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The destruction of elastic fibers has been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). Emphysema has been described in autosomal dominant cutis laxa, which can be caused by mutations in the elastin gene. Previously, a rare functional mutation in the terminal exon of elastin was found in a case of severe, early-on...
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... our 31 amplicons in 180 total subjects, 95% of DNA melts were successfully completed. A total of 254 sequencing reactions were performed on these subjects, resulting in identification of a total of 28 SNPs (Table 2). Of these SNPs, eight were present in dbSNP (build 129). ...
Similar publications
Cutis laxa tip1b is a rare autosomal recessive disorder caused by FBLN 4 mutation and primarily characterized by vascular anomalies. Herein, we present five patients who are the members of the same family. The primary cardiac findings of these patients were giant aortic aneurysms. One 2.5-year-old patient with a massive aneurysm of the ascending ao...
Citations
... Ligamentous laxity (50) is seen as well as early wrinkling and facial drooping of the skin (51). More recently, lung phenotypes have been described in these individuals and in mouse models that suggest air trapping and lung obstruction that increases with age (52)(53)(54)(55)(56)(57). Because WS impacts 24 to 26 genes beyond ELN, individuals with this condition manifest additional features attributable to those genes such as developmental delays, a characteristic hyper-social personality, and hypercalcemia (for review, see Ref. 58). ...
Elastin provides recoil to tissues that stretch such as the lung, blood vessels and skin. It is deposited in a brief window starting in the prenatal period and extending to adolescence in vertebrates, and then slowly turns over. Elastin insufficiency causes conditions such as Williams-Beuren syndrome and elastin-related supravalvar aortic stenosis, which are associated with a range of vascular and connective tissue manifestations. Regulation of the elastin (ELN) gene occurs at multiple levels including promoter activation/inhibition, mRNA stability, interaction with microRNAs, and alternative splicing. However, these mechanisms are incompletely understood. Better understanding of the processes controlling ELN gene expression may improve medicine's ability to intervene in these rare conditions, as well as to replace age-associated losses by re-initiating elastin production. This review describes what is known about the ELN gene promoter structure, transcriptional regulation by cytokines and transcription factors, and post-transcriptional regulation via mRNA stability and micro-RNA and highlights new approaches that may influence regenerative medicine.
... Single nucleotide variants in the 3 end of ELN (the elastin gene) cause autosomal dominant cutis laxa (MIM #123700), which is associated with severe emphysema and characteristically lax skin [5,6]. Additionally, isolated severe chronic obstructive pulmonary disease (COPD) was described in two pedigrees with the c.2318 G > A; p.G773D variant in the extreme C-terminus [7,8]. More recently, a proband and his father were identified with a variant in the start codon of ELN (c.2T > C; p.M1T), causing elastin haploinsufficiency and supravalvular aortic stenosis (SVAS, MIM #185500) [9]. ...
Williams–Beuren syndrome (WS) results from the deletion of 25–27 coding genes, including elastin (ELN), on human chromosome 7q11.23. Elastin provides recoil to tissues; emphysema and chronic obstructive pulmonary disease have been linked to its destruction. Consequently, we
hypothesized that elastin insufficiency would predispose to obstructive features. Twenty-two adults with WS (aged 18–55) and controls underwent pulmonary function testing, 6 min walk, and chest computed tomography (CT). Lung and airspace dimensions were assessed in Eln+/ and control mice via microCT and histology. The forced expiratory volume in 1 s (FEV1) and the ratio of FEV1 to forced vital capacity (FVC) were lower in adults with WS (p < 0.0001 and p < 0.05, respectively).
The FEV1/FVC ratio was more frequently below the lower limit of normal in cases (p < 0.01). The ratio of residual volume to total lung capacity (RV/TLC, percent predicted) was higher in cases (p < 0.01), suggesting air trapping. People with WS showed reduced exercise capacity (p < 0.0001). In Eln+/ mice, ex vivo lung volumes were increased (p < 0.0001), with larger airspaces (p < 0.001).Together these data show that elastin insufficiency impacts lung physiology in the form of increased
air trapping and obstruction, suggesting a role for lung function monitoring in adults with WS.
