Functional analysis of candidate genes in 2q13 deletion syndrome implicates FBLN7 and TMEM87B deficiency in congenital heart defects and FBLN7 in craniofacial malformations.

Recurrent 2q13 deletion syndrome is associated with incompletely penetrant severe cardiac defects and craniofacial anomalies. We used an atypical, overlapping 1.34 Mb 2q13 deletion in a patient with pathogenically similar congenital heart defects (CHD) to narrow the putative critical region for CHD to 474 kb containing six genes. To determine which of these genes is responsible for severe cardiac and craniofacial defects noted in the patients with the deletions, we used zebrafish morpholino knockdown to test the function of each orthologue during zebrafish development. Morpholino-antisense-mediated depletion of fibulin-7B, a zebrafish orthologue of fibulin-7 (FBLN7), resulted in cardiac hypoplasia, deficient craniofacial cartilage deposition and impaired branchial arch development. TMEM87B depletion likewise resulted in cardiac hypoplasia but with preserved branchial arch development. Depletion of both fibulin-7B and TMEM87B resulted in more severe defects of cardiac development, suggesting that their concurrent loss may enhance the risk of a severe cardiac defect. We postulate that heterozygous loss of FBLN7 and TMEM87B account for some of the clinical features, including cardiac defects and craniofacial abnormalities associated with 2q13 deletion syndrome.

3xTg-AD mice exhibit an activated central stress axis during early-stage pathology.

Activation of the hypothalamic-pituitary-adrenal (HPA) axis occurs in response to the organism's innate need for homeostasis. The glucocorticoids (GCs) that are released into the circulation upon acute activation of the HPA axis perform stress-adaptive functions and provide negative feedback to turn off the HPA axis, but can be detrimental when in excess. Long-term activation of the HPA axis (such as with chronic stress) enhances susceptibility to neuronal dysfunction and death, and increases vulnerability to Alzheimer's disease (AD). However, little is known how components of the HPA axis, upstream of GCs, impact vulnerability to AD. This study examined basal gene expression of stress-related molecules in brains of 3xTg-AD mice during early-stage pathology. Basal GC levels and mRNA expression of the glucocorticoid receptor (GR), mineralocorticoid receptor (MR), and corticotropic releasing hormone (CRH) in several stress- and emotionality-related brain regions were measured in 3-4-month-old 3xTg-AD mice. Despite normal GC levels, young 3xTg-AD mice exhibit an activated central HPA axis, with altered mRNA levels of MR and GR in the hippocampus, GR and CRH in the paraventricular nucleus of the hypothalamus, GR and CRH in the central nucleus of the amygdala, and CRH in the bed nucleus of the stria terminalis. This HPA axis activation is present during early-stage neuropathology when 3xTg-AD mice show mild behavioral changes, suggesting an ongoing neuroendocrine regulation that precedes the onset of severe AD-like pathology and behavioral deficits.