A novel mutation in the antithrombin gene (insT 7429-30) causes superior mesenteric vein thrombosis.
Explore the source record for details and available documents.
Antithrombins↗
Biomedical subjects
J Corral
Publications and source records attributed to J Corral.
Clinical and molecular analysis of X-linked Charcot-Marie-Tooth disease type 1 in Spanish population.
From 1995 to 2004, 979 families with hereditary peripheral neuropathy were referred to the Genetic Diagnosis Center. Using single-strand conformation analysis (SSCA), the connexin 32 gene was analysed in all the patients from 498 families with sporadic or dominant inheritance with no male-to-male transmission and absence of the 17p2 duplication or deletion. Affected males had pes cavus, distal leg weakness, muscular distal atrophy, areflexia and distal sensory loss. The 106 families in which SSCA revealed abnormal migration electrophoresis were directly sequenced. We found 34 families (59 patients) with mutations in connexin 32 gene. In electrophysiological studies, 58.8% families presented slow and 14.7% intermediate nerve conduction velocities. Molecular findings revealed that codon 164 (29.4 +/- 15.3%) and the second extracellular (EC2) domain (44.1 +/- 16.6%) were the most frequently affected codon and domain of the connexin 32. Six novel mutations, Leu39fs, Glu47Gly, His153fs, Cys179Tyr, Cys201Phe and Ser211fs, were found in our study.
Amino Acid Sequence↗
Platelet septin complexes form rings and associate with the microtubular network.
BACKGROUND: Septins are important effectors in molecular mechanisms involving membrane partitioning. To date, a growing repertoire of septins in mammals includes 13 different proteins (SEPT1 to SEPT13) that can be classified into four distinct categories based on sequence similarity. AIM: In this study, we document the human platelet septin, SEPT5, as part of a complex composed of multiple septin proteins. RESULTS: Biochemical and immunofluorescent data place the majority of these complexes in the platelet periphery as part of the platelet circumferential band copurifying with the platelet microtubule coil and tubulin. The presence of a prominent platelet septin ring in resting platelets appears to be left intact in the activated platelet, as a similar ring structure is observed following platelet spreading on fibrinogen. The ablation of SEPT5 in the knock-out mouse model had previously been reported to result in a platelet phenotype with aggregation using subthreshold levels of agonist. Speculation on the role of SEPT5 in the platelet-release reaction suggested that SEPT5 regulates platelet function by association with platelet storage granules. We now report that the absence of SEPT5 results in increased ATP release from stimulated platelets. CONCLUSION: These studies document the presence of platelet septin complexes and validate the importance of septins for platelet physiology.
Adenosine Triphosphate↗
Spinocerebellar ataxia type 2 (SCA2) with white matter involvement.
Two sisters presented with olivopontocerebellar atrophy, neuronal loss in the substantia nigra, intranuclear ubiquitin-, ataxin-2-positive inclusions in neurons, and severe demyelination and axon loss of the cerebral white matter with no accompanying inflammatory pathology. The genetic study demonstrated a 22/36 CAG triplet expansion in the SCA2 gene in one of the sisters; SCA1, SCA3, SCA6, SCA7, SCA8, SCA12, SCA17 and DRPL were ruled out in this patient. The present report shows that severe cerebral white matter pathology may occur in the context of SCA2.
Adult↗
Autosomal dominant cerebellar ataxias in Spain: molecular and clinical correlations, prevalence estimation and survival analysis.
