As we move closer to space travel becoming more feasible for the average person (hopefully in the coming decades), physicians will have to face the reality of astronauts experiencing health problems beyond the borders of a hospital, where there is less help available. While astronauts are selected to be in good health and unlikely to develop severe health complications while traveling, one will eventually suffer an adverse event. Previously healthy athletes’ hearts have been known to stop during exercise on rare occasions, possibly due to undiagnosed heart defects, such as hypertrophic cardiomyopathy. Fortunately, it is a possibility that NASA considers.

We also need to understand more ways to prevent such an event from occurring so we do not have to rely on such contingencies. A group of Japanese researchers sought to find answers for this problem. Will it make space travel safer? Remember to give my article claps and read it all the way through to support me as a writer!

Heart attacks and strokes are ultimately caused by fat deposits in your blood vessels breaking apart, driving a series of reactions that eventually obstruct the vessel, starving your heart or brain of essential oxygen. A way to better understand this process, so we can keep you (and astronauts) safe using the wonders of modern medicine, is to know how the genes in your blood vessels are affected by external triggers, such as a fat plaque deciding it had enough or microgravity. This is where it gets interesting when considering space travel!

A group of scientists created a device called a clinostat that can mimic a low-gravity environment by rotating the cells in blood vessels at a particular rate (so less need to conduct expensive space station experiments). They found that we have gravity-sensitive genes in our blood vessels that produce more or less of their downstream products (think of DNA like a conveyor belt where DNA is used to make other things) when gravity changes! But how is this evidence convincing and exciting?

The group found that the gene SLCO2A1 appeared to be the gravity-dependent gene (stay tuned because there will likely turn out to be other gravity-dependent genes). This gene is notable because others have found its expression linked with cardiovascular disease (like heart attacks) and high blood pressure. While more research, perhaps using mathematical approaches as I use in my genetics research, will be required to clarify the intersection between this gene, heart disease, and gravity changes, it is a good step toward understanding how being in space changes our bodies! So what needs to happen now?

Due to the nature of being among the first to explore this piece of science, the group focused on genes that are more commonly expressed. Future studies could study the expression of all roughly 20,000 genes to see if there is anything else interesting that changes. This study used only cells, which can behave differently in mammals like us or mice. Finding a way to non-invasively measure blood vessel gene expression in these more complex models could further clarify the role of this gene or other genes that could be contributing. There is still a lot that we can do. That is what makes science so exciting!

Aerospace medicine and our understanding of how being in space changes the body has made progress. Unanswered questions could also help us navigate the stars while ensuring travelers are well cared for. Studies such as this help understand how being in an unfamiliar place can change our bodies, thus offering targets to monitor as they could influence astronaut health or risk of developing diseases down the road. Give it time, and we’ll have a better sense of it all, making your orbital flight that much safer.

If you liked this article, be sure to give me claps and subscribe. It would be fantastic to have you as a follower! Let me know your thoughts on aerospace medicine or your thoughts on the article in the comments. Thanks for reading! 🙂

The post Gene Expression Changes in Heart Cells: A New Threat to Astronaut Health? appeared first on Medika Life.

New emerging research raises important questions and could also potentially affect our understanding of the coronaviruses. To really understand the content of this article, a little refresher course in basic biology is required for reference. I’ve tried to keep it as simple as possible and we are going to take a few side roads to arrive at the conclusion. Stay with us as we examine the most studied viruses in the world, discover how they’ve mastered the art of subterfuge, and examine our efforts to stay one step ahead.

A human cell

Although there are many different cells within our bodies, for simplicity we’ll look at a generalized cell structure. A cell consists of three parts: the cell membrane, the nucleus, and, between the two, the cytoplasm. Within the cytoplasm lie intricate arrangements of fine fibers and hundreds or even thousands of minuscule but distinct structures called organelles.

The vaccine manufacturers are at pains to point out that the mRNA they use in their vaccines bypasses our DNA (your DNA is encased within your cell in the nucleus, the purple and deep blue bit in the image below). Vaccine mRNA is delivered directly to the cytoplasm of a cell (the light blue section below), in effect, replicating our cell’s DNA-based processes of making(transcribing) RNA within the nucleus of the cell. Our DNA also releases any messenger RNA it creates into the cytoplasm. 

