So what is ELN?
ELN is one of the genes affected by the microdeletion on chromosome 7 that causes WS. I often hear many refer to it as a chromosomal deletion which is not the case at all. In fact, it's a gene deletion called a microdeletion because very few genes are missing- only about 25 on average. Your body has 46 different chromosomes. 23 came from your mother and 23 came from your father. Together, they make you a whole person. Inside those chromosomes sit a series of genes that code for various proteins. On chromosome 7, the one affected in WS, there sits between 1,000-1,300 genes. If you had a chromosomal deletion, you'd be missing all 1,000+ because one entire chromosome would be missing. WS, in contrast is missing roughly 25 genes that sit on one of the lower arms of the chromosome. This is called a microdeletion. It's just a small section of the gene sequence was left behind during a phase of meiosis when the body jumbles the genes to create diverse offspring. (See the genetics page of this blog for more info on crossing over).
Out of those 25 genes, one of them is called ELN. ELN is deleted in such a high majority of WS individuals, it creates a very reliable gene to "look for" in genetic testing. Before we knew so much about ELN, we focused most of our research about WS on symptoms such as narrow arteries. The presence of narrow arteries is the number one reason individuals with WS have life-threatening issues. Because of this, it is considered a high priority area to study in the WS research world. At the time, they took a backwards approach to genetics. Researchers would study the disorder, identify how the tissues were arranged or functioned differently and then tried to pinpoint the protein that caused that change. From there they would look for the gene that coded for that protein. In SVAS, they determined that gene was ELN. Now that we know the region where the genes are missing, we can use a much more efficient molecular genetics to identify proteins and explore WS. The discovery of ELN not only helped better diagnose the disorder, it opened many doors in genetic research to better understand that portion of the genome.
Genetic testing used to diagnose WS is a relatively "new" method. Prior to this diagnostic test WS facial characteristics and common symptoms had to be recognized by a medical doctor. In the 1990's the FISH test (Fluorescence in situ hybridization) for ELN was created. The use of this diagnostic tool increased the means to diagnose and better understand WS. (learn more about FISH testing here). As our knowledge of the genetic world increases, we learn more and more about ELN, increase information available to doctors and families by new diagnostic testing, such as in microarrays and increase the potential to lessen the effects of the missing genes using gene therapy.
How does the absence of ELN become a problem such as a heart defect?
Your chromosomes are made up of so many genes, each like a book in a library or a chapter in an instruction manual. Each gene codes for a specific protein. Proteins are the workers of your body. Their functions span many areas such as building materials, enzymes that make important reactions happen, tunnels that transport materials across membranes, even tubes that transport materials around the cell. Some of your genes are only active during specific events in your life such as embryonic development or puberty and others are active all the time- maintaining cell structures or aiding in reactions that help you digest food.ELN is the type of gene that is expressed or "read" during fetal development and during the first few years of life and then continually through adolescence until your body completes its growth. After puberty, the ELN gene essentially sits dormant for the remainder of your life. Because of its relatively long lifespan- lasting up to 70 years, the body's need for making new elastin decreases greatly as we age.
When geneticists talk about a gene being expressed, they are referring to the process that occurs in the cell where the DNA is transcribed to RNA and RNA is used to create a protein. During fetal development, the baby's body is building many new structures. The organs in your body are made up of many different combinations of materials and tissues. The gene sequences such as ELN are very active during this stage of life in order to build functional organs and structures. It all starts inside the nucleus during transcription. The section of chromosome 7 that contains ELN unwinds. An enzyme named RNA polymerase unzips the section of DNA and matches the base pairs with RNA bases, essentially copying it. When it reaches the end of the segment, the new RNA strand (called messenger RNA or mRNA) leaves the nucleus to deliver the sequence to the protein maker- the ribosome.
When it reaches the ribosome, the mRNA feeds through this structure and is translated. During translation, the ribosome matches codons- or groups of 3 base pairs to an anticodon on a transfer RNA. The transfer RNA are aptly called this because they transfer the amino acid or protein building block to the ribosome. This match allows the cell to build or connect each amino acid into a strand in the proper order needed to make the desired protein.
