# ELN

## Overview
The ELN gene, located on chromosome 7, is responsible for encoding the protein elastin, a major component of the extracellular matrix in connective tissues. Elastin is crucial for providing elasticity and resilience to various tissues, including skin, lungs, and arteries, allowing them to return to their original shape after stretching or contracting. This protein is synthesized as a soluble precursor, tropoelastin, which is then cross-linked into a durable, insoluble polymer that forms elastic fibers. Mutations in the ELN gene can lead to disorders such as supravalvular aortic stenosis and cutis laxa, which are characterized by compromised elastic tissue function (Kozel2010Elastin; Li1997Elastin). Elastin's interactions with other proteins and its role in tissue mechanics underscore its importance in human health and disease (Shin2019Recent).

## Structure
The molecular structure of the elastin protein, encoded by the ELN gene, is characterized by its unique arrangement of alternating hydrophobic and cross-linking domains. These domains are crucial for the protein's function, with hydrophobic regions contributing to elastic recoil and crosslinking domains facilitating the binding of tropoelastin monomers through lysine-derived crosslinks such as desmosine and isodesmosine (Duque2018Elastin-driven; Keeley2013The). 

Tropoelastin, the precursor to elastin, features a primary structure that includes regions like exon 30 forming anti-parallel beta sheets, which are essential for the microassembly of monomers (Duque2018Elastin-driven). The secondary structure of tropoelastin includes structured elements like polyproline II structures and β-turns, despite its generally disordered nature (Keeley2013The). 

At the tertiary and quaternary levels, tropoelastin undergoes multimerization and crosslinking to form the mature elastin polymer, which is highly stable and integral to tissue elasticity (Duque2018Elastin-driven). Post-translational modifications are significant, including the formation of lysinonorleucine crosslinks that enhance the protein's structural integrity and function (Duque2018Elastin-driven).

The ELN gene is also subject to alternative splicing, leading to different tropoelastin isoforms that may influence the diversity of disease manifestations related to elastin (Duque2018Elastin-driven).

## Function
The ELN gene encodes elastin, a key protein in the extracellular matrix of connective tissues, crucial for providing elasticity and resilience, particularly in tissues like skin, lungs, and arteries. Elastin allows these tissues to resume their shape after stretching or contracting, playing a vital role in lung function and vascular mechanics. The protein is synthesized as a soluble monomer called tropoelastin, which then undergoes extensive cross-linking through lysine residues catalyzed by enzymes from the lysyl oxidase gene family. This cross-linking is essential for forming stable, insoluble elastin polymers that contribute to the structural integrity and function of elastic fibers (Park2006Novel; Kozel2010Elastin).

Elastin's molecular structure includes hydrophobic sequences and lysine-containing cross-linking motifs, which are crucial for its elastic properties. Over 80% of the lysine residues in elastin are involved in forming covalent cross-links, providing the necessary resilience against the hemodynamic stresses exerted by cardiac systole and diastole (Kozel2010Elastin). Additionally, specific exons within the ELN gene, such as exon 30, are critical for the microassembly of tropoelastin monomers, influencing the mechanical properties and structural integrity of elastin (Duque2018Elastin-driven).

Mutations or deletions in critical areas of the ELN gene can disrupt normal elastin assembly and function, leading to various genetic disorders associated with elastin insufficiency, such as supravalvular aortic stenosis and cutis laxa (Kozel2010Elastin).

## Clinical Significance
Mutations in the ELN gene, which encodes elastin, are linked to several genetic disorders, primarily affecting the structural integrity and function of connective tissues. Supravalvular aortic stenosis (SVAS), a condition characterized by the narrowing of the ascending aorta, is directly associated with point mutations, deletions, and splice site mutations in the ELN gene. These genetic alterations can lead to reduced elastin production, disrupting the elasticity of the aorta and other major arteries, which can result in severe cardiovascular complications (Urbán2000Isolated; Tassabehji1997Elastin:; Li1997Elastin).