INTRODUCTION: The genetic and clinical profile of autosomal dominant cerebellar ataxias (ADCA) displays marked geographical and ethnical variability. MATERIALS AND METHODS: We have analysed the molecular and clinical correlations in an ethnically homogeneous sample of 30 Spanish ADCA kindreds. Minimal point prevalence for the region of Cantabria was estimated. RESULTS: Seventy per cent of the families harboured known mutations. Areflexia, slow saccades and hypopallesthesia predominated in SCA2; nystagmus, pyramidal signs or areflexia restricted to the legs in SCA 3; and retinal degeneration, pyramidal signs and slow saccades in SCA 7. Anticipation and intergenerational instability were greater in SCA 7. Length of expansions and age at onset were inversely correlated in all SCA subtypes. Larger expansions correlated with areflexia in SCA 2, with pyramidal signs in SCA 3 and with early visual impairment in SCA 7. Survival was similar among the different SCA subtypes. Prevalence of ADCA in Cantabria was 1.6 cases per 100,000 population. CONCLUSIONS: This report shows the epidemiological, clinical and genetic profile of ADCA in Spain, providing additional data regarding the broad clinical heterogeneity of these disorders and the variability of the genotype-phenotype correlations.
Adolescent↗
Expanded GAA repeats and clinical variation in Friedreich's ataxia.
INTRODUCTION: One of the main features of Friedreich's ataxia (FA) is phenotypic variability that can now be explained by the molecular mechanism (GAA expansion) underlying the disease. MATERIALS AND METHODS: We have analyzed genotype-phenotype correlations in a group of 40 patients homozygous for the GAA expansion. RESULTS: The smaller GAA expansion (GAA1 allele) size correlated with age at onset and progression disease rate, but we found no correlation between the larger GAA expansion (GAA2 allele) size and these clinical parameters. The frequency of pes cavus, scoliosis, axonal sensory neuropathy and areflexia increased with the size of GAA1, whereas some signs such as sphincter disturbances, cerebellar atrophy on MRI, amyotrophy, dysarthria and decreased vibration sense were associated with increased duration of the disease. CONCLUSION: GAA1 size is the main determinant of FA phenotype and GAA2 size is a poor predictor of clinical variation. Some clinical features are independent of GAA1 and GAA2 sizes and are determined by the duration of the disease.
Adolescent↗
Genetic variants of the extra-large stimulatory Gs protein alpha-subunit and risk of thrombotic and haemorrhagic disorders.
A polymorphism of the gene encoding the extra-large stimulatory G-protein alpha-subunit (XLalphas), originally identified in three patients with a bleeding tendency, involved a 36-bp insertion and two missense changes. A paternally-inherited insertion displayed a moderate platelet Gsalpha over-expression, which lead to platelet hypo-reactivity. These data prompted us to investigate the genetic, functional and clinical relevance of this polymorphism in the Mediterranean population. We included 414 healthy subjects and three case/control studies: 263 consecutive patients with a first episode of primary intracerebral haemorrhage, 195 patients with deep venous thrombosis, and 104 patients with cerebrovascular disease. Controls were selected by approximating criteria to match selected risk factors to patients. Moreover, we performed studies of platelet function. We developed a simple method to determine the methylated allele, by digestion of genomic DNA with Sma I before polymerase chain reaction amplification. We identified two new rare variants, resulting from the loss of repeat units 7 and 5. The AB genotype was present in 3.6% of healthy population and the prevalence of the B allele was similar among cases and controls. Accordingly, the non-methylated B allele did not modify either the expression of platelet Gsalpha or the platelet response to Gs-agonists. Thus, our study suggests a minor functional role of XLalphas polymorphism in thrombotic or in haemorrhagic disorders.
Aged↗
Evaluation of refrigerated platelet concentrates supplemented with low doses of second messenger effectors.
