A functional mutation in the terminal exon of elastin in severe, early onset chronic obstructive pulmonary disease

Kelleher, Catherine McArdle; Silverman, Edwin K.; Broekelmann, Thomas J.; Litonjua, AA; Hernandez, M.; Sylvia, Jody S.; Stoler, Joan M.; Reilly, John J.; Chapman, Harold A.; Speizer, Frank E.; Weiss, ST; Mecham, Robert P.; Raby, Benjamin A.

doi:10.1016/j.rmedu.2006.01.019

Cited by 22 publications

(30 citation statements)

References 31 publications

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“…In a previous study, we described a rare, missense variant of elastin (G773D) in a pedigree with severe early onset emphysema (25). This single amino acid change compromises the ability of the mutant protein to undergo normal elastin assembly.…”

Section: Discussionmentioning

confidence: 99%

“…Intrapulmonary instillation of elastolytic enzymes, for example, confirmed that destruction of existing elastic fibers leads to emphysema-like lesions (24,27,46). There is also evidence that functional variants of elastin may increase lung susceptibility to cigarette smoke-induced damage by altering elastic fiber assembly and integrity (25). More recently, experiments in mice have shown that deficiency in elastin or in the elastic fiber proteins fibrillin-1, LTBP-3 and -4, fibulin-4 and -5, and EMILIN (elastin microfibril interface located protein) all result in emphysema-like lung morphology at birth (6,35,36,49,51,56,58).…”

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confidence: 95%

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Elastin protein levels are a vital modifier affecting normal lung development and susceptibility to emphysema

Shifren¹,

Durmowicz²,

Knutsen³

et al. 2007

American Journal of Physiology-Lung Cellular and Molecular Phys

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 95%

Elastin protein levels are a vital modifier affecting normal lung development and susceptibility to emphysema

Shifren¹,

Durmowicz²,

Knutsen³

et al. 2007

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…It has been shown that a polymorphism of MMP-9 (C-1562T) is associated with upper lung dominant emphysema [50,51]. In addition, a genetic predisposition for proteolysis of elastin in connection with the expression of a variant of the terminal exon in human elastin has been described for patients with severe COPD [52]. The interest shown in the gene coding for phospholipase A 2 , a protein involved in the metabolism of fatty acids, is related to the fact that the plasma concentration of this enzyme is high in a certain number of inflammatory diseases [53].…”

Section: Genetic Factorsmentioning

confidence: 99%

Epidemiology of COPD

Rahérison¹,

Girodet²

2009

Eur Respir Rev

429

281

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Chronic obstructive pulmonary disease (COPD) is responsible for early mortality, high death rates and significant cost to health systems. The projection for 2020 indicates that COPD will be the third leading cause of death worldwide (from sixth in 1990) and fifth leading cause of years lost through early mortality or handicap (disability-adjusted life years) (12th in 1990). Active smoking remains the main risk factor, but other factors are becoming better known, such as occupational factors, infections and the role of air pollution. Prevalence of COPD varies according to country, age and sex. This disease is also associated with significant comorbidities. COPD is a disorder that includes various phenotypes, the continuum of which remains under debate. The major challenge in the coming years will be to prevent onset of smoking along with early detection of the disease in the general population.

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“…Most elastin mutations associated with this disease are single nucleotide deletions near the 3Ј end of the gene 9 -11 resulting in missense sequence that alters the character of a biologically important domain at the end of the tropoelastin molecule. 12 ELN has also been suggested to be a susceptibility gene for hypertension, 13 emphysema, 14 and intracranial aneurysms. 15 ELN encodes a protein made up of alternating hydrophobic and crosslinking domains.…”

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Functional Rescue of Elastin Insufficiency in Mice by the Human Elastin Gene

Hirano

Knutsen

Sugitani

et al. 2007

Circulation Research

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Abstract-Diseases linked to the elastin gene arise from loss-of-function mutations leading to protein insufficiency (supravalvular aortic stenosis) or from missense mutations that alter the properties of the elastin protein (dominant cutis laxa). Modeling these diseases in mice is problematic because of structural differences between the human and mouse genes. To address this problem, we developed a humanized elastin mouse with elastin production being controlled by the human elastin gene in a bacterial artificial chromosome. The temporal and spatial expression pattern of the human transgene mirrors the endogenous murine gene, and the human gene accurately recapitulates the alternative-splicing pattern found in humans. Human elastin protein interacts with mouse elastin to form functional elastic fibers and when expressed in the elastin haploinsufficient background reverses the hypertension and cardiovascular changes associated with that phenotype. Elastin from the human transgene also rescues the perinatal lethality associated with the null phenotype. The results of this study confirm that reestablishing normal elastin levels is a logical objective for treating diseases of elastin insufficiency such as supravalvular aortic stenosis. This study also illustrates how differences in gene structure and alternative splicing present unique problems for modeling human diseases in mice. (Circ Res. 2007;101:523-531.)Key Words: elastin Ⅲ supravalvular aortic stenosis Ⅲ vascular disease Ⅲ transgenic mice M utations within the elastin gene lead to several elastinopathies in humans that affect large blood vessels, the skin, and the lung. For example, loss-of-function mutations that produce haploinsufficiency have been linked to supravalvular aortic stenosis (SVAS-MIM185500), a congenital narrowing of the ascending aorta and other vessels. SVAS can occur sporadically or as a familial condition with autosomaldominant inheritance. 1 More than 50 different mutations have been described that lead to isolated SVAS. [2][3][4][5][6][7] SVAS is also a component of Williams-Beuren syndrome (WBS-MIM194050), 3,8 a frequent heterozygous deletion of a Ϸ1.6 Mb segment at chromosome 7q11.23 that includes the elastin gene. 3 In contrast to the loss-of-function mutations typical of SVAS, evidence suggests that autosomal dominant cutis laxa (ADCL-MIM123700) occurs through a dominant-negative mechanism. ADCL is characterized by lax skin with other internal organ involvement. Most elastin mutations associated with this disease are single nucleotide deletions near the 3Ј end of the gene 9 -11 resulting in missense sequence that alters the character of a biologically important domain at the end of the tropoelastin molecule. 12 ELN has also been suggested to be a susceptibility gene for hypertension, 13 emphysema, 14 and intracranial aneurysms. 15 ELN encodes a protein made up of alternating hydrophobic and crosslinking domains. 16 This repeating arrangement reflects the exon structure of the gene, with each type of domain encoded by distinct exon...

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A functional mutation in the terminal exon of elastin in severe, early onset chronic obstructive pulmonary disease

Cited by 22 publications

References 31 publications

Elastin protein levels are a vital modifier affecting normal lung development and susceptibility to emphysema

Elastin protein levels are a vital modifier affecting normal lung development and susceptibility to emphysema

Epidemiology of COPD

Functional Rescue of Elastin Insufficiency in Mice by the Human Elastin Gene

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