1,721,031 research outputs found
Coagulation factor V
No full textThe coagulation cascade involves sequential enzymatic activations of serine protease zymogens that converge on the generation of thrombin. Factor V (FV) takes part in this process as a component of the prothrombinase complex. Besides its role as procoagulant factor, it is also involved in the physiologic anticoagulant pathway, by participating in the inactivation of activated factor VIII (FVIIIa). Given the dual role of FV, genetic defects in FV gene may result in opposite hemorrhagic or thrombotic phenotypes. This review focuses on the structure, function (procoagulant and anticoagulant), regulation (activation and inactivation) of FV as well as on the genetic defects associated with mutations in the FV gene
Inherited defects of coagulation factor V : the hemorrhagic side
No full textCoagulation factor V (FV) is the protein cofactor required in vivo for the rapid generation of thrombin catalyzed by the prothrombinase complex. It also represents a central regulator in the early phases of blood clot formation, as it contributes to the anticoagulant pathway by participating in the downregulation of factor VIII activity. Conversion of precursor FV to either a procoagulant or anticoagulant cofactor depends on the local concentration of procoagulant and anticoagulant enzymes, so that FV may be regarded as a daring tight-rope walker gently balancing opposite forces. Given this dual role, genetic defects in the FV gene may result in opposite phenotypes (hemorrhagic or thrombotic). Besides a concise description on the structural, procoagulant and anticoagulant properties of FV, this review will focus on bleeding disorders associated with altered levels of this molecule. Particular attention will be paid to the mutational spectrum of type I FV deficiency, which is characterized by a remarkable genetic heterogeneity and by an uneven distribution of mutations throughout the FV gene
The molecular basis of quantitative fibrinogen disorders
No full textHereditary fibrinogen disorders include type I deficiencies (afibrinogenemia and hypofibrinogenemia, i.e. quantitative defects), with low or unmeasurable levels of immunoreactive protein; and type II deficiencies (dysfibrinogenemia and hypodysfibrinogenemia, i.e. qualitative defects), showing normal or altered antigen levels associated with reduced coagulant activity. While dysfibrinogenemias are in most cases autosomal dominant disorders, type I deficiencies are generally inherited as autosomal recessive traits. Patients affected by congenital afibrinogenemia or severe hypofibrinogenemia may experience bleeding manifestations varying from mild to severe. This review focuses on the genetic bases of type I fibrinogen deficiencies, which are invariantly represented by mutations within the three fibrinogen genes (FGA, FGB, and FGG) coding for the three polypeptide chains Aalpha, Bbeta, and gamma. From the inspection of the mutational spectrum of these disorders, some conclusions can be drawn: (i) genetic defects are scattered throughout the three fibrinogen genes, with only few sites appearing to represent relative mutational hot spots; (ii) several different types of genetic lesions and pathogenic mechanisms have been described in affected individuals (including gross deletions, point mutations causing premature termination codons, missense mutations affecting fibrinogen assembly/secretion, and uniparental isodisomy associated with a large deletion); (iii) the possibility to express recombinant fibrinogen mutants in eukaryotic cells is rapidly shedding light into the molecular mechanisms responsible for physiologic and pathologic properties of the molecule; (iv) though mutation analysis of the fibrinogen cluster does not yield precise information for predicting genotype/phenotype correlations, it still provides a valuable tool for diagnosis confirmation, identification of potential carriers, and prenatal diagnosis
Shedding light on the dark side of the genome : overlapping genes in higher eukaryotes
No full textGene overlap, consisting of two or more adjacent genes with partially or totally overlapping expressible units,has very recently emerged as a common feature, rather than an exception to the rule, in a significant portion of eukaryotic genomes. Considering the lack of strong evolutionary pressure on genome size in eukaryotes, the frequent recurrence of such a gene disposition is unexpected. However, these findings, along with the recent estimate that fewer genes than expected are encoded in the human genome, strengthen the hypothesis that organism complexity may reside in the interaction within and among genome, transcriptome and proteome. In this context, overlapping genes could represent a hidden source of complexity to modulate gene expression. In fact, overlapping genes, when transcribed in the opposite directions, give rise to sense-antisense transcript pairs, which often exhibit reciprocal expression patterns. These natural antisense transcripts (NATs) have been demonstrated to play a role in a variety of processes, including mRNA splicing and stability, RNA editing, genomic imprinting and control of translation. Here we present the first review on eukaryotic overlapping genes, an attempt of shedding light on this dark side of the genome. We also report the most interesting and well-studied cases and depict a general frame of this phenomenon