When ELN is translated, it creates the protein called tropoelastin. When translation finishes the assembly of the amino acid strand the endoplasmic reticulum or ER takes the protein and coaxes it into a properly folded formation. Protein amino acids vary in their chemical composition. Many of them have polar or charged portions that attract to oppositely charge areas on other amino acids. This allows the protein to fold twist and connect to areas creating a unique shape. This shape is very functional. It gives the protein functional active sites that are designed to attract or repel molecules and "make things happen" within the cell.
The shape of tropoelastin is that of three parts or regions. The head of the molecule (labeled NC in the figure) is the portion that gives elastin its spring. It can stretch up to 8 times its relaxed state and then spring right back to its original structure unharmed. This becomes very important to its function in the tissues, which we'll get to in a bit. The second region just under the head is called the bridge. The bridge is an area that acts like a shock absorber. It absorbs energy from the coiled portion in order to prevent its base from becoming dislodged. The base functions to connect tropoelastin to an area of the tissue called the extracellular matrix. It is essentially an anchor to hold the tropoelastin in place.
So, is tropoelastin the same as elastin?
No! Tropoelastin is the main building block to a fiber called elastin. Once tropoelastin is created and packaged into its unique shape by the ER, it then is used as a building material to make elastin. Elastin is a fiber made of tropoelastin, microfibrils and is assembled by a group of five enzymes- called lysyl oxidases. As tropoelastin is created, it is shipped an area outside of the cell membrane where they accumulate. As they accumulate, one of the enzymes facilitates a chemical reaction on the tropoelastin to create cross-links or areas where they can soon connect. Essentially, it's like nailing brackets onto the structural material so you can connect them into a sheet. The cross-linked tropoelastin are then attached and woven to a series of microfibrils or tiny protein fibers that make up the extracellular matrix of connective tissue. This is basically a net that creates the foundation of a tissue and contains fibers, cells and is surrounded by nutrient rich fluids. The result is the fiber elastin.So, in an individual with WS, this assembly line of elastin production has a decrease output because one set of the ELN is absent. ELN is still transcribed and tropoelastin is still assembled but only in half the output as a typical person. Think about a factory that assembles a product. If you cut your workforce and materials by half, you'll only get half the product. That is what occurs in WS. They still make the tissues and build the organs but because less tropoelastin accumulates outside the cell, the resulting elastin fibers are smaller and less springy.
How does this cause symptoms of WS?
Elastin is a major component of many connective tissues. There are several different types of connective tissue that have many different functions- the most important being support. Most connective tissue acts to do just that- connect organs in the body. They, for example, provide a net of support for epithelial (skin) layers in the body, they connect muscle to various organs to provide that organ movement. They might connect vessels and fat to the organ to provide important nutrients. They can store water, fat and salts needed for the organ's function. They also provide support to maintain the organ's shape- a key function of elastin.
Within all connective tissue are many different structures- there are the cells, often called fibroblasts which make the fibers, like tropoelastin. There are fibers such as elastin and collagen that provide elastic properties or collagen which is strong and structural. There are several proteins such as microfibrils that provide a framework or net and the extracellular matrix is often filled with fluids. So, as you can see, the structure of an organ often requires elastin as a major structural component needed for the connective tissue to function properly.
Elastin is essentially needed in any organ that requires some sort of stretch in order to work properly. These organs include the heart and vessels, the skin, the lungs, and the joints. As those organs stretch or widen, elastin stretches, (much like a rubber band but so much better!) and then springs back to an unaffected relaxed state. This molecule is so good at this stretching job that most people's elastin can function properly for 70 plus years... pretty amazing material!
Much of the symptoms related to elastin have been discussed elsewhere in this blog. Below is some additional information about the disorders related to elastin and then you'll find a link to the blog page that gives more information.
Elastin and Arteries
Until the early 1990's, little was known about the link between elastin and one of the most common vessel issues in WS- Supra-valvular aortic stenosis (SVAS) refers to the narrowing of the major vessel that leaves the heart- the aorta. The narrowing occurs just above a valve or doorway that prevents the blood from falling backwards into the heart. Typically in WS there can be overall narrowing in all the major arteries of the body- four of primary concern are the aorta, pulmonary arteries (going to the lungs), the coronaries (delivering blood directly to the heart tissue) and renal arteries (those that deliver blood to the kidneys).