According to the manufacturers, their mRNA can not be reintegrated into the nucleus and DNA of our cells. in other words, their mRNA cannot cross the nuclear membrane. Everything is restricted to the cytoplasm, as with the coronaviruses, on which their vaccines are molded. Is their explanation consistent with emerging science? 

If you’re still having trouble visualizing cell layout, have a quick look at this article that breaks down cell structure to its basic levels.

The wonders of the viral world

To truly appreciate the complexity and subtle beauty of life and nature, and to appreciate the limitations of our understanding, examine the humble virus and its life cycle. We are toddlers in a new world, just learning to read and the limits of our knowledge are reflected by our vulnerability.

Certain viruses are capable of hijacking our DNA. In fact, it is such a common occurrence, that a small portion of every person’s DNA is comprised of bits of viral code. We carry with us a history book of our ancestor’s brushes with viruses. The human genome is replete with endogenous retroviruses (HERVs, also known as retrotransposons) that have entered the human germline at various times in the evolutionary past and now occupy 8.3% of our genome. 

The HIV virus is perhaps best known for exploiting this mechanism, commandeering our DNA, from where it then orchestrates its attacks. It’s one of the reasons HIV has been so difficult to combat. This is a typical trait of the family of viruses known as retroviruses.

What’s the main difference between these viruses and your standard-issue, run-of-the-mill virus? Two key processes that differentiate retroviruses from standard viruses are reverse transcription and genome integration. Remember we learned earlier that transcription is simply another name in cell biology for ‘making’, so reverse transcription simply means reverse or backward making. Genome integration refers to the ability of these viruses to invade and commander our bodies’ DNA via their RNA, incorporating their genetic material into ours. 

Without becoming too technical, retroviruses are a type of virus in the viral family called Retroviridae. They use RNA as their genetic material and are named after a special enzyme that’s a vital part of their life cycle, namely reverse transcriptase. Simply put, this enzyme allows retrovirus RNA access to the nucleus of our cells. 

You might wonder why we’re headed down this route, as coronaviruses arent classified as retroviruses, but rather RNA viruses. RNA viruses typically invade a cell and conduct their business in the cytoplasm, where they replicate without accessing our DNA. So why the retrovirus thing? Read on, all will be revealed.

Retroviruses are capable of insane amounts of cellular and genetic engineering, processes so intricate and delicate that you cannot but be left in awe at their complexity and ingenuity. Their ingenious design is not apparent until you understand the complex engineering they can undertake to hijack our cells and reprogram our DNA for their own use. For science, these viruses pose a massive headache and it can take decades to develop mechanisms to combat them.

An important part of the retroviral war is the virus’s ability to hide within our cells without being “active”. These stowaways are referred to as latent reservoirs. infected individuals appear completely healthy. You can even pass all the tests science can throw at you and the stowaways will remain undetected. Viruses can also employ another trick to evade the body’s defenses, hiding in plain sight where the body’s natural immune system doesn’t look, so-called “immunoprivileged sites”.

Dormancy can last weeks, months, or years, ensuring the virus survives. In some instances, as with the Ebola virus, and EVD, individuals who test negative for the virus or who are asymptomatic, are in fact contaminated with latent reservoirs of the Ebola virus and can act as vectors for new outbreaks. Coronaviruses are capable of this little trick as well. For instance, in a study, infected men were found to have traces of the SARS-CoV2 virus in their semen, two to three days after recovery. Semen is the perfect hiding place for a virus and it’s one of the places Ebola chooses.

The testes, along with the eyes, placenta, fetus, and central nervous system, are considered to be “immunoprivileged sites”, which means they are protected from severe inflammation associated with an immune response. This is probably an evolutionary adaptation that protects vital structures. Immune cells are prevented from interacting with cells in the testes and the brain by means of blood-tissue barriers(BTB). 

