Sequencing of cDNA from 50 unrelated patients reveals that mutations in the triple-helical domain of type III procollagen are an infrequent cause of aortic aneurysms.

Tromp, Gerard; Wu, Yuli; Prockop, Darwin J.; Madhatheri, S; Kleinert, Caren; Earley, James J.; Zhuang, Jiapiao; Norrgård, Örjan; Darling, R. Clement; Abbott, William M.

doi:10.1172/jci116490

Cited by 98 publications

(55 citation statements)

References 38 publications

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“…34,35 There is also accumulating evidence indicating that overdegradation of vascular structural proteins by proteinases is an important mechanism involved in the development and rupture of aneurysms. 7 The present study sought to ascertain whether polymorphisms in MMP genes influence the susceptibility of intracranial aneurysms.…”

Section: Discussionmentioning

confidence: 99%

Polymorphisms in Matrix Metalloproteinase-1, -3, -9, and -12 Genes in Relation to Subarachnoid Hemorrhage

Zhang

Dhillon

Geary

et al. 2001

Stroke

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Background and Purpose-Intracranial aneurysm, which underlies the vast majority of subarachnoid hemorrhage incidences, has a multifactorial etiology, and the importance of genetic factors is increasingly recognized. Development and rupture of intracranial aneurysms involve degradation and remodeling of the vascular wall matrix in which the matrix metalloproteinases (MMPs) play an important role. The possible impact of MMP gene polymorphisms on susceptibility to intracranial aneurysms is still controversial, with conflicting data from different reported studies. Methods-In this study we analyzed 5 different functional promoter polymorphisms in the MMP-1, MMP-3, MMP-9, and MMP-12 genes in a sample of 92 patients with aneurysmal subarachnoid hemorrhage and 158 healthy control subjects, all from southern England. Results-No significant difference was detected between the patient and control groups in genotype distribution of any of the polymorphisms studied. Conclusions-The

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Section: Discussionmentioning

confidence: 99%

Polymorphisms in Matrix Metalloproteinase-1, -3, -9, and -12 Genes in Relation to Subarachnoid Hemorrhage

Zhang

Dhillon

Geary

et al. 2001

Stroke

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“…4). Genetic analysis was then carried out by examining the coding sequence of messenger ribonucleic acid (mRNA) of cultured dermal fibroblasts as described [11]. A missense base mutation was revealed in the COL3A1 gene heterozygously, which converted the glycine codon GGT at amino acid position 727 to the codon GAT which codes for aspartate.…”

Section: Case Reportmentioning

confidence: 99%

Ehlers-Danlos syndrome type IV with few extrathoracic findings: a newly recognized point mutation in the COL3A1 gene

et al. 2001

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Ehlers-Danlos syndrome type IV (EDS IV) is caused by mutation within the COL3A1 gene, resulting in the disorder of type III procollagen. The diagnosis is confirmed by demonstrating the synthesis of abnormal type III procollagen molecules from cultured dermal fibroblasts or by identifying the mutation in the COL3A1 gene.The authors report a case of EDS IV caused by a novel point mutation in the COL3A1 gene in a 16-yr-old female. Recurrent haemoptysis and cavitary formation of the lung were evidence of pulmonary involvement. However, extrathoracic manifestations of EDS IV were mostly absent.To the best of the authors9 knowledge, all previously reported Ehlers-Danlos syndrome IV patients with respiratory disease had the characteristic findings or histories of Ehlers-Danlos syndrome IV. In the present case, connective tissue friability was suspected due to tissue laceration observed in the biopsied lung specimen, and the diagnosis was made beginning from this pivotal finding.

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“…Numerous clinical studies have established associations between AAA and aging, atherosclerosis, and male gender, as well as cigarette smoking, pulmonary emphysema, and high blood pressure (4). Aneurysms also occur with a familial tendency that suggests a genetically inherited component to the disease (5)(6)(7)(8), but specific gene defects underlying the common forms of AAA have yet to be identified (9,10). Whereas aneurysmal degeneration is thought to arise through mechanisms of vascular wall remodeling distinct from those observed in either aging, atherosclerosis, or hypertension alone, the etiology of AAA remains unresolved (11)(12)(13).…”

Section: Introductionmentioning

confidence: 99%

Expression and localization of macrophage elastase (matrix metalloproteinase-12) in abdominal aortic aneurysms.

Curci¹,

Liao²,

Huffman³

et al. 1998

J. Clin. Invest.

435

336

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Elastolytic matrix metalloproteinases (MMPs) have been implicated in the pathogenesis of abdominal aortic aneurysms (AAA), a disorder characterized by chronic aortic wall inflammation and destruction of medial elastin. The purpose of this study was to determine if human macrophage elastase (HME; MMP-12) might participate in this disease. By reverse transcription-polymerase chain reaction, HME mRNA was consistently demonstrated in AAA and atherosclerotic occlusive disease (AOD) tissues (six of six), but in only one of six normal aortas. Immunoreactive proteins corresponding to proHME and two products of extracellular processing were present in seven of seven AAA tissue extracts. Total HME recovered from AAA tissue was sevenfold greater than normal aorta ( P Ͻ 0.001), and the extracted enzyme exhibited activity in vitro. Production of HME was demonstrated in the media of AAA tissues by in situ hybridization and immunohistochemistry, but HME was not detected within the media of normal or AOD specimens. Importantly, immunoreactive HME was specifically localized to residual elastin fragments within the media of AAA tissue, particularly areas adjacent to nondilated normal aorta. In vitro, the fraction of MMP-12 sequestered by insoluble elastin was two-to fivefold greater than other elastases found in AAA tissue. Therefore, HME is prominently expressed by aneurysm-infiltrating macrophages within the degenerating aortic media of AAA, where it is also bound to residual elastic fiber fragments. Because elastin represents a critical component of aortic wall structure and a matrix substrate for metalloelastases, HME may have a direct and singular role in the pathogenesis of aortic aneurysms.

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Sequencing of cDNA from 50 unrelated patients reveals that mutations in the triple-helical domain of type III procollagen are an infrequent cause of aortic aneurysms.

Abstract: Clin. Invest. 1993. 91:2539-2545

Cited by 98 publications

References 38 publications

Polymorphisms in Matrix Metalloproteinase-1, -3, -9, and -12 Genes in Relation to Subarachnoid Hemorrhage

Polymorphisms in Matrix Metalloproteinase-1, -3, -9, and -12 Genes in Relation to Subarachnoid Hemorrhage

Ehlers-Danlos syndrome type IV with few extrathoracic findings: a newly recognized point mutation in the COL3A1 gene

Expression and localization of macrophage elastase (matrix metalloproteinase-12) in abdominal aortic aneurysms.

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