Insertions/Deletions in the Antithrombin Gene: 3 Mutations Associated with Non-Expression

1992 ◽  
Vol 67 (05) ◽  
pp. 521-525 ◽  
Author(s):  
Martina Daly ◽  
David J Perry ◽  
Paul L Harper ◽  
Helena M Daly ◽  
Antoine W W Roques ◽  
...  
Keyword(s):  
Molecular Basis ◽  
Novel Mutation ◽  
Direct Sequencing ◽  
Protein Translation ◽  
Thromboembolic Disease ◽  
Cloning And Sequencing ◽  
Antithrombin Deficiency ◽  
The Third ◽  
History Of ◽  
Variant Alleles

SummaryWe have investigated the molecular basis of antithrombin deficiency in 3 individuals, 2 of whom had a proven family history of thromboembolic disease. An approximate 50% reduction in functional and immunologic levels of antithrombin was detected in plasma from the propositi indicating an allelic deficiency of antithrombin. In each case direct sequencing of amplified DNA revealed a novel mutation involving single bases: two being insertions, of a T in codon 48 and an A in codon 208, and the third being the deletion of an A in codon 370. The three mutations, which were confirmed by cloning and sequencing the normal and variant alleles, all caused frameshifts leading to premature termination of protein translation. In no case could a truncated antithrombin be detected in plasma from the propositus suggesting either that it fails to be secreted, or is rapidly degraded.

The Molecular Basis of Antithrombin Deficiency in Belgian and Dutch Families

1998 ◽  
Vol 80 (09) ◽  
pp. 376-381 ◽  
Author(s):  
W. Lissens ◽  
S. Seneca ◽  
P. Capel ◽  
B. Chatelain ◽  
P. Meeus ◽  
...  
Keyword(s):  
Molecular Basis ◽  
Gene Deletion ◽  
Direct Sequencing ◽  
Genetic Defect ◽  
Polymorphism Analysis ◽  
Type I ◽  
Type Ii ◽  
Antithrombin Deficiency ◽  
Venous Thromboembolic Events ◽  
At Deficiency

SummaryThe molecular basis of hereditary antithrombin (AT) deficiency has been investigated in ten Belgian and three Dutch unrelated kindreds. Eleven of these families had a quantitative or type I AT deficiency, with a history of major venous thromboembolic events in different affected members. In the other two families a qualitative or type II AT deficiency was occasionally diagnosed.DNA studies of the AT gene were performed, using polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) analysis, followed by direct sequencing of the seven exons and intronexon junction regions. Six novel point mutations were identified: four missense, one nonsense mutation and a single nucleotide deletion near the reactive site, causing a frameshift with premature translation termination. In two kindreds the underlying genetic defect was caused by a whole gene deletion, known as a rare cause of AT deficiency. In these cases, Southern blot and polymorphism analysis of different parts of the AT gene proved useful for diagnosis. In another kindred a partial gene deletion spanning 698 basepairs could precisely be determined to a part of intron 3B and exon 4. In two type I and in both type II AT deficient families a previously reported mutation was identified. In all cases, the affected individuals were heterozygous for the genetic defect.

scholarly journals Hereditary antithrombin deficiency: heterogeneity of the molecular basis and mortality in Dutch families

Blood ◽  
1994 ◽  
Vol 84 (12) ◽  
pp. 4209-4213 ◽  
Author(s):  
HH van Boven ◽  
RJ Olds ◽  
SL Thein ◽  
PH Reitsma ◽  
DA Lane ◽  
...  
Keyword(s):  
Genetic Heterogeneity ◽  
Molecular Basis ◽  
Excess Mortality ◽  
Direct Sequencing ◽  
Pcr Amplification ◽  
Base Substitution ◽  
Antithrombin Deficiency ◽  
Single Base ◽  
Molecular Defects ◽  
Mild Defect