... The gene Activin A receptor type 1B (ACVR1B) is related to emphysema distribution [103]. In contrast, exonic elastin variants do not appear to be common risk factors for emphysema [104]. ...
Introduction: Distinct pathologies can cause chronic obstructive pulmonary disease (COPD). Emphysema is a COPD-phenotype characterized by destruction of lung parenchyma. Alpha-1 antitrypsin deficiency (AATD) is a genetic cause of emphysema, whereas smoking is the most important risk factor of non-AATD emphysema. A general underappreciation of non-AATD emphysema has hampered progress in the field, and clinical guidelines have prohibited the use of emphysema as a diagnosis. Non-AATD emphysema, however, is far from irrelevant as it associates with dyspnea, reduced exercise capacity and relevant outcome measures.
Areas covered: Mechanisms underlying enhanced tissue loss in emphysema are protease/antiprotease imbalance, increased oxidative stress, several fundamental cell biological processes such as programmed cell death and autophagy, and impaired repair mechanisms. Therapeutic options for emphysema vary from smoking cessation to lung volume reduction. Current pharmacological treatments have less favorable effects in emphysematous than in non-emphysematous COPD patients.
Expert opinion: We advocate the acknowledgement of non-AATD emphysema as a clinical diagnosis and propose to end the era of bringing all pathologies that may lead to chronic airflow limitation together under the umbrella-term of COPD. Decelerating proteolysis and restoring damage should be main targets in emphysema. Vitamin A/K, hyaluronan, copper and roflumilast are promising candidates.
... We added recently described genome-wide significant associations to moderate-to-severe COPD or severe COPD, including RIN3, MMP12, and TGFB2 41,47-51 . We also considered genes causing Mendelian syndromes which include emphysema as part of their syndrome constellation: alpha-1 antitrypsin deficiency (SERPINA1) and cutis laxa (ELN and FBLN5) 52,53 . These 11 genes, in toto, were subsequently used as seed genes for network analyses. ...
The polygenic nature of complex diseases offers potential opportunities to utilize network-based approaches that leverage the comprehensive set of protein-protein interactions (the human interactome) to identify new genes of interest and relevant biological pathways. However, the incompleteness of the current human interactome prevents it from reaching its full potential to extract network-based knowledge from gene discovery efforts, such as genome-wide association studies, for complex diseases like chronic obstructive pulmonary disease (COPD). Here, we provide a framework that integrates the existing human interactome information with experimental protein-protein interaction data for FAM13A, one of the most highly associated genetic loci to COPD, to find a more comprehensive disease network module. We identified an initial disease network neighborhood by applying a random-walk method. Next, we developed a network-based closeness approach (CAB) that revealed 9 out of 96 FAM13A interacting partners identified by affinity purification assays were significantly close to the initial network neighborhood. Moreover, compared to a similar method (local radiality), the CAB approach predicts low-degree genes as potential candidates. The candidates identified by the network-based closeness approach were combined with the initial network neighborhood to build a comprehensive disease network module (163 genes) that was enriched with genes differentially expressed between controls and COPD subjects in alveolar macrophages, lung tissue, sputum, blood, and bronchial brushing datasets. Overall, we demonstrate an approach to find disease-related network components using new laboratory data to overcome incompleteness of the current interactome.
... We added recently described genome-wide significant associations to moderate-to-severe COPD or severe COPD, including RIN3, MMP12, and TGFB2 41, [47][48][49][50][51] . We also considered genes causing Mendelian syndromes which include emphysema as part of their syndrome constellation: alpha-1 antitrypsin deficiency (SERPINA1) and cutis laxa (ELN and FBLN5) 52,53 . These 11 genes, in toto, were subsequently used as seed genes for network analyses. ...
