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Identification of the same factor V gene mutation in 47 out of 50 thrombosis-prone families with inherited resistance to activated protein C

Resistance to activated protein C (APC) is the most prevalent inherited cause of venous thrombosis. The APC resistance phenotype is associated with a single point mutation in the factor V gene, changing Arg506 in the APC cleavage site to a Gln. We have investigated 50 Swedish families with inherited APC resistance for this mutation and found it to be present in 47 of them. Perfect cosegregation be

Homozygous APC-resistance combined with inherited type I protein S deficiency in a young boy with severe thrombotic disease

Inherited resistance to activated protein C (APC) is a frequent cause of familial thrombosis. It is associated with a factor V gene point mutation replacing arginine506 in the APC-cleavage site with a glutamine. Thrombotic events are rare during childhood even in patients with homozygous APC-resistance. We now wish to report on a case of severe venous thrombosis, in a 10-year-old boy. He was found

Inherited resistance to activated protein C caused by presence of the FV:Q506 allele as a basis of venous thrombosis

Inherited resistance to activated protein C (APC) was recently discovered as a cause of familial thrombophilia and is now known to be the most common genetic risk factor for venous thrombosis. In a majority of cases, APC resistance is associated with a single point mutation in the factor V gene, which results in substitution of arginine (R) at position 506 by glutamine (Q) (FV:Q506). The mutation

Activated protein C resistance due to a common factor V gene mutation is a major risk factor for venous thrombosis

Inherited resistance to activated protein C (APC) was recently discovered to be a cause of familial thrombophilia and is now known to be the most common genetic risk factor for venous thrombosis. It is caused by a single point mutation in the gene for factor V, which predicts substitution or arginine (R) at position 506 with a glutamine (Q). Accordingly, the activated form of mutated factor V (FVa

Factor V:Q506 mutation and anticardiolipin antibodies in systemic lupus erythematosus

Inherited resistance to activated protein C (APC resistance) is an important risk factor of venous thrombosis. It is caused by a point mutation in the gene coding for coagulation factor V, called FV:Q506. Arterio-venous thrombosis is a common and serious medical problem in patients with systemic lupus erythematosus (SLE). We studied the prevalence of the factor V mutation associated with APC resis

Structural determinants in ApoA-I amyloidogenic variants explain improved cholesterol metabolism despite low HDL levels

Twenty Apolipoprotein A-I (ApoA-I) variants are responsible for a systemic hereditary amyloidosis in which protein fibrils can accumulate in different organs, leading to their failure. Several ApoA-I amyloidogenic mutations are also associated with hypoalphalipoproteinemia, low ApoA-I and high-density lipoprotein (HDL)-cholesterol plasma levels; however, subjects affected by ApoA-I-related amyloid

Plasma stem cell factor levels are associated with risk of cardiovascular disease and death

OBJECTIVE: Stem cell factor (SCF) is a key growth factor for several types of stem and progenitor cells. There is experimental evidence that such cells are of importance for maintaining the integrity of the cardiovascular system. We investigated the association between circulating levels of SCF and risk for development of cardiovascular events and death.METHODS: SCF was analysed by the proximity e

Molecular mechanisms controlling phosphate-induced downregulation of the yeast Pho84 phosphate transporter

In Saccharomyces cerevisiae, phosphate uptake is mainly dependent on the proton-coupled Pho84 permease under phosphate-limited growth conditions. Phosphate addition causes Pho84-mediated activation of the protein kinase A (PKA) pathway as well as rapid internalization and vacuolar breakdown of Pho84. We show that Pho84 undergoes phosphate-induced phosphorylation and subsequent ubiquitination on am

Bridging across length scales : multi-scale ordering of supported lipid bilayers via lipoprotein self-assembly and surface patterning

We show that a two-step process, involving spontaneous self-assembly of lipids and apolipoproteins and surface patterning, produces single, supported lipid bilayers over two discrete and independently adjustable length scales. Specifically, an aqueous phase incubation of DMPC vesicles with purified apolipoprotein A-I results in the reconstitution of high density lipoprotein (rHDL), wherein nanosca