With the goal of producing haemostatically effective platelet concentrates (PCs) with a longer shelf-life, we aimed to identify a simple combination of platelet inhibitors, with a low pharmacological load, which could avoid the unacceptable loss of platelets stored under refrigerated conditions. PCs stored with different combinations of second messenger effectors were analysed at days 5, 10 and 15 of storage and compared with those supplemented with ThromboSol--a combination of six platelet inhibitors that protects cells from cold damage. The following parameters were analysed: platelet counts, biochemical parameters (glucose, pH, bicarbonate, lactate), cell lysis (lactic dehydrogenase, LDH), membrane glycoproteins (GPs), platelet aggregation, fibrinogen binding and hypotonic shock response. We characterized the combination of amiloride and sodium nitroprusside (at 1/2 the dose included in ThromboSol). This was found to be similar to ThromboSol and superior to nontreated units in the prevention of cold-induced platelet aggregation at day 15 of storage (maintenance of 78% and 80% of initial platelet counts, respectively), preservation of GPIbalpha (11% and 12% better maintenance of mean fluorescence intensity compared with control units, respectively), and reduced cell lysis (13% and 11% decrease in supernatant LDH, respectively). The reduced pharmacological load with the identified solution compared with ThromboSol is an argument in favour of the potential use of these agents when designing strategies to improve PC storage.
Blood Platelets↗
Human platelet antigen systems in allogeneic peripheral blood progenitor cell transplantation: effect of human platelet antigen mismatch on platelet engraftment and graft-versus-host disease.
BACKGROUND: Alloimmune incompatibility in allo-geneic stem cell transplantation (ASCT), pregnancy, and blood transfusion might trigger an immune response with clinical consequences. Human PLT antigens (HPAs), which play a significant role in pregnancy or blood transfusion-associated alloimmune thrombocytopenia, are also expressed on the surface of tissues affected by GVHD. Thus, HPA mismatch in HLA-identical ASCT could play a potential role in PLT engraftment and GVHD. STUDY DESIGN AND METHODS: We studied the HPA-1, -2, and -5 genotypes in Caucasian donors and patients involved in 77 HLA-identical ASCTs. We evaluated the association of HPA compatibility with clinical outcome, analyzing the relevance of host-versus-donor HPA incompatibility in PLT engraftment and donor-versus-host HPA incompatibility in GVHD. RESULTS: PLT engraftment and transfusion require-ments were similar in HPA-compatible and HPA-incompatible ASCT. Cases with severe thrombocytopenia or significant delayed PLT engraftment did not display host-versus-donor HPA incompatibility. Moreover, the incidence of GVHD did not correlate with HPA compatibility. CONCLUSION: Our results support no role for these antigens in immune complications of ASCT: PLT engraftment, requirement of PLT transfusions, and GVHD.
Adolescent↗
Mutations in the shutter region of antithrombin result in formation of disulfide-linked dimers and severe venous thrombosis.
BACKGROUND: Missense mutations causing conformational alterations in serpins can be responsible for protein deficiency associated with human diseases. However, there are few data about conformational consequences of mutations affecting antithrombin, the main hemostatic serpin. OBJECTIVES: To investigate the conformational and clinical effect of mutations affecting the shutter region of antithrombin. PATIENTS AND METHODS: We identified two families with significant reduction of circulating antithrombin displaying early and severe venous thrombosis, frequently associated with pregnancy or infection. Mutations were determined by standard molecular methods. Biochemical studies were performed on plasma samples. One variant (P80S) was purified by heparin-affinity chromatography and gel filtration, and evaluated by proteomic analysis. Finally, we modelled the structure of the mutant dimer. RESULTS: We identified two missense mutations affecting the shutter region of antithrombin: P80S and G424R. Carriers of both mutations presented traces of a similar abnormal antithrombin, supporting inefficiently expressed rather than non-expressed variants. The abnormal antithrombin purified from P80S carriers is an inactive disulfide-linked dimer of mutant antithrombin whose properties are consistent with head-to-head insertion of the reactive loop. CONCLUSIONS: Our data support the conclusion that missense mutations affecting the shutter region of serpins have specific conformational effects resulting in the formation of mutant oligomers. The consequent inefficiency of secretion explains the accompanying deficiency and loss of function, but the severity of thrombosis associated with these mutations suggests that the oligomers also have new and undefined pathological properties that could be exacerbated by pregnancy or infection.
Adult↗
Effect of factor VII -323 Del/Ins polymorphism on the daily variability of factor VIIc and INR in steady anticoagulated patients with acenocoumarol.