We studied the molecular basis and genetic heterogeneity of hereditary antithrombin (III) deficiency in nine Dutch families. Polymerase chain reaction (PCR) amplification and direct sequencing of all antithrombin gene exons and flanking intronic regions identified mutations in eight families. Given the opportunity to correlate the molecular basis with survival, we addressed the relevance of molecular defects to mortality in inherited antithrombin deficiency. The defects included single nucleotide deletions (7671 del G, 7768–69 del G) and insertions (5501 ins A, 2463 G-->TC) that lead to frameshifts, a single base substitution [5381 C-->T (129Arg-->stop)] leading to a premature termination codon, and single base substitutions resulting in amino acid substitutions [2652 A-->C (63Tyr-->Ser), 13380 T-->C (421Ile-->Thr), and 13407 G-->T (430Cys-->Phe)]. All affected individuals were heterozygous for the defects. Previously we found in Dutch families that antithrombin deficiency did not lead to higher mortality compared with the general population. In accordance with these findings, we observed no excess mortality in the nine families [Observed:Expected, 52:52.6; standardised mortality ratio (SMR) 1.0, 95% confidence interval (CI), 0.7–1.3]. Our findings confirmed a considerable genetic heterogeneity underlying antithrombin deficiency. We therefore concluded that the lack of excess mortality in these families is not caused by a Dutch mild defect. We suggest that the longevity is not affected by molecular defects in the antithrombin gene and hypothesize that differences in mortality or natural history between families most likely result from other (genetic) risk factors.

scholarly journals Molecular basis for type 1 antithrombin deficiency: identification of two novel point mutations and evidence for a de novo splice site mutation

Blood ◽  
1994 ◽  
Vol 84 (11) ◽  
pp. 3742-3748 ◽  
Author(s):  
K Jochmans ◽  
W Lissens ◽  
T Yin ◽  
JJ Michiels ◽  
L van der Luit ◽  
...  
Keyword(s):  
Splice Site ◽  
Molecular Basis ◽  
De Novo ◽  
Direct Sequencing ◽  
Point Mutations ◽  
Protein Translation ◽  
Base Substitution ◽  
Nucleotide Position ◽  
At Deficiency

Inherited type 1 antithrombin (AT) deficiency is characterized by a reduction in both immunologically and functionally detectable protein. The disorder is associated with a high risk of thromboembolic disease. We have investigated the molecular basis of type 1 AT deficiency in three unrelated families. We have used the polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) analysis, followed by direct sequencing of the seven exons and the intron-exon junctions of the AT gene. Two novel point mutations were identified. A T to C single-base substitution was found in codon 421 in exon 6 (nucleotide position 13380), leading to an AT 421 isoleucine to threonine substitution. In another kindred, one of three Cs at nucleotide (nt) positions 5448 to 5450 in exon 3A (codon 151 or 152) was deleted, resulting in a frameshift mutation and predicting premature termination of protein translation at codon 251. In a third family, a previously reported G to A substitution, at nt position 9788 in intron 4, 14 bp in front of exon 5, was found. We have demonstrated the creation of a de novo exon 5 splice site by ectopic transcript analysis of lymphocyte mRNA. In all cases, the affected individuals were heterozygous for the mutation and no variant AT protein was detected.

scholarly journals Epidemiology, Pathophysiology, and Natural History of Pulmonary Embolism

2018 ◽  
Vol 35 (02) ◽  
pp. 92-98 ◽  
Author(s):  
Meredith Turetz ◽  
Andrew Sideris ◽  
Oren Friedman ◽  
Nidhi Triphathi ◽  
James Horowitz
Keyword(s):  
Pulmonary Embolism ◽  
Natural History ◽  
Cardiovascular Death ◽  
Thromboembolic Disease ◽  
Venous Thromboembolic Disease ◽  
Common Cause ◽  
The Third ◽  
Venous Thromboembolic ◽  
History Of ◽  
Residual Thrombus

AbstractPulmonary embolism (PE) is a common and potentially deadly form of venous thromboembolic disease. It is the third most common cause of cardiovascular death and is associated with multiple inherited and acquired risk factors as well as advanced age. The prognosis from PE depends on the degree of obstruction and hemodynamic effects of PE and understanding the pathophysiology helps in risk-stratifying patients and determining treatment. Though the natural history of thrombus is resolution, a subset of patients have chronic residual thrombus, contributing to the post-PE syndrome.