These “immunoprivileged sites” are, in effect, safe zones where viruses may be protected from the host’s immune response, if, and only if, the viruses are able to penetrate the BTB. We know SARS.CoV2 is capable of penetrating these barriers, but don’t as yet understand how it achieves this. This is evidenced by infected cells in the central nervous system. You can read a more detailed explanation of the impact of coronavirus on the brain here.

Let’s examine the mechanism viruses use to pull off their stowaway act, as this involves, amongst other tricks, reverse transcription and this, as we’ll discuss later, may have relevance to the mRNA vaccines. Then we can examine the real reason we’re here, data released in a preprint from Harvard and MIT, entitled SARS-CoV-2 RNA reverse-transcribed and integrated into the human genome.

The viral magic trick called reverse transcription

Sciencemag first published a reference to the study above in December of 2020 in an article entitled “The coronavirus may sometimes slip its genetic material into human chromosomes — but what does that mean?”. Perhaps the best way to understand how this process works is to examine HIV, one of the most studied and best understood retroviruses on the planet. I also chose HIV as it is not subject to the flurry of conflicting information that surrounds the coronavirus.

You can skip over this, but understanding the processes these viruses use is key to understanding emerging and existing questions relating to mRNA technology.

HIV is called a retrovirus because it works in a back-to-front way. Unlike other viruses, retroviruses store their genetic information using RNA instead of DNA, meaning they need to ‘find’ DNA when they enter a human cell in order to make new copies of themselves. To achieve this, they need to access the nucleus of the cell to get at the DNA it contains. To make this easier to understand we need to examine the structure of HIV to understand what happens. Here’s a graphic to help you visualize how this works.

• HIV specifically targets CD4 cells, the body’s principal defenders against infection, using them to make copies of the virus.

Inside the virus envelope is a layer called the matrix. The core of the virus, or nucleus, is held in the capsid, a cone-shaped structure in the center of the virion. The capsid contains two enzymes essential for HIV replication, the reverse transcriptase and integrase molecules. It also contains two strands of RNA — which hold HIV’s genetic material. HIV’s RNA is made up of nine genes that contain all the instructions to make new viruses.

I’m going to skip over the virus’s attachment and fusing to the cell and focus on what happens after attachment. You can find a more detailed explanation of the HIV life cycle here. 

Reverse transcription and Integration

When HIV RNA enters the cell it must be `reverse transcribed` into proviral DNA before it can be integrated into the DNA of the host cell. HIV uses its reverse transcriptase enzyme to convert RNA into proviral DNA inside the cell.

After HIV RNA is converted into DNA, HIV’s integrase enzyme attaches itself to the end of the proviral DNA strands and it is passed through the wall of the cell nucleus. Once the proviral DNA enters the cell nucleus, it binds to the host DNA and then the HIV DNA strand is inserted into the host cell DNA.

After the proviral DNA is integrated into the DNA of the host cell, HIV remains dormant within the cellular DNA. This stage is called latency and the cell is described as ‘latently infected’. It can be difficult to detect these latently infected cells even when using the most sensitive tests.

Transcription and Translation, the final phase

The cell will now produce HIV RNA (remember, DNA produces RNA) if it receives a signal to become active. Our CD4 cells become activated if they encounter an infectious agent. When the cell becomes active, HIV uses the host enzyme RNA polymerase to make messenger RNA. This messenger RNA provides the instructions for making new viral proteins in long chains. 

The long chains of HIV proteins are cut into smaller chains by HIV’s protease enzyme and are assembled into a new copy of the virus inside the cytoplasm of the infected cell. The new copy of the virus then exits its host and sets off in search of another CD4 cell to infect.

Is the SARS-CoV2 virus capable of accessing the nucleus of an infected cell?

To answer this, let’s start by examining existing literature for older coronaviruses, notably SARS and MERS. What does the scientific literature say about the ability of these viruses to access our DNA? 

The problem we immediately encounter here is the scarcity of research. A lot of the outbreaks for these viruses were small, affecting sample sizes, geographical locations posed challenges in terms of collecting reliable data, and the duration of often isolated and contained outbreaks was brief. Unlike Covid, there was no widespread testing of populations, so even something as simple as suggested mortality rates are skewed for these viruses, as scientists were unable to account for asymptomatic and mild infections in the broader populations.