Explore the source record for details and available documents.
Acenocoumarol↗
GAA expansion size and age at onset of Friedreich's ataxia.
Explore the source record for details and available documents.
Adolescent↗
Assessment of thoracoabdominal bands to detect respiratory effort-related arousal.
It would be helpful to be able to identify respiratory effort-related arousal (RERA) without needing to measure oesophageal pressure. Thoracoabdominal movements yield an indirect flow measurement from which reduction of amplitude and alteration of the inspiratory flow curve can be detected. The aim of this study was to evaluate the accuracy of using the shape and amplitude of signals from thoracoabdominal bands (inductance plethysmography) to detect RERAs. Altogether, 94 subjects suspected of having sleep apnoea but with an apnoea/hypopnoea index < or = 10 in full polysomnography with oesophageal pressure were studied. A routine polysomnographical analysis was carried out. The polysomnographies were then reanalysed at random to determine which of the identified arousals were due to RERA, as determined either by oesophageal pressure or by induction bands without an oesophageal pressure signal. Altogether, 14,617 arousals were analysed. The sensitivity and specificity to find RERA (arousal by arousal) from bands versus oesophageal pressure were both 94%. The average difference of RERA index between oesophageal pressure and bands was -0.6. The correlation between RERA index determined by oesophageal pressure and bands was 0.98. To evaluate the intra and interobserver agreement, 1183 arousals were additionally analysed. The intraobserver agreement was 91% for RERAs by oesophageal pressure and 80% by bands. The interobserver agreement was 89% by oesophageal pressure and 85% by bands. The thoracoabdominal bands can be used to identify respiratory effort-related arousal (obstructive events not detected by thermistor) with similar efficacy to oesophageal pressure measurement. Since bands are routinely used in most polysomnographies, they can be used as the usual method to detect respiratory effort-related arousal, using a thermistor to evaluate apnoeas and hypopnoeas or as a complement to other methods, such as nasal cannula, which can detect apnoeas, hypopnoeas and respiratory effort-related arousal.
Abdomen↗
Sequence conservation of RAG-1 and RAG-2 genes in hematologic malignancies.
Explore the source record for details and available documents.
DNA Mutational Analysis↗
Platelet aggregation through prothrombinase activation induced by non-aggregant doses of platelet agonists.
Activation of the prothrombinase complex, which catalyzes the formation of thrombin from prothrombin, is crucial for the (patho)physiological processes of hemostasis and thrombosis. We here report that washed platelets supplemented with prothrombin can be irreversibly aggregated with otherwise non-aggregant doses of adenosine diphosphate (10 micromol/l), thrombin (0.06 U/ml), or collagen (1 microg/ml). Prothrombinase-catalyzed prothrombin to thrombin conversion most probably supports this aggregation response, since inhibitors of thrombin (hirudin or heparin) and an inhibitor of activated factor X (DX-9065a) impair the response. A certain degree of agonist-induced platelet activation seems to be required for this prothrombin-supported aggregation response, since prothrombin alone does not induce aggregation, and blockade of glycoprotein Ia/IIa with a specific antibody inhibits the platelet aggregation response to collagen and prothrombin. These results may suggest that activation of the prothrombinase complex could be a common step of the platelet response to distinct agonists, which may be achieved at low levels of platelet stimulation.
Adenosine Diphosphate↗
Polymorphisms of clotting factors modify the risk for primary intracranial hemorrhage.
