.