Now would be the perfect time to underscore the rationale for widespread testing. We can not truly assess the impact of a virus on a population unless we can develop a cohesive data set for a large majority of the group. Say you‘ve’ an island of a hundred thousand people, 1000 are hospitalized and 100 die. Can you claim a ten percent mortality rate for the virus? Absolutely not. Can you ascertain if asymptomatic carriers are transmitting the virus or how long they act as reservoirs? Absolutely not. 

While you can argue that a percentage of this data may be compromised as a result of human error, it remains essential. Testing, as widespread as possible, is critical to forming a proper understanding of any virus and highlighting areas of concern. It’s how investigative research has arrived at the report below. Discrepancies are showing up in PCR tests that cannot be explained away with historical research.

The Preprint

When you have eliminated the impossible, whatever remains, however improbable, must be the truth.

Sir Arthur Conan Doyle’s Sherlock Holmes

Sir Arthur Conan Doyle’s fictitious crime solver, Sherlock Holmes would have felt very much at home in a modern virology setting but may have frowned on the profession’s proclivity for forcing data to conform to accepted models, rather than examining alternate solutions, however improbable. Researchers at MIT and Harvard have uncovered evidence of segments of SARS-CoV2’s genetic material mixed in with ours. They’ve come up with a hypothesis to explain these bits of viral code, backed by in vitro experiments. 

You can access the preprint in the NIH National Library of Medicine, and I have referenced large portions of it below. The paper, “SARS-CoV-2 RNA reverse-transcribed and integrated into the human genome” is already contentious, simply by its title alone. It’s the scientific version of covid research clickbait and the question we need to ask is does it hold up under scrutiny? Below is the paper’s abstract and I have highlighted portions in bold.

Prolonged SARS-CoV-2 RNA shedding and recurrence of PCR-positive tests have been widely reported in patients after recovery, yet these patients most commonly are non-infectious. Here we investigated the possibility that SARS-CoV-2 RNAs can be reverse-transcribed and integrated into the human genome and that transcription of the integrated sequences might account for PCR-positive tests. In support of this hypothesis, we found chimeric transcripts consisting of viral fused to cellular sequences in published data sets of SARS-CoV-2 infected cultured cells and primary cells of patients, consistent with the transcription of viral sequences integrated into the genome. To experimentally corroborate the possibility of viral retro-integration, we describe evidence that SARS-CoV-2 RNAs can be reverse transcribed in human cells by reverse transcriptase (RT) from LINE-1 elements or by HIV-1 RT, and that these DNA sequences can be integrated into the cell genome and subsequently be transcribed. Human endogenous LINE-1 expression was induced upon SARS-CoV-2 infection or by cytokine exposure in cultured cells, suggesting a molecular mechanism for SARS-CoV-2 retro-integration in patients. This novel feature of SARS-CoV-2 infection may explain why patients can continue to produce viral RNA after recovery and suggests a new aspect of RNA virus replication.

To test whether SARS-CoV-2’s RNA genome could integrate into the DNA of our chromosomes, the researchers added the gene for reverse transcriptase (RT), an enzyme that converts RNA into DNA, to human cells and cultured the engineered cells with SARS-CoV-2. In one experiment, the researchers used an RT gene from HIV. They also provided RT using human DNA sequences known as LINE-1 elements, which are remnants of ancient retroviral infections and make up about 17% of the human genome. Cells making either form of the enzyme led to some chunks of SARS-CoV-2 RNA being converted to DNA and integrated into human chromosomes.

This was consistent with the findings of fragmented viral material from the PCQR tests in the general population.

You can begin to see why this paper and research could be viewed as contentious and why it’s been met with resistance. It not only challenges our current understanding of RNA viruses, suggesting the viruses may possess a broader skillset than previously imagined, it also potentially raises new questions relating to the use of mRNA vaccines. If the vaccine mRNA is modeled on a portion of the virus, and the virus is capable, under certain circumstances of reverse transcription, what then of claims by mRNA vaccines that their products cannot contaminate our DNA?