Mapping the structural transition in an amyloidogenic apolipoprotein A-I

The single amino acid mutation G26R in human apolipoprotein A-I (apoA-IIOWA) leads to the formation of beta-secondary structure rich amyloid fibrils in vivo. Here we show that full-length apoA-IIOWA has a decreased lipid-binding capability, an increased amino-terminal sensitivity to protease, and a propensity to form annular protofibrils visible by electron microscopy. The molecular basis for the

Identification, expression, and functional analyses of a thylakoid ATP/ADP carrier from Arabidopsis

In plants the chloroplast thylakoid membrane is the site of light-dependent photosynthetic reactions coupled to ATP synthesis. The ability of the plant cell to build and alter this membrane system is essential for efficient photosynthesis. A nucleotide translocator homologous to the bovine mitochondrial ADP/ATP carrier (AAC) was previously found in spinach thylakoids. Here we have identified and c

Electron paramagnetic resonance spectroscopy of site-directed spin labels reveals the structural heterogeneity in the N-terminal domain of apoA-I in solution

Apolipoprotein A-I (apoA-I) is the major protein constituent of high density lipoprotein (HDL) and plays a central role in phospholipid and cholesterol metabolism. This 243-residue long protein is remarkably flexible and assumes numerous lipid-dependent conformations. Consequently, definitive structural determination of lipid-free apoA-I in solution has been difficult. Using electron paramagnetic

Structure and function of the GTP binding protein Gtr1 and its role in phosphate transport in Saccharomyces cerevisiae

The Pho84 high-affinity phosphate permease is the primary phosphate transporter in the yeast Saccharomyces cerevisiae under phosphate-limiting conditions. The soluble G protein, Gtr1, has previously been suggested to be involved in the derepressible Pho84 phosphate uptake function. This idea was based on a displayed deletion phenotype of Deltagtr1 similar to the Deltapho84 phenotype. As of yet, th

Structural modeling of dual-affinity purified Pho84 phosphate transporter

The phosphate transporter Pho84 of Saccharomyces cerevisiae is predicted to contain 12 transmembrane (TM) regions, divided into two partially duplicated parts of 6 TM segments. The three-dimensional (3D) organization of the Pho84 protein has not yet been determined. However, the 3D crystal structure of the Escherichia coli MFS glycerol-3-phosphate/phosphate antiporter, GlpT, and lactose transporte

Effects of methylphosphonate, a phosphate analogue, on the expression and degradation of the high-affinity phosphate transporter Pho84, in Saccharomyces cerevisiae

In Saccharomyces cerevisiae, the Pho84 high-affinity transport system is the major phosphate transporter activated when the cells experience a limitation in external phosphate. In this study, we have compared the phosphate-responsive mechanism of cells expressing PHO84 with a Deltapho84 strain by use of a phosphate analogue, methylphosphonate, which was judged to be suitable for assessment of phos

Regulation of phosphate acquisition in Saccharomyces cerevisiae

Membrane transport systems active in cellular inorganic phosphate (P(i)) acquisition play a key role in maintaining cellular P(i) homeostasis, independent of whether the cell is a unicellular microorganism or is contained in the tissue of a higher eukaryotic organism. Since unicellular eukaryotes such as yeast interact directly with the nutritious environment, regulation of P(i) transport is maint

Mutagenic and functional analysis of the C-terminus of Saccharomyces cerevisiae Pho84 phosphate transporter

A widely accepted mechanism for selective degradation of plasma membrane proteins is via ubiquitination and/or phosphorylation events. Such a regulated degradation has previously been suggested to rely on the presence of a specific SINNDAKSS sequence within the protein. Modification of a partly conserved SINNDAKSS-like sequence in the C-terminal tail of the Pho84 phosphate transporter, in combinat