When the body builds an artery, it assembles the structure using four main tissues- inside, the endothelial layer is built of epithelial tissue. This is like a skin-like lining that comes into contact with the blood. Outside the inner layer is the media tunic. This is composed of connective tissue and smooth muscle. In a typical artery, the media layer is made up of very organized parallel bundles of smooth tissue and elastin. This layer functions to control the size of the artery and regulate blood pressure. In WS, the elastin, like discussed early, is much smaller in size due to the lack of tropoelastin present in the tissue. Studies of the media tissue layer suggest that the pattern of elastin and smooth muscle becomes very disorganized and due to the lack of elastin, excess smooth muscle is layed down in an effort to compensate causing the vessel to loose it's stretchy quality and a much narrower formation is created.
Diagram shows WS elastin on the left (notice the lack of tropoelastin) and a typical elastin on the right.
Considering that SVAS is the most life-threatening condition for those with WS, there is a large amount of research being conducted to better understand the mechanism or ways the vessel becomes narrow. Unlike pulmonary stenosis, SVAS can worsen as a person ages. As scientists isolate exactly how this occurs, there is hope that they can develop medications that might decrease the inflammation and decrease the degradation of elastin to control the worsening of the disorder.
Learn more about SVAS and it's affect on the body on the cardiovascular page of this blog.
ELN and its task force
While scientists have identified that the lack of one ELN gene is the cause of SVAS, they are suspect that ELN in combination with other genes that regulate its expression are involved in many other symptoms of WS including soft skin, premature aging, and facial features such as puffiness above the eyes. Studies of ELN began with SVAS because it was so prevalent in individuals with WS. As many parents are aware, WS has a spectrum of symptoms. Even though 99% of individuals are missing one ELN then why doesn't everyone have the same symptoms at the same level of severity? The answer is in the enzymes. The expression of a gene takes an entire task force to copy the gene, create the protein, organize the protein, and build it into its final structure. Even then when the fiber is damaged, there is a task force to either repair or replace it. This is all orchestrated by proteins and that is probably where the spectrum effect lies.
Scientists have been busy at work trying to identify the genes and enzymes that have a hand in causing the more severe cases of WS. As the amount of research improves and these genes and enzymes are identified, we may find better ways of predicting issues and treating them.
For a great example of this, visit the section on scoliosis in this blog.
ELN and the skin
Elastin is an important component of the skin. It's found in a layer called the dermis which sits under a thin protective layer called the epidermis. The dermis has many different functions and is the working portion of the skin. In the layer closest to the epidermis is called areolar tissue. It's loosely woven with collagen (for strength), elastin (for stretch), cells called fibroblasts (for building more fibers), and a salty water environment. You use this portion to store water and salts and create sweat. It has many blood vessels, nerves and hair follicles that live here, too. Under the areolar tissue is a layer called dense irregular. This is densely packed with collagen and elastin fibers in bundles that twist and turn in many different directions.This is the portion that creates structure to your skin. Imagine a pregnant belly. As it grows and grows the skin must stretch and adapt. Then after pregnancy it (ideally!) returns back to normal. Now I can't speak from experience with this (ha ha) but if you can maintain the integrity of the elastin and collagen fibers, the tissue can remain in tact. If you can't, there are enzymes that gobble up the damaged skin and quickly lay down a repaired section- leaving you with stretch marks (which is essentially scar tissue).
Now, your probably thinking "how does this all have to do with WS?" I use the pregnancy example because its easy to visualize the damage that can occur. Damage also occurs with everyday life. Aging is definitely something that everyone has to deal with. Overtime, the lifespan of elastin can break down and lose its integrity. As we become exposed to sun, smoke and other carcinogens the damage can accelerate. Individuals with WS tend to have early onset of aging and it all has to do with damaged elastin. As damaged elastin is discovered, the body disassembles it with an enzyme called elastase. You also have another enzyme called alpha 1 antitrypsin (AAT) that slows down or inhibits elastase. It's basically a control so the enzyme doesn't go crazy and gobble up all the elastin in site. Scientists have been studying AAT trying to identify its role in WS. There is some evidence that some variations of AAT may contribute to more severe issues related to elastin. There are still many questions unanswered but many clues to the complicated role to how genes and proteins influence one another.
