Structural/functional characterization of fibrillin, the gene product involved in Marfan syndrome.
Item
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Title
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Structural/functional characterization of fibrillin, the gene product involved in Marfan syndrome.
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Identifier
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AAI9432368
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identifier
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9432368
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Creator
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Pereira, Lygia Veiga.
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Contributor
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Adviser: Francesco Ramirez
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Date
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1994
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Language
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English
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Publisher
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City University of New York.
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Subject
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Biology, Genetics | Biology, Molecular
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Abstract
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Marfan syndrome (MFS) is a systemic disorder of connective tissue inherited as an autosomal dominant trait. The three major manifestations of the disease--aortic dilatation, ectopia lentis and skeletal malformations--present a wide clinical variability. For several years the molecular lesion in MFS has been the subject of investigation. Recently fibrillin, a major component of microfibrils, was recognized as the defective gene product in MFS.;The major theme of this study was to provide the basic tools for a thorough molecular investigation of the pathogenesis of MFS and of microfibril assembly. Toward this end this work can be divided in two parts. The first one focuses on the human fibrillin gene, providing its complete coding sequence and intron/exon organization, and identifying novel polymorphic markers in order to help the diagnosis of familial cases of MFS. The second part addresses the question of structure/function correlation of fibrillin, using the technology of homologous recombination in embryonic-stem cells (ES-cells).;Completion of the primary sequence of fibrillin, along with elucidation of the gene organization, shed new light on the structure and function of this protein, as well as the evolutionary origin of the fibrillin gene family. In addition, the results of this study have substantially improved the diagnosis and identification of individuals at risk for MFS. Completion of the fibrillin transcript sequence will now enable the screening of MFS patients for mutations in its entire length. Moreover, the determination of the sequences of all FBN1 intron/exon junctions will greatly facilitate this process by extending the screening to the genomic level. Additionally, the highly informative set of intragenic polymorphic markers identified in this work will be essential for the pre-natal and pre-symptomatic diagnosis of familial cases of MFS.;Finally, this study has initiated a broader body of work aimed at establishing the transgenic mouse as an animal model for the study of fibrillin biosynthesis and microfibril assembly. Isolation of the mouse fibrillin transcript has revealed a high degree of conservation between the human and murine fibrillin. These data were utilized to design vectors for fibrillin gene targeting in mouse ES-cells. The successful generation of ES-cell lines bearing two different mutations in the fibrillin gene has laid the ground for future investigations aimed at characterizing the mechanisms and factors responsible for microfibril pathogenesis.
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Type
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dissertation
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Source
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PQT Legacy CUNY.xlsx
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degree
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Ph.D.
