Arg77His and Trp187Arg are the Most Common Mutations Causing FXIII Deficiency in Iran

The aim of this study was to review the literature for the genetic mutations causing inherited factoe XIII (FXIII) deficiency in patients from Iran, where the consanguineous marriage is common. Data were collected from 30 patients (18 males and 12 females) with FXIII deficiency, from 26 unrelated families. Data of mutation analysis were obtained from 2 previously published studies. A total of 7 mutations consisting of 5 new mutations and 2 previously reported mutations were identified. Of the 5 novel missense mutations, 2, Arg77His and Trp187Arg, were the most common in Iranian FXIII-deficient patients. In regions like Iran with high rate of consanguineous marriages, the identification of common mutations in disease like severe FXIII deficiency increases the capacity to make a precise screening and diagnosis assays to screen and diagnose families with high risk of FXIII deficiency for prevention of clinical complications in them

New results on precautionary saving under two risks

This paper identifies a new sufficient condition for a prudent agent to have positive precautionary saving in the presence of labor income and interest rate risks of any size. We also provide three economic interpretations for this condition focusing respectively on the marginal effect of saving on total income variance, on the sign of the covariance between total income and the return of saving, and on the effect of saving on the utility premium

Some conditions for the equivalence between risk aversion, prudence and temperance

We study relationships between different aspects of risk preferences. We show that, under the assumptions of non-satiation and bounded marginal utility, some additional conditions on the asymptotic behaviour of the indices of relative prudence and relative temperance ensure that risk aversion, prudence and temperance are equivalent. Similar conclusions are derived for higher-degree risk aversion. Moreover, some links between indices of relative risk aversion of different degrees are derived. The implications of these results for several economic problems which involve risk changes are discussed

On the relationship between comparisons of risk aversion of different orders

We show conditions which ensure that the comparisons between risk aversion of different orders of two decision makers are related. In particular, we derive a condition ensuring that greater downside risk aversion implies greater risk aversion and a different condition ensuring that the opposite implication holds. We then generalize these results to higher order greater risk aversion, obtaining conditions which make it possible to infer the direction of the comparison for risk aversion of a given order from the knowledge of the direction for a different order

Understanding the Impact of Aberrant Splicing in Coagulation Factor V Deficiency

Rare inherited coagulation disorders (RICDs) are congenital deficiencies of the plasma proteins that are involved in blood coagulation, which generally lead to lifelong bleeding manifestations. These diseases are generally qualitative and/or quantitative defects that are associated with monoallelic or biallelic mutations in the relevant gene. Among RICDs, factor V (FV) deficiency is one of the least characterized at the molecular level. Here, we investigated four unrelated patients with reduced plasma FV levels (three severe, one mild), which were associated with a moderately severe bleeding tendency. Sequence analysis of the FV gene identified seven different variants, five hitherto unknown (p.D1669G, c.5789-11C>A, c.5789-12C>A, c.5789-5T>G, and c.6528G>C), and two previously reported (c.158+1G>A and c.5789G>A). The possible pathogenic role of the newly identified missense variant was studied by in silico approaches. The remaining six genetic defects (all putative splicing mutations) were investigated for their possible effects on pre-mRNA splicing by transient transfection experiments in HeLa cells with plasmids expressing appropriate hybrid minigenes. The preparation of minigene constructs was instrumental to demonstrate that the two adjacent variants c.5789-11C>A and c.5789-12C>A are indeed present in cis in the analyzed FV-deficient patient (thus leading to the c.5789-11_12CC>AA mutation). Ex vivo experiments demonstrated that each variant causes either a skipping of the relevant exon or the activation of cryptic splice sites (exonic or intronic), eventually leading to the introduction of a premature termination codon

A recurrent Gly43Asp substitution in coagulation Factor X rigidifies its catalytic pocket and impairs catalytic activity and intracellular trafficking

Factor X (FX) deficiency is one of the most severe among recessively inherited coagulation disorders. The homozygous Gly222Asp mutation (Gly43Asp in the chymotrypsinogen numbering) on the FX gene was found in fifteen patients with severe FX deficiency (FX:C < 1%). The Gly43 residue is located at the highly conserved 42-58 residues region shared among all trypsinogen-like proteins. In vitro expression studies showed that the replacement of a neutral Gly by a charged Asp residue into the so-called loop-40 of the FX (comprising residues from 42 to 58) causes an impairment of its catalytic competence as well as a secretion defect. Steady state kinetic studies showed also a severe defect of activation by FVIIa of the FX43Asp. Surprisingly, molecular dynamics studies clearly indicated that the Gly43Asp mutation neither disrupts nor destabilizes the FXa native structure of the catalytic site. Rather, it makes it more rigid, by thickening the H-bonding network around its catalytic site. Altogether, the defects of FX43Asp explain the severe bleeding symptoms in the patients and outline the relevance of the plasticity in the FXa catalytic pocket for maintenance of its catalytic competence. \ua9 2013 Elsevier Ltd

A recurrent Gly43Asp substitution in coagulation Factor X rigidifies its catalytic pocket and impairs catalytic activity and intracellular trafficking

Factor X (FX) deficiency is one of the most severe among recessively inherited coagulation disorders. The homozygous Gly222Asp mutation (Gly43Asp in the chymotrypsinogen numbering) on the FX gene was found in fifteen patients with severe FX deficiency (FX:C <1%). The Gly43 residue is located at the highly conserved 42-58 residues region shared among all trypsinogen-like proteins. In vitro expression studies showed that the replacement of a neutral Gly by a charged Asp residue into the so-called loop-40 of the FX (comprising residues from 42 to 58) causes an impairment of its catalytic competence as well as a secretion defect. Steady state kinetic studies showed also a severe defect of activation by FVIIa of the FX43Asp. Surprisingly, molecular dynamics studies clearly indicated that the Gly43Asp mutation neither disrupts nor destabilizes the FXa native structure of the catalytic site. Rather, it makes it more rigid, by thickening the H-bonding network around its catalytic site. Altogether, the defects of FX43Asp explain the severe bleeding symptoms in the patients and outline the relevance of the plasticity in the FXa catalytic pocket for maintenance of its catalytic competenc