So, in conclusion, everyone has a degree of elastin damage as we age. In WS, where they are beginning with less elastin present in the dermis, the aging process will become more transparent over time.
ELN and the vocal cords
As we speak, we manipulate the pressure within the larynx which moves and vibrates a portion called the vocal folds. The histology or layers within the vocal folds are mainly made of elastin. There is one jelly-like layer that is primarily elastic and another layer called the lamina propria that is thicker with elastin. This provides the flexibility of the folds to move with the pressure difference of the larynx during speech. Another, leaf shaped flap called the epiglottis sits over the vocal folds. This flap is responsible for closing off the windpipe when you swallow food. It can also vibrate as well, contributing to the sound of your voice. The vocal folds are primarily composed of elastin layers so in WS they do not vibrate and move as easily causing a hoarse tone of sound.
ELN and the digestive system
The last place in the body that is most affected by the absence of elastin is the digestive system. The abdomen is a relatively open area, not containing any bones to shelter the organs. Because of this it relies on a combination of muscle and connective tissue for support. There is a layer of integument or skin that creates the internal lining of the abdomen, called the peritoneum. The peritoneum, like the skin, has a layer composed of elastin netting that allows it to stretch. This lining is important in pulling in the abdomen and supporting the core.When elastin is weak here there, the internal organs, mainly the intestines, can bulge through the netting and get caught up in the abdominal wall. This is called a hernia and can be pretty common in WS. The problem with hernias is that they can be uncomfortable but they can also get infected if feces or bacteria get stuck in them. This can cause inflammation. Hernias are typically noticeable on the outside of the skin because a pocket or bulge will form under the skin. Hernias need to be repaired surgically.
The most common type of hernia is the inguinal hernia. This occurs during infancy and is most common in males but can still occur in females. In males, as the reproductive system develops, there is a canal, called the inguinal canal, that the testes descend or move down through. This canal then closes up, typically. In inguinal hernias the intestines slip down through the canal as well and a hernia develops in the groin. This can be attributed to missing elastin because the wall of the abdomen and the canal itself is looser than typical.
Another issue that can occur as people age is diverticulitis. This is similar to hernias but instead of the intestine getting caught in weak spots of the abdominal wall, weak spots on the intestine, itself create loose pockets. This too can get infected. This disorder is usually found in the elderly population but because of the nature of the elastin in WS, it can happen much sooner. There are records of people as young as 17 who have developed diverticulitis in the WS population.
ELN in the joints
The final area of the body that is affected by elastin is the joints. Most notably the intervertebral discs of the spine. I have a lengthy post on posture that discusses this topic. Go here for more info.
In sum...
As you can see, not all symptoms or complications of WS are attributed to ELN but its discovery was infinitely important in today's understanding of WS. It opened doors in genetics to help diagnose and better understand the region where WS occurs. It opened doors in cardiology to help understand and treat the #1 cause of fatal complications. It's discovery has completely changed the care and open avenues for research in the WS world.
Sources:
- Sigmoid divertculitis in patients with Williams Van-Beurun syndrome
- Elastin gene point mutation in patients with inguinal hernia
- An investigation of voice quality in individuals with inherited elastin deficiencies
- Williams-Van Beuren Syndrome Genes and Mechanisms
- Medical Process: Williams syndrome New England Journal of Medicine by Pober
- A Human Vascular disorder, supravalvular disorder, maps to chromosome 7 by Ewart et al.
- Genetic approaches to cardiovascular disease: supra-valvular aortic stenosis, Williams syndrome and Long-QT syndrome by Keating
- The extracellular matrix
- The science of elastin
- Genetics Home reference: US National reference of genetics
- Tropoelastin bridge region positions the cell-interactive C terminus and contributes to elastic fiber assembly by Yeo et. all
- Elastin Based Constructs; Lisa Nivison-Smith and Anthony Weiss