It’s important at this point, to explain that mRNA vaccines don’t reproduce the entire virus in your cytoplasm, they merely create a copy of the spike protein attached to the virus which helps it bind with our own cells. Reproducing a portion of the virus minimizes risk and allows our body the opportunity to mount an early defense against the spike protein when we encounter the SARS-CoV2 virus in the wild. Of equal importance is the length of time for which the vaccine RNA stays viable in the cytoplasm, and we’ll examine this issue towards the end of the article.

What prompted this research?

What prompted these researchers to investigate whether viral RNA could become hardwired into our genomic DNA? Their motive had nothing to do with mRNA vaccines. They were simply puzzled by the growing number of people who were testing positive for COVID-19 by PCR long after the infection was gone. It was known that these people were not reinfected, so where was the viral genetic material the PCQR tests were identifying coming from?

The authors sought to answer how a PCR test is able to detect segments of viral RNA when the virus is presumably no longer present in a person’s body. They hypothesized that somehow segments of the viral RNA were being copied into DNA and then integrated permanently into the DNA of somatic cells. This would allow these cells to continuously churn out pieces of viral RNA that would be detected in a PCR test, even though no active infection existed. 

Through their experiments, they did not find full-length viral RNA integrated into genomic DNA; rather, they found smaller segments of the viral DNA, mostly representing the nucleocapsid (N) protein of the virus, although other viral segments were found integrated into human DNA at a lower frequency. It is important to note that the authors emphasize their results don’t imply that SARS-CoV-2 establishes permanent genetic residence in human cells to keep pumping out new copies, as HIV does.

How has the scientific community reacted?

“This is a very interesting molecular analysis and speculation with supportive data provided. I do not think it is a complete story to be certain … but as is, I like it and my guess is it will be right.” — Robert Galeo, Head of the Institute of Human Virology

“Impressive and unexpected. Because it is all pieces of the coronaviral genome, it can’t lead to infectious RNA or DNA and therefore it is probably biologically a dead end. It is also not clear if, in people, the cells that harbor the reverse transcripts stay around for a long time or they die. The work raises a lot of interesting questions.” — David Baltimore, a virologist at the California Institute of Technology who won the Nobel Prize for his role in discovering RT

“LINE-1 elements in the human genome rarely are active. It is not clear what the activity would be in different primary cell types that are infected by SARS-CoV-2.” — Zandrea Ambrose, a retrovirologist at the University of Pittsburgh

“I’m not yet convinced but it’s believable, solid evidence shows that LINE-1 RT can allow viral material to integrate in people. The evidence of SARS-CoV-2 sequences in people should be more solid, and the in vitro experiments conducted by Jaenisch’s team lack controls I would have liked to have seen. All in all, I doubt that the phenomenon has much biological relevance, despite the authors’ speculation.” — John Coffin, Retrovirologist at Tufts University

What has the paper established

1) Segments of SARS-CoV-2 Viral RNA can become integrated into human genomic DNA.

2) This newly acquired viral sequence is not silent, meaning that these genetically modified regions of genomic DNA may be transcriptionally active (DNA is being converted back into RNA). Note the paper does not confirm this, merely indicates it, their FISH data is not conclusive and more study is required.

3) Segments of SARS-CoV-2 viral RNA retro-integrated into human genomic DNA in cell culture. This retro-integration into genomic DNA of COVID-19 patients is also implied indirectly from the detection of chimeric RNA transcripts in cells derived from COVID-19 patients. Although their RNAseq data suggest that genomic alteration is taking place in COVID-19 patients, the point needs to be proven conclusively. This is a gap that needs to be closed in the research. The in vitro data in human cell lines, however, is air-tight.

4) This viral retro-integration of RNA into DNA can be induced by endogenous LINE-1 retrotransposons, which produce an active reverse transcriptase (RT) that converts RNA into DNA. (All humans have multiple copies of LINE-1 retrotransposons residing in their genome.). The frequency of retro-integration of viral RNA into DNA is positively correlated with LINE-1 expression levels in the cell.

5) These LINE-1 retrotransposons can be activated by viral infection with SARS-CoV-2, or cytokine exposure to cells, and this increases the probability of retro-integration.

What questions can we now ask?