Williams-Beuren Syndrome (WBS), a complex developmental disorder, involves deletions at the 7q11.23 locus that includes the ELN gene. Individuals with WBS exhibit cardiovascular abnormalities, distinctive facial features, and connective tissue anomalies, underscoring the critical role of elastin in vascular and connective tissue health (Urbán2000Isolated; Guemann2014ELNgene).

Additionally, autosomal dominant cutis laxa (ADCL), characterized by loose, sagging skin and potentially severe systemic manifestations, is associated with mutations in the ELN gene. These mutations lead to abnormal elastin fibers, affecting the skin's elasticity and resilience (Duz2017A; Graul‐Neumann2008Highly).

These conditions highlight the importance of the ELN gene in maintaining the structural and functional integrity of connective tissues, with mutations leading to a range of phenotypic expressions and clinical outcomes.

## Interactions
The ELN gene encodes elastin, a protein that interacts with various other proteins crucial for the formation and function of elastic fibers in connective tissues. Elastin interacts with microfibrillar-associated glycoproteins during elastogenesis, which is essential for the proper assembly of the microfibrillar scaffold needed for elastic fiber formation (Li1997Elastin). Additionally, elastin binds to fibulin-5 (FBLN5) and fibulin-4 (FBLN4), which facilitate its deposition onto microfibrils and influence the maturation of coacervates, a process essential for elastin's function (Shin2019Recent). The interaction between elastin and fibrillin-1 (FBN1) supports the assembly and mechanical function of elastic fibers, with FBN1 binding directly to tropoelastin, the precursor of elastin (Shin2019Recent). Furthermore, elastin's interaction with cell surface heparin, facilitated by basic amino acids in its terminal exon, assists in the growth and stabilization of the elastin multimer (Duque2018Elastin-driven). Mutations in specific exons of ELN, such as exon 16 and exon 30, can disrupt these interactions, leading to diseases like supravalvular aortic stenosis by affecting the structural integrity and cellular interactions of elastin (Duque2018Elastin-driven; Li1997Elastin).


## References


[1. (Graul‐Neumann2008Highly) Luitgard M. Graul‐Neumann, Ingrid Hausser, Maximilian Essayie, Anita Rauch, and Cornelia Kraus. Highly variable cutis laxa resulting from a dominant splicing mutation of the elastin gene. American Journal of Medical Genetics Part A, 146A(8):977–983, March 2008. URL: http://dx.doi.org/10.1002/ajmg.a.32242, doi:10.1002/ajmg.a.32242. (83 citations) 10.1002/ajmg.a.32242](https://doi.org/10.1002/ajmg.a.32242)

[2. (Park2006Novel) Seonmin Park, Eul-Ju Seo, Han-Wook Yoo, and Youngho Kim. Novel mutations in the human elastin gene (eln) causing isolated supravalvular aortic stenosis. International Journal of Molecular Medicine, August 2006. URL: http://dx.doi.org/10.3892/ijmm.18.2.329, doi:10.3892/ijmm.18.2.329. (20 citations) 10.3892/ijmm.18.2.329](https://doi.org/10.3892/ijmm.18.2.329)

[3. (Duque2018Elastin-driven) Maria Laura Duque Lasio and Beth A. Kozel. Elastin-driven genetic diseases. Matrix Biology, 71–72:144–160, October 2018. URL: http://dx.doi.org/10.1016/j.matbio.2018.02.021, doi:10.1016/j.matbio.2018.02.021. (90 citations) 10.1016/j.matbio.2018.02.021](https://doi.org/10.1016/j.matbio.2018.02.021)

[4. (Kozel2010Elastin) Beth A. Kozel, Robert P. Mecham, and Joel Rosenbloom. Elastin, pages 267–301. Springer Berlin Heidelberg, December 2010. URL: http://dx.doi.org/10.1007/978-3-642-16555-9_8, doi:10.1007/978-3-642-16555-9_8. (29 citations) 10.1007/978-3-642-16555-9_8](https://doi.org/10.1007/978-3-642-16555-9_8)