Intracranial hemorrhage is the third most frequent cause of cerebrovascular disease, but few genetic risk factors have been associated with its development. Recently, it has been reported that some polymorphisms that affect clotting factors increase the risk for thrombosis. However, reports have analyzed the effect of polymorphisms influencing the hemostatic state in bleeding disorders insufficiently. A case-control study was conducted of 201 patients with spontaneous intracranial hemorrhage and 201 control subjects matched for age, race, sex, and selected risk factors (hypertension, smoking, and alcohol consumption). Genomic polymerase chain reaction was used to analyze the prevalence of 4 polymorphisms: factor V Leiden, prothrombin 20210A, factor VII-323 Del/Ins of a decanucleotide, and factor XIII V34L. Subjects with factor V Leiden had decreased risk for spontaneous intracranial hemorrhage (odds ratio, 0.19; 95% confidence interval, 0.03-0.95). The frequency of the prothrombin 20210A/G genotype was also lower among patients than controls (1.5% vs 3%, respectively). Moreover, carriers of the -323 Ins allele of factor VII had a 1.54-fold risk for intracranial hemorrhage (95% CI, 1.03-2.72). Finally, no significant differences were observed in the prevalence of factor XIII V34L polymorphism between patients and controls. Therefore, new genetic factors affecting the risk for spontaneous intracranial hemorrhage were identified. These data, together with the relevance of these polymorphisms in thrombotic diseases, support the idea that a polymorphism may play opposite roles in thrombosis and hemorrhage, suggesting an explanation for the high frequency of these polymorphisms in the general population.
Aged↗
Role of factor XIII Val 34 Leu polymorphism in patients with migraine.
At present, it is contradictory to determine if the combination of certain prothrombotic polymorphisms and migraine increases the risk to develop ischaemic cerebrovascular disease. Recently, the common Val34Leu polymorphism of the A-chain factor XIII gene, associated with variations in factor XIII activity, has been suggested to play a significant role in the development of arterial and venous thrombotic disorders. We analysed the prevalence of this polymorphism in 17 patients with coexisting ischaemic cerebrovascular disease and migraine (5 with aura, and 12 without aura), 89 patients with migraine (43 with aura, and 46 without aura), 116 patients with ischaemic cerebrovascular disease, and 467 healthy Caucasian controls from the South of Spain. Genomic PCR amplification, using a mutated oligonucleotide, and allele-specific restriction assays were used for genotyping. The factor XIII Leu 34 variant was present in 47.1; 40.5; 34.9; and 35.1% of patients with coexisting ischaemic cerebrovascular disease and migraine, ischaemic cerebrovascular disease, migraine, and control subjects, respectively. These data suggest that the factor XIII Leu 34 allele does not play a protective role against these disorders in our population.
Adult↗
Polymorphisms of P-selectin glycoprotein ligand-1 are associated with neutrophil-platelet adhesion and with ischaemic cerebrovascular disease.
P-selectin glycoprotein ligand (PSGL-1) shares common features with platelet glycoprotein Ibalpha. A recently described polymorphism in this receptor that results in a variable number of tandem repeats (VNTR) sequence present either 16, 15 or 14 times (alleles A, B or C) could, similar to GPIbalpha, be functionally relevant. The allelic frequency of this polymorphism was investigated in 469 individuals from the south of Spain, and was similar to that previously described in other Caucasian populations: 85% A, 14% B and 1% C alleles. We identified two new polymorphisms genetically linked to the C isoform, resulting in the Ser273Phe and Met274Val changes. To assess the functional consequence of the polymorphisms in the receptor, we performed flow cytometric analysis of P-selectin dependent neutrophil-platelet interaction. Neutrophils carrying the shortest C allele and the amino acid variations in residues 273 and 274 exhibited a significantly lower capacity to bind activated platelets than A/B and A/A samples (mean fluorescence intensity of CD42b+ neutrophils 262 versus 303 and 319 respectively, P < 0.05). The distribution of the VNTR was analysed in three case-control studies including 104 cerebrovascular (CVD), 101 coronary heart disease (CHD) and 150 deep venous thrombosis (DVT) patients. The results showed that smaller (B and C) alleles seem to be associated with a lower risk of developing CVD (P = 0.008) but not to be related to CHD or DVT. In conclusion, polymorphisms of the PSGL-1 receptor may influence the neutrophil-platelet binding, and represent a risk factor for CVD.
Adolescent↗