Supravalvular aortic stenosis and total occlusion of the brachiocephalic trunk

In a 4-year-old girl supravalvular aortic stenosis was diagnosed by echocardiography. Her younger brother was operated on for the same heart disease one year before.     

Supravalvular aortic stenosis. Autosomal dominant form of congenital cardiopathy

We describe a family in which two generations are affected: two brothers and one of their maternal uncles. One of their two half-sisters (same mother) is also suspected of having the same cardiopathy. This observation confirms the autosomal dominant transmission of the disease and shows its variable expressivity in the family under study.     

The molecular basis of retinoid absorption: a genetic dissection

The intestine and other tissues are able to synthesize retinyl esters in an acyl-CoA-dependent manner involving an acyl-CoA:retinol acyltransferase (ARAT). However, the molecular identity of this ARAT has not been established. Recent studies of lecithin:retinol acyltransferase (LRAT)-deficient mice indicate that LRAT is responsible for the preponderance of retinyl ester synthesis in the body, aside from in the intestine and adipose tissue. Our present studies, employing a number of mutant mouse models, identify diacylglycerol acyltransferase 1 (DGAT1) as an important intestinal ARAT in vivo. The contribution that DGAT1 makes to intestinal retinyl ester synthesis becomes greater when a large pharmacologic dose of retinol is administered by gavage to mice. Moreover, when large retinol doses are administered another intestinal enzyme(s) with ARAT activity becomes apparent. Surprisingly, although DGAT1 is expressed in adipose tissue, DGAT1 does not catalyze retinyl ester synthesis in adipose tissue in vivo. Our data also establish that cellular retinol-binding protein, type II (CRBPII), which is expressed solely in the adult intestine, in vivo channels retinol to LRAT for retinyl ester synthesis. Contrary to what has been proposed in the literature based on in vitro studies, CRBPII does not directly prevent retinol from being acted upon by DGAT1 or other intestinal ARATs in vivo.     

Quantitative genetic dissection of complex traits in a QTL-mapping pedigree

This paper summarizes and modifies quantitative genetic analyses on a pedigree used to map genetic factors (i.e., QTLs) underlying a complex trait. The total genetic variance can be exactly estimated based on the F₂ family derived from two homozygous parents for alternative alleles at all QTLs of interest. The parents, F₁ hybrids, and two backcrosses are combined to each parent, and the total number of QTLs and the number of dominant QTLs are estimated under the assumptions of gene association with the two parents, equal gene effect, no linkage, and no epistasis among QTLs. Further relaxation for each of the assumptions are made in detail. The biometric estimator for the QTL number and action mode averaged over the entire genome could provide some basic and complementary information to QTL mapping designed to detect the effect and location of specific genetic factors.     

The genetic dissection of complex traits in a founder population

We estimated broad heritabilities (H(2)) and narrow heritabilities (h(2)) and conducted genomewide screens, using a novel association-based mapping approach for 20 quantitative trait loci (QTLs) among the Hutterites, a founder population that practices a communal lifestyle. Heritability estimates ranged from.21 for diastolic blood pressure (DBP) to.99 for whole-blood serotonin levels. Using a multipoint method to detect association under a recessive model we found evidence of major QTLs for six traits: low-density lipoprotein (LDL), triglycerides, lipoprotein (a) (Lp[a]), systolic blood pressure (SBP), serum cortisol, and whole-blood serotonin. Second major QTLs for Lp(a) and for cortisol were identified using a single-point method to detect association under a general two-allele model. The heritabilities for these six traits ranged from.37 for triglycerides to.99 for serotonin, and three traits (LDL, SBP, and serotonin) had significant dominance variances (i.e., H(2) > h(2)). Surprisingly, there was little correlation between measures of heritability and the strength of association on a genomewide screen (P>.50), suggesting that heritability estimates per se do not identify phenotypes that are influenced by genes with major effects. The present study demonstrates the feasibility of genomewide association studies for QTL mapping. However, even in this young founder population that has extensive linkage disequilibrium, map densities <5 cM may be required to detect all major QTLs.     

The Anopheles albimanus white gene: molecular characterization of the gene and a spontaneous white gene mutation

We have cloned and characterized the white gene of Anopheles albimanus. Comparison of the deduced amino acid sequence of this white gene with its homologs from six species of Diptera show that the An. albimanus gene is most similar to the white gene of An. gambiae (92% identity). A spontaneous white-eyed mutant An. albimanus was caused by an approximately 10 kb insertion into a CT dinucleotide repeat region of intron 2 of the white locus. The flanks of this insertion are long (at least 400 bp), nearly perfect inverted terminal repeat sequences. This cloned white gene should be useful as a marker for germ line transformation of An. albimanus. This revised version was published online in July 2006 with corrections to the Cover Date.     

The central complex and the genetic dissection of locomotor behaviour

The central complex is one of the most prominent, yet functionally enigmatic structures of the insect brain. Recently, behavioural, neuroanatomical and molecular approaches in Drosophila have joined forces to disclose specific components of higher locomotion control in larvae and adult flies, such as those that guarantee the optimal length and across-body symmetry of strides and an appropriate activity.     

Chemical suppression of a genetic mutation in a zebrafish model of aortic coarctation

Conventional drug discovery approaches require a priori selection of an appropriate molecular target, but it is often not obvious which biological pathways must be targeted to reverse a disease phenotype. Phenotype-based screens offer the potential to identify pathways and potential therapies that influence disease processes. The zebrafish mutation gridlock (grl, affecting the gene hey2) disrupts aortic blood flow in a region and physiological manner akin to aortic coarctation in humans. Here we use a whole-organism, phenotype-based, small-molecule screen to discover a class of compounds that suppress the coarctation phenotype and permit survival to adulthood. These compounds function during the specification and migration of angioblasts. They act to upregulate expression of vascular endothelial growth factor (VEGF), and the activation of the VEGF pathway is sufficient to suppress the gridlock phenotype. Thus, organism-based screens allow the discovery of small molecules that ameliorate complex dysmorphic syndromes even without targeting the affected gene directly.     