Antithrombin Cambridge II (Ala384Ser): Clinical, Functional and Haplotype Analysis of 18 Families

1998 ◽  
Vol 79 (02) ◽  
pp. 249-253 ◽  
Author(s):  
M. E. Daly ◽  
R. C. Tait ◽  
I. D. Walker ◽  
K. Brown ◽  
N. J. Beauchamp ◽  
...  
Keyword(s):  
High Frequency ◽  
Blood Donors ◽  
Haplotype Analysis ◽  
Single Point ◽  
Thromboembolic Disease ◽  
Single Point Mutation ◽  
Repeat Polymorphism ◽  
Antithrombin Deficiency ◽  
Core Haplotype ◽  
History Of

SummaryThirty-one individuals from 18 unrelated families with antithrombin deficiency have been identified as having a single point mutation within codon 384 (13268 GCA→TCA) resulting in an alanine to serine substitution. Six families (11 individuals) were identified by the screening of individuals with thromboembolic disease or with a family history of thromboembolic disease, whilst the remaining 12 families (20 individuals) were identified by screening of asymptomatic blood donors. Four individuals had a history of venous thrombotic disease, a further 2 gave a history of superficial thrombophlebitis but the remaining 25 individuals were asymptomatic. Affected individuals demonstrated normal immunological levels of antithrombin but a decrease in anti-IIa activity in the presence of heparin. Haplotype analysis was used to examine the possibility of a founder effect to explain the high frequency of this non-CpG mutation. 29/31 individuals showed a single common “core” haplotype, the only variation existing in the number of copies of an (ATT)n repeat polymorphism – 13, 14, 15 or 17. The results suggest that at most there are four independent origins for this mutation.

scholarly journals A frameshift mutation leading to type 1 antithrombin deficiency and thrombosis

Blood ◽  
1990 ◽  
Vol 76 (11) ◽  
pp. 2182-2186 ◽  
Author(s):  
RJ Olds ◽  
DA Lane ◽  
G Finazzi ◽  
T Barbui ◽  
SL Thein
Keyword(s):  
Null Allele ◽  
Frameshift Mutation ◽  
Antithrombin Iii ◽  
Novel Mutation ◽  
Direct Sequencing ◽  
Antithrombin Deficiency ◽  
Molecular Defects ◽  
Enzymatic Amplification ◽  
High Incidence

Abstract Type 1 antithrombin III (ATIII) deficiency, which is the commonest form of inherited ATIII defect, is characterized by a quantitative reduction in both immunologically and functionally detectable protein. This condition is associated with a high incidence of thromboembolic disorder. Previous investigations have shown that the ATIII genes in the majority of cases are grossly intact, but the precise underlying molecular defects remain unknown. We have investigated the molecular basis of a type 1 ATIII deficiency in an Italian kindred by enzymatic amplification of the ATIII gene sequences in affected family members and direct sequencing of the amplified genomic DNA. A novel mutation, the deletion of a single T in the second position of codon 119, was identified in each of the affected individuals. The resulting frameshift leads to a premature termination in codon 126, effectively resulting in a null allele.

scholarly journals A frameshift mutation leading to type 1 antithrombin deficiency and thrombosis

Blood ◽  
1990 ◽  
Vol 76 (11) ◽  
pp. 2182-2186
Author(s):  
RJ Olds ◽  
DA Lane ◽  
G Finazzi ◽  
T Barbui ◽  
SL Thein
Keyword(s):  
Null Allele ◽  
Frameshift Mutation ◽  
Antithrombin Iii ◽  
Novel Mutation ◽  
Direct Sequencing ◽  
Antithrombin Deficiency ◽  
Molecular Defects ◽  
Enzymatic Amplification ◽  
High Incidence

Type 1 antithrombin III (ATIII) deficiency, which is the commonest form of inherited ATIII defect, is characterized by a quantitative reduction in both immunologically and functionally detectable protein. This condition is associated with a high incidence of thromboembolic disorder. Previous investigations have shown that the ATIII genes in the majority of cases are grossly intact, but the precise underlying molecular defects remain unknown. We have investigated the molecular basis of a type 1 ATIII deficiency in an Italian kindred by enzymatic amplification of the ATIII gene sequences in affected family members and direct sequencing of the amplified genomic DNA. A novel mutation, the deletion of a single T in the second position of codon 119, was identified in each of the affected individuals. The resulting frameshift leads to a premature termination in codon 126, effectively resulting in a null allele.