[5. (Keeley2013The) Fred W. Keeley. The Evolution of Elastin, pages 73–119. Springer Berlin Heidelberg, 2013. URL: http://dx.doi.org/10.1007/978-3-642-36002-2_4, doi:10.1007/978-3-642-36002-2_4. (21 citations) 10.1007/978-3-642-36002-2_4](https://doi.org/10.1007/978-3-642-36002-2_4)

[6. (Duz2017A) Mehmet B. Duz, Emre Kirat, Paul J. Coucke, Erkan Koparir, Alper Gezdirici, Anne De Paepe, Bert Callewaert, and Mehmet Seven. A novel case of autosomal dominant cutis laxa in a consanguineous family: report and literature review. Clinical Dysmorphology, 26(3):142–147, July 2017. URL: http://dx.doi.org/10.1097/mcd.0000000000000179, doi:10.1097/mcd.0000000000000179. (5 citations) 10.1097/mcd.0000000000000179](https://doi.org/10.1097/mcd.0000000000000179)

[7. (Shin2019Recent) Seung Jae Shin and Hiromi Yanagisawa. Recent updates on the molecular network of elastic fiber formation. Essays in Biochemistry, 63(3):365–376, August 2019. URL: http://dx.doi.org/10.1042/ebc20180052, doi:10.1042/ebc20180052. (48 citations) 10.1042/ebc20180052](https://doi.org/10.1042/ebc20180052)

[8. (Urbán2000Isolated) Zsolt Urbán, Virginia V. Michels, Stephen N. Thibodeau, Elaine C. Davis, Jean-Paul Bonnefont, Arnold Munnich, Benedicte Eyskens, Marc Gewillig, Koen Devriendt, and Charles D. Boyd. Isolated supravalvular aortic stenosis: functional haploinsufficiency of the elastin gene as a result of nonsense-mediated decay. Human Genetics, 106(6):577–588, May 2000. URL: http://dx.doi.org/10.1007/s004390000285, doi:10.1007/s004390000285. (97 citations) 10.1007/s004390000285](https://doi.org/10.1007/s004390000285)

[9. (Tassabehji1997Elastin:) M Tassabehji. Elastin: genomic structure and point mutations in patients with supravalvular aortic stenosis. Human Molecular Genetics, 6(7):1029–1036, July 1997. URL: http://dx.doi.org/10.1093/hmg/6.7.1029, doi:10.1093/hmg/6.7.1029. (101 citations) 10.1093/hmg/6.7.1029](https://doi.org/10.1093/hmg/6.7.1029)

[10. (Guemann2014ELNgene) Anne-Sophie Guemann, Joris Andrieux, Florence Petit, Emmanuel Halimi, Sonia Bouquillon, Sylvie Manouvrier-Hanu, Jiddeke Van De Kamp, Catherine Boileau, Nadine Hanna, Guillaume Jondeau, Guy Vaksmann, Veronique Houfflin-Debarge, and Muriel Holder-Espinasse. Elngene triplication responsible for familial supravalvular aortic aneurysm. Cardiology in the Young, 25(4):712–717, June 2014. URL: http://dx.doi.org/10.1017/s1047951114000766, doi:10.1017/s1047951114000766. (21 citations) 10.1017/s1047951114000766](https://doi.org/10.1017/s1047951114000766)

[11. (Li1997Elastin) D. Li. Elastin point mutations cause an obstructive vascular disease, supravalvular aortic stenosis. Human Molecular Genetics, 6(7):1021–1028, July 1997. URL: http://dx.doi.org/10.1093/hmg/6.7.1021, doi:10.1093/hmg/6.7.1021. (196 citations) 10.1093/hmg/6.7.1021](https://doi.org/10.1093/hmg/6.7.1021)