Author
Therese M. Goralka
Bio: Therese M. Goralka is an academic researcher from Genentech. The author has contributed to research in topics: Gene & Haemophilia A. The author has an hindex of 2, co-authored 2 publications receiving 1146 citations.
Topics: Gene, Haemophilia A, Haemophilia, Population, Exon
Papers
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TL;DR: The complete 186,000 base-pair (bp) human factor VIII gene has been isolated and consists of 26 exons ranging in size from 69 to 3,106 bp and introns as large as 32.4 kilobases as mentioned in this paper.
Abstract: The complete 186,000 base-pair (bp) human factor VIII gene has been isolated and consists of 26 exons ranging in size from 69 to 3,106 bp and introns as large as 32.4 kilobases (kb). Nine kb of mRNA and protein-coding DNA has been sequenced and the mRNA termini have been mapped. The relationship between internal duplications in factor VIII and evolution of the gene is discussed.
988 citations
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TL;DR: The present work elucidates the molecular genetic basis of haemophilia in some individuals using the recently cloned factor VIII gene as a probe, and identifies two different nonsense point mutations in the factor VII gene of haenophiliacs, as well as two different partial deletions of the gene.
Abstract: The most common inherited bleeding disorder in man, haemophilia A, is caused by defect in factor VIII, a component in the blood coagulation pathway. The X-chromosome-linked disease almost certainly stems from a heterogeneous collection of genetic lesions. Because, without proper treatment, haemophilia can be a fatal disease, new mutations are necessary to account for its constant frequency in the population. In addition, haemophilia A displays a wide range of severity, and some 15% of haemophiliacs generate high levels of antibodies against factor VIII ('inhibitor patients'). The present work elucidates the molecular genetic basis of haemophilia in some individuals. Using the recently cloned factor VIII gene as a probe, we have identified two different nonsense point mutations in the factor VIII gene of haemophiliacs, as well as two different partial deletions of the gene. Our survey of 92 haemophiliacs indicates no firm correlation between antibody (inhibitor) production and gross gene defects.
189 citations
Cited by
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TL;DR: By offering a tenfold increase in the size of the DNA molecules that can be cloned into a microbial host, this system addresses a major gap in existing experimental methods for analyzing complex DNA sources.
Abstract: Fragments of exogenous DNA that range in size up to several hundred kilobase pairs have been cloned into yeast by ligating them to vector sequences that allow their propagation as linear artificial chromosomes. Individual clones of yeast and human DNA that have been analyzed by pulsed-field gel electrophoresis appear to represent faithful replicas of the source DNA. The efficiency with which clones can be generated is high enough to allow the construction of comprehensive libraries from the genomes of higher organisms. By offering a tenfold increase in the size of the DNA molecules that can be cloned into a microbial host, this system addresses a major gap in existing experimental methods for analyzing complex DNA sources.
1,488 citations
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TL;DR: This work focuses on the molecular basis of blood coagulation with particular attention to the biochemistry and regulation of this pathway as it relates to humans in health and disease.
1,298 citations
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TL;DR: Of the various types of hemophilia, the most common of these lifelong bleeding disorders are due to an inherited deficiency of factor VIII or factor IX (Table 1).
Abstract: Of the various types of hemophilia, the most common of these lifelong bleeding disorders are due to an inherited deficiency of factor VIII or factor IX (Table 1). The genes for these blood coagulat...
964 citations
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TL;DR: Determination of the thrombin cleavage sites in plasma-derived factor VIII polypeptides allows prediction of the domains involved in the associated activation and inactivation of the protein.
Abstract: The deduced amino acid sequence of human factor VIII, obtained from the DNA sequence, predicts a mature polypeptide of 2,332 amino acids containing a triplicated domain structure. The polypeptide has 35% sequence homology with the copper-binding plasma protein, ceruloplasmin. Determination of the thrombin cleavage sites in plasma-derived factor VIII polypeptides allows prediction of the domains involved in the associated activation and inactivation of the protein.
914 citations
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TL;DR: Findings are consistent with methylation-induced deamination of 5-methyl cytosine and suggest that methylation of DNA within coding regions may contribute significantly to the incidence of human genetic disease.
Abstract: Reports of single base-pair mutations within gene coding regions causing human genetic disease were collated. Thirty-five per cent of mutations were found to have occurred within CpG dinucleotides. Over 90% of these mutations were C → T or G → A transitions, which thus occur within coding regions at a frequency 42-fold higher than that predicted from random mutation. These findings are consistent with methylation-induced deamination of 5-methyl cytosine and suggest that methylation of DNA within coding regions may contribute significantly to the incidence of human genetic disease.
881 citations