A Universe of Societies

2018 ◽  
Author(s):  
Didier Debaise
Keyword(s):  
Spatial Relations ◽  
The Third ◽  
The Status ◽  
History Of ◽  
Temporal And Spatial

Which kind of relation exists between a stone, a cloud, a dog, and a human? Is nature made of distinct domains and layers or does it form a vast unity from which all beings emerge? Refusing at once a reductionist, physicalist approach as well as a vitalistic one, Whitehead affirms that « everything is a society » This chapter consequently questions the status of different domains which together compose nature by employing the concept of society. The first part traces the history of this notion notably with reference to the two thinkers fundamental to Whitehead: Leibniz and Locke; the second part defines the temporal and spatial relations of societies; and the third explores the differences between physical, biological, and psychical forms of existence as well as their respective ways of relating to environments. The chapter thus tackles the status of nature and its domains.

The Origins of Gritty Realism on British Television: Euston Films and Special Branch

2014 ◽  
Vol 11 (1) ◽  
pp. 23-40 ◽  
Author(s):  
Max Sexton
Keyword(s):  
Cultural Discourse ◽  
Technological Changes ◽  
Television Drama ◽  
The Third ◽  
Fourth Series ◽  
History Of

Euston Films was the first film subsidiary of a British television company that sought to film entirely on location. To understand how the ‘televisual imagination’ changed and developed in relationship to the parent institution's (Thames Television) economic and strategic needs after the transatlantic success of its predecessor, ABC Television, it is necessary to consider how the use of film in television drama was regarded by those working at Euston Films. The sources of realism and development of generic verisimilitude found in the British adventure series of the early 1970s were not confined to television, and these very diverse sources both outside and inside television are well worth exploring. Thames Television, which was formed in 1968, did not adopt the slickly produced adventure series style of ABC's The Avengers, for example. Instead, Thames emphasised its other ABC inheritance – naturalistic drama in the form of the studio-based Armchair Theatre – and was to give the adventure series a strong London lowlife flavour. Its film subsidiary, Euston Films, would produce ‘gritty’ programmes such as the third and fourth series of Special Branch. Amid the continuities and tensions between ABC and Thames, it is possible to discern how economic and technological changes were used as a cultural discourse of value that marks the production of Special Branch as a key transformative moment in the history of British television.

Displace of Documentary Heritage from the Soviet Union to Poland during the Third Decade of the XXth Century

2014 ◽  
Vol 3 ◽  
pp. 127-137
Author(s):  
Tatsiana Hiarnovich
Keyword(s):  
Soviet Union ◽  
International Agreements ◽  
Peace Treaty ◽  
Actual Process ◽  
Xxth Century ◽  
The Third ◽  
The Soviet Union ◽  
History Of ◽  
Selection Of

The paper explores the displace of Polish archives from the Soviet Union that was performed in 1920s according to the Riga Peace Treaty of 1921 and other international agreements. The aim of the research is to reconstruct the process of displace, based on the archival sources and literature. The object of the research is those documents that were preserved in the archives of Belarus and together with archives from other republics were displaced to Poland. The exploration leads to clarification of the selection of document fonds to be displaced, the actual process of movement and the explanation of the role that the archivists of Belarus performed in the history of cultural relationships between Poland and the Soviet Union. The articles of the Treaty of Riga had been formulated without taking into account the indivisibility of archive fonds that is one of the most important principles of restitution, which caused the failure of the treaty by the Soviet part.

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