The author of this paper is well respected and considered brilliant by his peers. There can be no doubt about the authenticity of the research and although the paper has not yet been subjected to peer review, another consequence of the pandemic, it certainly will be. It is our hope that the results from the research act to spur on further research to eliminate or conclusively show the validity of the suggested mechanisms, both in -vivo and in-vitro. 

It’s well known that in-vivo results don’t always translate when the experiment is transferred to a living host, therefore it’s essential we continue the research to its logical conclusion. The paper raises a number of issues, possibilities that we don’t as yet have conclusive answers to. The mere fact we now have to ask these questions would suggest caution moving forward until we have conclusively addressed potential concerns.

1. Can RNA from an RNA virus, SARS-CoV2, reach our DNA?

It would almost certainly seem so. Whether in one piece or in genetics bits, the virus appears to be finding its way into our DNA. PCR tests are finding the viral genetic material when they shouldn’t. If the mechanism the paper describes is responsible, that is cause for concern. There may prove to be other mechanisms involved we don’t as yet understand, perhaps involving immunoprivileged sites. More research is required.

2. If viral RNA can find its way into our DNA, can the same hold true for synthetic RNA?

It is a possibility that we cannot conclusively rule out, particularly given the fact that synthetic RNA has been engineered to be more resilient and produce more proteins than its less chemically stable natural version. This makes the cell more alert to the presence of synthetic RNA and offers the cell more time to address the foreign body chemically. In other words, the likelihood of whatever processes the natural RNA is subjected to being expressed on the synthetic version, increases exponentially. 

3. Can I infect anyone with this genetic material?

The obvious answer to this is no. This is not the same way in which the HIV virus we learned about earlier operates. These are fragments of RNA, so think of it like a computer program. If you cut the program into sections, those individual pieces may or may not be able to run on their own, but they cannot perform the original function of the program. The paper does not suggest you would become infectious to others.

The statement above does not mean that you would be unable to transmit these segments to other people, simply that the recipient won’t be able to develop covid from the fragments. 

4. Do I need to be worried about this?

Absolutely not. This paper simply explores and deepens our understanding of viruses and reminds us that we are still learning about many aspects of a virus’s life cycle. Viruses are as unique and gifted as we are and each possesses its own toolbox of tricks to ensure its survival. Remember as you sit and read this, an 8th of your body is made of bits of viral genetic code. We’ve done just fine up to now as a species co-existing with viruses and there may very well be a selective advantage to us as a species to incorporate bits of viral genetic material into our own genome. We are still learning and as technology advances, so does our understanding of this infinitely complex system.

5. So where does this leave mRNA vaccines?

mRNA covid vaccines are proving in the short term to be safer and less likely to elicit allergic responses than the more traditional covid vaccines. They also appear efficacious against new strains and can be reverse engineered to address emerging strains far more rapidly than conventional vaccines. The technology is fantastic and holds huge promise for the future of medicine. Do we know what the long-term consequences, if any, will be to us from the use of the mRNA vaccine? No. That’s the honest answer.

It’s too early into the life cycle of this technology to know for sure and we lack detailed long-term evaluations of the impacts on our bodies. The urgency of the pandemic has robbed us of the opportunity to subject these vaccines to rigorous long-term scrutiny (all the covid vaccines, not merely the mRNA vaccines) but let’s not forget, that without the pandemic, we would not have made this leap in technology, perhaps not for another five or six years, perhaps longer. 

So in answer to the question, is there any chance these vaccines could have their RNA incorporated into our DNA, the answer, for now, would have to be this.

We cannot emphatically rule out the possibility and nature says ‘never say never’. It’s one of the reasons we need to proceed with as much caution as possible and Medika strongly supports an individual’s right to choice in the matter of vaccination. Educate yourself and then choose, but understand that in terms of risk, if you are in an at-risk category for covid, the mRNA and other vaccines are a no-brainer. Get vaccinated. 

Compare the risk of death with an almost negligible, unquantified possibility of genetic absorption that may, or may not be deleterious to your health. Then roll up that sleeve and thank your nurse.

The post mRNA Technology, Human DNA and The Traffic Flow of Genetic Material appeared first on Medika Life.