Autosomal dominant nocturnal frontal lobe epilepsy : a critical overview
No full textAutosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is an idiopathic epilepsy, with a spectrum of clinical manifestations, ranging from brief, stereotyped, sudden arousals to more complex dystonic-dyskinetic seizures. Video-polysomnography allows a correct differential diagnosis. There is no difference between sporadic nocturnal frontal lobe epilepsy (NFLE) and ADNFLE in the clinical and neurophysiological findings. ADNFLE is the first idiopathic epilepsy for which a genetic basis has been identified. Mutations have been found in two genes (CHRNA4 and CHRNB2) coding for neuronal nicotinic receptor subunits (alpha4 and beta2, respectively). Contrasting data have been reported on the effect of these mutations on the functionality of the receptor.Moreover, the incomplete data on the neuronal network/s in which this receptor is involved, make difficult the understanding of the genotype-phenotype correlation. This is an overview on the clinical and genetic aspects of ADNFLE including a discussion of some open questions on the role of the neuronal nicotinic receptor subunit mutations in the pathogenesis of this form of epilepsy
The DNA-pooling technique allowed for the identification of three novel mutations responsible for afibrinogenemia
No full textBACKGROUND AND OBJECTIVES: Afibrinogenemia and hypofibrinogenemia are rare inherited coagulation disorders characterized by hemorrhagic manifestations of variable entity and by plasma fibrinogen deficiency. So far, 57 mutations have been associated with these disorders, and 18 of these are missense mutations. The aim of this study was to characterize the molecular mechanism underlying severe hypofibrinogenemia in a proband from India. DESIGN AND METHODS: The mutational screening was accomplished by DNA sequencing of the three fibrinogen genes. The mutant protein was expressed in COS-1 cells, and intracellular and secreted mutant fibrinogen was analyzed by means of pulse-chase experiments. RESULTS: A novel homozygous G-->A transition in exon 8 (nucleotide position 8017) was found in the proband's fibrinogen Bbeta-chain gene. The resulting G434D missense mutation (fibrinogen Mumbai) involves a highly conserved amino acid residue, located in the C-terminal globular D domain. In vitro expression experiments demonstrated intracellular retention of the mutant fibrinogen and marked reduction of its secretion. INTERPRETATION AND CONCLUSIONS: The G434D substitution causes severe hypofibrinogenemia by impairing fibrinogen secretion. Expression data confirm the importance of Bbeta-chain D domain folding in the intracellular processing of fibrinogen
Frontal lobe epilepsy and mutations of the cortitropin-releasing hormone gene
No full textNocturnal frontal lobe epilepsy up to now has been considered a channelopathy caused by mutations in the alpha(4) and beta(2) subunits of the neuronal nicotinic acetylcholine receptor. However, these mutations account for only a minority of patients, and the existence of at least a new locus for the disease has been demonstrated. In one Italian nocturnal frontal lobe epilepsy family, we identified two new putative loci on chromosomes 3 and 8, where several candidate genes are mapped. In particular, on chromosome 8, corticotropin-releasing hormone gene (CRH) appears to be a good candidate. We therefore searched for CRH mutations in the proband. The study allowed the identification of a nucleotide variation in the promoter that was subsequently detected in all affected and obligate carrier members of the same family, in two sporadic cases, in all affected members of an additional compliant family, and in the proband of a noncompliant family. Moreover, a different mutation in the promoter was detected in a familial case. In vitro experiments showed altered levels of gene expression. CRH alterations could explain several autosomal dominant nocturnal frontal lobe epilepsy clinical features
Does 9-azaguanine induce or select for chromosome number instability in human cell hybrids?
No full textSegregant clones resistant to 8-Azaguanine (8AG) obtained from hybrids between clonal derivatives of the EUE line were analysed for chromosome number distribution. In almost all cases the 8AGR clones show chromosome losses and a greater variability in chromosome numbers than that of the parental hybrids and their non-selected subclones. A study of the karyotypic evolution of 8AGR segregant clones maintained for a prolonged period either in 8AG or in drug-free medium did not reveal any correlation between chromosome variability and the presence of 8AG. The preadaptive nature of the segregation to 8AG resistance is also indicated by the results of a fluctuation test
The DNA pooling technique applied to the mutational screening of human congenital afibrinogenemia : identification of 3 novel mutations
No full textCharacterization of the F11 alternative splicing pattern : identification of a novel coagulation FXI isoform
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