The polygenic nature of complex diseases offers potential opportunities to utilize network-based approaches that leverage the comprehensive set of protein-protein interactions (the human interactome) to identify new genes of interest and relevant biological pathways. However, the incompleteness of the current human interactome prevents it from reaching its full potential to extract network-based knowledge from gene discovery efforts, such as genome-wide association studies, for complex diseases like chronic obstructive pulmonary disease (COPD). Here, we provide a framework that integrates the existing human interactome information with new experimental protein-protein interaction data for FAM13A, one of the most highly associated genetic loci to COPD, to find a more comprehensive disease network module. We identified an initial disease network neighborhood by applying a random-walk method. Next, we developed a network-based closeness approach (CAB) that revealed 9 out of 96 FAM13A interacting partners identified by affinity purification assays were significantly close to the initial network neighborhood. Moreover, compared to a similar method (local radiality), the CAB approach predicts low-degree genes as potential candidates. The candidates identified by the network-based closeness approach were combined with the initial network neighborhood to build a comprehensive disease network module (163 genes) that was enriched with genes differentially expressed between controls and COPD subjects in alveolar macrophages, lung tissue, sputum, blood, and bronchial brushing datasets. Overall, we demonstrate an approach to find disease-related network components using new laboratory data to overcome incompleteness of the current interactome.
... In addition to the SVAS and ADCL phenotypes, the rare ELN point mutation c.2318G>A resulting in p.Gly773Asp (exon 34) was identified in a large pedigree with severe early onset chronic obstructive pulmonary disease (COPD) [72,73]. This mutation results in a non-conservative amino acid change in a position that is conserved across species, and is predicted to be probably damaging by in silico testing. ...
... This mutation results in a non-conservative amino acid change in a position that is conserved across species, and is predicted to be probably damaging by in silico testing. This variant was identified in one further proband following screening of ~1300 individuals genotyped through the Boston Early-Onset COPD Study and the National Emphysema Treatment Trial but other causative variants in ELN have not been identified in the numbers evaluated [72]. ...
Elastic fibers provide recoil to tissues that undergo repeated deformation, such as blood vessels, lungs and skin. Composed of elastin and its accessory proteins, the fibers are produced within a restricted developmental window and are stable for decades. Their eventual breakdown is associated with a loss of tissue resiliency and aging. Rare alteration of the elastin (ELN) gene produces disease by impacting protein dosage (supravalvar aortic stenosis, Williams Beuren syndrome and Williams Beuren region duplication syndrome) and protein function (autosomal dominant cutis laxa). This review highlights aspects of the elastin molecule and its assembly process that contribute to human disease and also discusses potential therapies aimed at treating diseases of elastin insufficiency.
... We did not, for example, consider gene-gene interactions or gene-environment interaction. The genotyping and imputation in this study are not well-suited to address the role of rare variants, which may also be important in explaining COPD susceptibility [95][96][97] . Our definition of cases and controls was based only on the presence of moderate, or moderate-tosevere airflow obstruction, yet COPD is highly heterogeneous. ...
Background
The genetic risk factors for susceptibility to chronic obstructive pulmonary disease (COPD) are still largely unknown. Additional genetic variants are likely to be identified by genome-wide association studies in larger cohorts or specific subgroups. We sought to identify risk loci for moderate to severe and severe COPD with data from several cohort studies.
Methods
We combined genome-wide association analysis data from participants in the COPDGene study (non-Hispanic white and African-American ethnic origin) and the ECLIPSE, NETT/NAS, and Norway GenKOLS studies (self-described white ethnic origin). We did analyses comparing control individuals with individuals with moderate to severe COPD and with a subset of individuals with severe COPD. Single nucleotide polymorphisms yielding a p value of less than 5 × 10−7 in the meta-analysis at loci not previously described were genotyped in individuals from the family-based ICGN study. We combined results in a joint meta-analysis (threshold for significance p<5 × 10−8).
