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The genetic basis of thoracic aortic...

Hasham, Sumera Nikhat.

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The genetic basis of thoracic aortic aneurysms and dissections: Genetic heterogeneity and mapping of TAAD1 and TAAD2 loci.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	The genetic basis of thoracic aortic aneurysms and dissections: Genetic heterogeneity and mapping of TAAD1 and TAAD2 loci./
Author:	Hasham, Sumera Nikhat.
Description:	217 p.
Notes:	Adviser: Dianna M. Milewicz.
Contained By:	Dissertation Abstracts International64-02B.
Subject:	Biology, Genetics. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3081464

The genetic basis of thoracic aortic aneurysms and dissections: Genetic heterogeneity and mapping of TAAD1 and TAAD2 loci.
Hasham, Sumera Nikhat.

The genetic basis of thoracic aortic aneurysms and dissections: Genetic heterogeneity and mapping of TAAD1 and TAAD2 loci. - 217 p.

Adviser: Dianna M. Milewicz.

Thesis (Ph.D.)--The University of Texas Health Science Center at Houston Graduate School of Biomedical Sciences, 2003.

Thoracic aortic aneurysms leading to aortic dissections (TAAD) are a major cause of morbidity and mortality in the United States. TAAD is a complication of some known genetic disorders, such as Marfan syndrome and Turner syndrome, but the majority of familial cases are not due to a known genetic syndrome. Previous studies by our group have established that nonsyndromic, familial TAAD is inherited in an autosomal dominant manner with decreased penetrance and variable expression. Using one large family with multiple members with TAAD for the genome wide scan, a major locus for familial TAAD was mapped to 5q13–14 (<italic>TAAD1</italic>). Nine out of 15 families studied were linked to this locus, establishing that <italic>TAAD1</italic> was a major locus, and that there was genetic heterogeneity for the condition. Mapping of <italic>TAAD2</italic> locus was accomplished using a single large family with multiple members with TAAD not linked to known loci of aneurysm formation. This established a second novel locus for familial TAAD on 3p24–25 (LOD score of 4.3), termed the <italic>TAAD2</italic> locus. Two putative loci with suggestive LOD scores were mapped on 4q and 12q through a genome scan carried out using three families. TAAD phenotype in 12 families did not segregate with known loci, indicating further genetic heterogeneity. An STS-tagged BAC based contig was constructed for 7.8Mb and 25Mb critical interval of <italic> TAAD1</italic> and <italic>TAAD2</italic> respectively and characterized to identify the defective gene. The hypothesis that the defective genes responsible for the <italic>TAAD1</italic> and <italic>TAAD2</italic> encoded extracellular matrix (ECM) proteins, the major components of the elastic fiber system in the aortic media was tested. Four genes encoding ECM proteins, versican, thrombospondin-3, <italic> CRTL1</italic>, on <italic>TAAD1</italic> and <italic>FBLN2</italic> at <italic> TAAD2</italic> were sequenced, but no disease-causing mutations were identified. Studies to identify the defective gene are initiated through the positional candidate gene approach using combination of bioinformatics and expression studies. The identification of the TAAD susceptibility genes will allow for presymptomatic diagnosis of individuals at risk for this life threatening disease. The identification of the molecular defects that contribute to TAAD will also further our understanding of the proteins that provide structural integrity to the aortic wall.Subjects--Topical Terms:

1017730
Biology, Genetics.

The genetic basis of thoracic aortic aneurysms and dissections: Genetic heterogeneity and mapping of TAAD1 and TAAD2 loci.
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035 $a (UnM)AAI3081464
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100 1 $a Hasham, Sumera Nikhat. $3 1253263
245 1 0 $a The genetic basis of thoracic aortic aneurysms and dissections: Genetic heterogeneity and mapping of TAAD1 and TAAD2 loci.
300 $a 217 p.
500 $a Adviser: Dianna M. Milewicz.
500 $a Source: Dissertation Abstracts International, Volume: 64-02, Section: B, page: 0524.
502 $a Thesis (Ph.D.)--The University of Texas Health Science Center at Houston Graduate School of Biomedical Sciences, 2003.
520 $a Thoracic aortic aneurysms leading to aortic dissections (TAAD) are a major cause of morbidity and mortality in the United States. TAAD is a complication of some known genetic disorders, such as Marfan syndrome and Turner syndrome, but the majority of familial cases are not due to a known genetic syndrome. Previous studies by our group have established that nonsyndromic, familial TAAD is inherited in an autosomal dominant manner with decreased penetrance and variable expression. Using one large family with multiple members with TAAD for the genome wide scan, a major locus for familial TAAD was mapped to 5q13–14 (<italic>TAAD1</italic>). Nine out of 15 families studied were linked to this locus, establishing that <italic>TAAD1</italic> was a major locus, and that there was genetic heterogeneity for the condition. Mapping of <italic>TAAD2</italic> locus was accomplished using a single large family with multiple members with TAAD not linked to known loci of aneurysm formation. This established a second novel locus for familial TAAD on 3p24–25 (LOD score of 4.3), termed the <italic>TAAD2</italic> locus. Two putative loci with suggestive LOD scores were mapped on 4q and 12q through a genome scan carried out using three families. TAAD phenotype in 12 families did not segregate with known loci, indicating further genetic heterogeneity. An STS-tagged BAC based contig was constructed for 7.8Mb and 25Mb critical interval of <italic> TAAD1</italic> and <italic>TAAD2</italic> respectively and characterized to identify the defective gene. The hypothesis that the defective genes responsible for the <italic>TAAD1</italic> and <italic>TAAD2</italic> encoded extracellular matrix (ECM) proteins, the major components of the elastic fiber system in the aortic media was tested. Four genes encoding ECM proteins, versican, thrombospondin-3, <italic> CRTL1</italic>, on <italic>TAAD1</italic> and <italic>FBLN2</italic> at <italic> TAAD2</italic> were sequenced, but no disease-causing mutations were identified. Studies to identify the defective gene are initiated through the positional candidate gene approach using combination of bioinformatics and expression studies. The identification of the TAAD susceptibility genes will allow for presymptomatic diagnosis of individuals at risk for this life threatening disease. The identification of the molecular defects that contribute to TAAD will also further our understanding of the proteins that provide structural integrity to the aortic wall.
590 $a School code: 2034.
650 4 $a Biology, Genetics. $3 1017730
650 4 $a Biology, Molecular. $3 1017719
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710 2 0 $a The University of Texas Health Science Center at Houston Graduate School of Biomedical Sciences. $3 1251166
773 0 $t Dissertation Abstracts International $g 64-02B.
790 $a 2034
790 1 0 $a Milewicz, Dianna M., $e advisor
791 $a Ph.D.
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856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3081464