Hybrid thoracic stent graft repair of a complex type B aortic dissection in a patient who presented three weeks after repair of a type a aortic dissection

Long-term management after repair of a type A aortic dissection includes aggressive medical therapy and routine surveillance with serial imaging to ensure thrombosis of the false lumen. Retained patency of the false lumen can lead to either the development of a false lumen aneurysm with a subsequent rupture or extension of dissection. Typically such events occur late, usually months after repair, and are treated with either a conventional one-stage open thoracoabdominal repair or a two-stage "elephant trunk" procedure. However, most patients who undergo such procedures experience major complications and the procedure-related mortality rate is high. We present a unique case of a 61-year-old woman who presented with a ruptured type B aortic dissection 3 weeks after repair of a type A aortic dissection. She underwent an emergent thoracotomy and primary repair of the ruptured aorta followed by concomitant arch debranching and thoracic stent graft placement. Simultaneous surgical debranching with a median sternotomy and endovascular repair with stent grafts is an attractive hybrid approach in patients who present with an acute rupture of a false lumen aneurysm soon after initial repair of an aortic dissection, a situation in which a conventional repair is not feasible. This report emphasizes that hybrid thoracic stent graft repair should be considered for such high-risk patients in the near future as it offers them relatively lower morbidity and mortality compared with what is seen with conventional repairs.     

Connection between elastin haploinsufficiency and increased cell proliferation in patients with supravalvular aortic stenosis and Williams-Beuren syndrome

To elucidate the pathomechanism leading to obstructive vascular disease in patients with elastin deficiency, we compared both elastogenesis and proliferation rate of cultured aortic smooth-muscle cells (SMCs) and skin fibroblasts from five healthy control subjects, four patients with isolated supravalvular aortic stenosis (SVAS), and five patients with Williams-Beuren syndrome (WBS). Mutations were determined in each patient with SVAS and in each patient with WBS. Three mutations found in patients with SVAS were shown to result in null alleles. RNA blot hybridization, immunostaining, and metabolic labeling experiments demonstrated that SVAS cells and WBS cells have reduced elastin mRNA levels and that they consequently deposit low amounts of insoluble elastin. Although SVAS cells laid down approximately 50% of the elastin made by normal cells, WBS cells deposited only 15% of the elastin made by normal cells. The observed difference in elastin-gene expression was not caused by a difference in the stability of elastin mRNA in SVAS cells compared with WBS cells, but it did indicate that gene-interaction effects may contribute to the complex phenotype observed in patients with WBS. Abnormally low levels of elastin deposition in SVAS cells and in WBS cells were found to coincide with an increase in proliferation rate, which could be reversed by addition of exogenous insoluble elastin. We conclude that insoluble elastin is an important regulator of cellular proliferation. Thus, the reduced net deposition of insoluble elastin in arterial walls of patients with either SVAS or WBS leads to the increased proliferation of arterial SMCs. This results in the formation of multilayer thickening of the tunica media of large arteries and, consequently, in the development of hyperplastic intimal lesions leading to segmental arterial occlusion.     

Poliovirus and its cellular receptor: a molecular genetic dissection of a virus/receptor affinity interaction

The ability of a virus to attach to a susceptible host cell is of utmost importance for the initiation of viral life cycle. Cell surface proteins called viral receptors mediate the initial steps of virus attachment and uptake. Poliovirus (PV) is one of the most studied animal viruses and its interaction with its cellular receptor, the human poliovirus receptor (hPVR) has been well characterized. This review will present our current understanding of the PV/hPVR interaction at the genetic and biochemical level. In addition, we will also discuss the implications of the PV/hPVR interaction on PV tissue tropism and the evolution of the three PV serotypes.     

A Gly1127Ser mutation in an EGF-like domain of the fibrillin-1 gene is a risk factor for ascending aortic aneurysm and dissection.

Ascending aortic disease, ranging from mild aortic root enlargement to aneurysm and/or dissection, has been identified in 10 individuals of a kindred, none of whom had classical Marfan syndrome (MFS). Single-strand conformation analysis of the entire fibrillin-1 (FBN1) cDNA of an affected family member revealed a G-to-A transition at nucleotide 3379, predicting a Gly1127Ser substitution. The glycine in this position is highly conserved in EGF-like domains of FBN1 and other proteins. This mutation was present in 9 of 10 affected family members and in 1 young unaffected member but was not found in other unaffected members, in 168 chromosomes from normal controls, and in 188 chromosomes from other individuals with MFS or related phenotypes. FBN1 intragenic marker haplotypes ruled out the possibility that the other allele played a significant role in modulating the phenotype in this family. Pulse-chase studies revealed normal fibrillin synthesis but reduced fibrillin deposition into the extracellular matrix in cultured fibroblasts from a Gly1127Ser carrier. We postulate that the Gly1127Ser FBN1 mutation is responsible for reduced matrix deposition. We suggest that mutations such as this one may disrupt EGF-like domain folding less drastically than do substitutions of cysteine or of other amino acids important for calcium-binding that cause classical MFS. The Gly1127Ser mutation, therefore, produces a mild form of autosomal dominantly inherited weakness of elastic tissue, which predisposes to ascending aortic aneurysm and dissection later in life.