Findings
Analysis of 6633 individuals with moderate to severe COPD and 5704 control individuals confirmed association at three known loci: CHRNA3 (p=6·38 × 10−14), FAM13A (p=1·12 × 10−14), and HHIP (p=1·57 × 10−12). We also showed significant evidence of association at a novel locus near RIN3 (p=5·25 × 10−9). In the overall meta-analysis (ie, including data from 2859 ICGN participants), the association with RIN3 remained significant (p=5·4 × 10−9). 3497 individuals were included in our analysis of severe COPD. The effect estimates for the loci near HHIP and CHRNA3 were significantly stronger in severe disease than in moderate to severe disease (p<0·01). We also identified associations at two additional loci: MMP12 (overall joint meta-analysis p=2·6 × 10−9) and TGFB2 (overall joint meta-analysis p=8·3 × 10−9).
Interpretation
We have confirmed associations with COPD at three known loci and identified three new genome-wide significant associations. Genetic variants other than in α-1 antitrypsin increase the risk of COPD.
Funding
US National Heart, Lung, and Blood Institute; the Alpha-1 Foundation; the COPD Foundation through contributions from AstraZeneca, Boehringer Ingelheim, Novartis, and Sepracor; GlaxoSmithKline; Centers for Medicare and Medicaid Services; Agency for Healthcare Research and Quality; and US Department of Veterans Affairs.
... TO THE EDITOR: Wan et al. [2010] reported in this journal a non-smoking adult person with Williams-Beuren syndrome and emphysema, and raised the question if defects in the elastin gene are associated with increased susceptibility toward developing chronic obstructive pulmonary disease (COPD) and emphysema. Additional support that haploinsufficiency for the elastin gene could play a role in the pathogenesis of emphysema is supported by the observation of a functional mutation in the elastin gene in two independent persons with early onset COPD [Kelleher et al., 2005;Cho et al., 2009], as well as the fact that changes in the elastin gene are also described in cases of autosomal dominant form of cutis laxa (OMIM 123700) associated with severe premature emphysema [Rodriguez-Revenga et al., 2004;Urban et al., 2005]. ELN expression plays a crucial role in development of the alveoli at both the alveolar duct and alveolar sac levels, most likely due to a defect in alveolar septal development and alveolar growth [Wendel et al., 2000;Shifren et al., 2006]. ...
... Imbalances between proteases and anti-proteases increase susceptibility towards developing COPD; the best described imbalance remains severe deficiency of α-1 antitrypsin, an antiprotease which acts against neutrophil elastase. Defects within the elastin gene may also contribute to COPD susceptibility -a functional mutation in the elastin gene has been found in two unrelated subjects with early-onset COPD [Cho 2009;Kelleher 2005]. Mutations in the elastin gene have also been described in cases of autosomal dominant cutis laxa (OMIM 123700) associated with severe, premature emphysema [Rodriguez-Revenga 2004;Urban 2005]. ...
Williams-Beuren syndrome (WBS) is caused by a submicroscopic deletion on chromosome 7q11.23 that encompasses the entire elastin (ELN) gene. Elastin, a key component of elastic fibers within the lung, is progressively destroyed in emphysema. Defects in the elastin gene have been associated with increased susceptibility towards developing chronic obstructive pulmonary disease (COPD) and emphysema in both humans and mice. We postulate that hemizygosity at the elastin gene locus may increase susceptibility towards the development of COPD and emphysema in subjects with WBS. We describe an adult subject with WBS who was a lifelong non-smoker and was found to have moderate emphysema. We also examined the pulmonary function of a separate cohort of adolescents and young adults with WBS. Although no significant spirometric abnormalities were identified, a significant proportion of subjects reported respiratory symptoms. Thus, while significant obstructive disease does not appear to be common in relatively young adults with WBS, subclinical emphysema and lung disease may exist which possibly could worsen with advancing age. Further investigation may elucidate the pathogenesis of non-smoking-related emphysema.
... However, a study on a polymorphism causing a serine/glycine mutation at amino acid position 422 did observe a link between this mutation and carotid artery distensibily and elasticity (Hanon, Luong et al. 2001). Recently, advanced sequencing technology has been applied to detect single nucleotide polymorphisms (SNPs) in human elastin (Cho, Ciulla et al. 2009) but so far, few links between mutations and disease phenotypes have been discovered. ...