• Alagille-Watson Syndrome
• Alagille’s syndrome
• arteriohepatic dysplasia (AHD)
• cardiovertebral syndrome
• cholestasis with peripheral pulmonary stenosis
• hepatic ductular hypoplasia
• hepatofacioneurocardiovertebral syndrome
• paucity of interlobular bile ducts
• Watson-Miller syndrome

Alagille syndrome is a genetic disorder that can affect the liver, heart, and other parts of the body.

One of the major features of Alagille syndrome is liver damage caused by abnormalities in the bile ducts. These ducts carry bile (which helps to digest fats) from the liver to the gallbladder and small intestine. In Alagille syndrome, the bile ducts may be narrow, malformed, and reduced in number (bile duct paucity). As a result, bile builds up in the liver and causes scarring that prevents the liver from working properly to eliminate wastes from the bloodstream. Signs and symptoms arising from liver damage in Alagille syndrome may include a yellowish tinge in the skin and the whites of the eyes (jaundice), itchy skin, and deposits of cholesterol in the skin (xanthomas).

Alagille syndrome is also associated with several heart problems, including impaired blood flow from the heart into the lungs (pulmonic stenosis). Pulmonic stenosis may occur along with a hole between the two lower chambers of the heart (ventricular septal defect) and other heart abnormalities. This combination of heart defects is called tetralogy of Fallot.

People with Alagille syndrome may have distinctive facial features including a broad, prominent forehead; deep-set eyes; and a small, pointed chin. The disorder may also affect the blood vessels within the brain and spinal cord (central nervous system) and the kidneys. Affected individuals may have an unusual butterfly shape of the bones of the spinal column (vertebrae) that can be seen in an x-ray.

Problems associated with Alagille syndrome generally become evident in infancy or early childhood. The severity of the disorder varies among affected individuals, even within the same family. Symptoms range from so mild as to go unnoticed to severe heart and/or liver disease requiring transplantation.

Some people with Alagille syndrome may have isolated signs of the disorder, such as a heart defect like tetralogy of Fallot, or a characteristic facial appearance. These individuals do not have liver disease or other features typical of the disorder.

How common is the condition?

The estimated prevalence of Alagille syndrome is 1 in 70,000 newborns. This figure is based on diagnoses of liver disease in infants, and may be an underestimation because some people with Alagille syndrome do not develop liver disease during infancy.

What Causes Alagille Syndrome

In more than 90 percent of cases, mutations in the JAG1 gene cause Alagille syndrome. Another 7 percent of individuals with Alagille syndrome have small deletions of genetic material on chromosome 20 that include the JAG1 gene. A few people with Alagille syndrome have mutations in a different gene, called NOTCH2.

The JAG1 and NOTCH2 genes provide instructions for making proteins that fit together to trigger interactions called Notch signaling between neighboring cells during embryonic development. This signaling influences how the cells are used to build body structures in the developing embryo. Changes in either the JAG1 gene or NOTCH2 gene probably disrupt the Notch signaling pathway. As a result, errors may occur during development, especially affecting the bile ducts, heart, spinal column, and certain facial features.

Inheritance Pattern

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered or deleted gene in each cell is sufficient to cause the disorder.

In approximately 30 to 50 percent of cases, an affected person inherits the mutation or deletion from one affected parent. Other cases result from new mutations in the gene or new deletions of genetic material on chromosome 20 that occur as random events during the formation of reproductive cells (eggs or sperm) or in early fetal development. These cases occur in people with no history of the disorder in their family.

The post Alagille syndrome appeared first on Medika Life.

• FBN
• FBN1_HUMAN
• fibrillin 1 (Marfan syndrome)
• MFS1
• SGS

The FBN1 gene provides instructions for making a large protein called fibrillin-1. This protein is transported out of cells into the extracellular matrix, which is an intricate lattice of proteins and other molecules that forms in the spaces between cells. In this matrix, molecules of fibrillin-1 attach (bind) to each other and to other proteins to form threadlike filaments called microfibrils.

Microfibrils form elastic fibers, which enable the skin, ligaments, and blood vessels to stretch. Microfibrils also provide support to more rigid tissues such as bones and the tissues that support the nerves, muscles, and lenses of the eyes. Microfibrils store a protein called transforming growth factor beta (TGF-β), a critical growth factor.

TGF-β affects development by helping to control the growth and division (proliferation) of cells, the process by which cells mature to carry out specific functions (differentiation), cell movement (motility), and the self-destruction of cells (apoptosis). Microfibrils help regulate the availability of TGF-β, which is turned off (inactivated) when stored in microfibrils and turned on (activated) when released.

Health Conditions related to genetic changes of FBN1

Acromicric Dysplasia

At least nine FBN1 gene mutations have been identified in people with acromicric dysplasia. This condition is characterized by severely short stature, short limbs, stiff joints, and distinctive facial features.

FBN1 gene mutations that cause acromicric dysplasia are located in an area of the gene called exons 41 and 42, and change single protein building blocks (amino acids) in a region of the fibrillin-1 protein called TGF-β binding-protein-like domain 5. The mutations result in a reduction and disorganization of the microfibrils. Without enough normal microfibrils to store TGF-β, the growth factor is abnormally active. These effects likely contribute to the physical abnormalities that occur in acromicric dysplasia, but the mechanisms are unclear.

It is unknown why the FBN1 gene mutations that cause acromicric dysplasia lead to short stature, while certain other FBN1 gene mutations that also increase TGF-β activity cause a disorder called Marfan syndrome (see below), which is characterized by tall stature.

Isolated Ectopia Lentis

More than 30 mutations in the FBN1 gene have been found to cause isolated ectopia lentis. In this condition, the lens in one or both eyes is off-center (displaced), which leads to vision problems. Most of the FBN1 gene mutations that cause this condition change single amino acids in the fibrillin-1 protein. As a result, the production of normal fibrillin-1 protein is reduced, leading to a decrease in microfibril formation or the formation of impaired microfibrils.

Without enough functional microfibrils to anchor the lens in its central position at the front of the eye, the lens becomes displaced, resulting in isolated ectopia lentis and related vision problems. Ectopia lentis is classified as isolated when it occurs alone, without signs and symptoms affecting other body systems.

However, some people initially diagnosed with isolated ectopia lentis caused by FBN1 gene mutations later develop additional features typical of a condition called Marfan syndrome (described below), such as abnormalities of the large blood vessel that distributes blood from the heart to the rest of the body (the aorta). In these cases, the diagnosis often changes from isolated ectopia lentis to Marfan syndrome.

Marfan Syndrome

Researchers have identified more than 1,300 FBN1 gene mutations that cause Marfan syndrome, a disorder that affects the connective tissue supporting the body’s joints and organs. Abnormalities in the connective tissue lead to heart and eye problems in people with this disorder. In addition, affected individuals are usually tall and slender with elongated fingers and toes and other skeletal abnormalities.

Most of the mutations that cause Marfan syndrome change a single amino acid in the fibrillin-1 protein. The remaining FBN1 gene mutations result in an abnormal fibrillin-1 protein that cannot function properly. FBN1 gene mutations that cause Marfan syndrome reduce the amount of fibrillin-1 produced by the cell, alter the structure or stability of fibrillin-1, or impair the transport of fibrillin-1 out of the cell.

These mutations lead to a severe reduction in the amount of fibrillin-1 available to form microfibrils. Without enough microfibrils, excess TGF-β growth factors are activated and elasticity in many tissues is decreased, leading to overgrowth and instability of tissues and the signs and symptoms of Marfan syndrome.

Weill-Marchesani syndrome

Mutations in the FBN1 gene have also been identified in Weill-Marchesani syndrome. One of the identified mutations deletes part of the gene, leading to the production of an unstable version of the fibrillin-1 protein. The unstable protein likely interferes with the assembly of microfibrils. Abnormal microfibrils weaken connective tissue, which causes the eye, heart, and skeletal abnormalities associated with Weill-Marchesani syndrome.

Other Disorders

Mutations in the FBN1 gene can cause a condition called stiff skin syndrome. This condition is characterized by very hard, thick skin covering most of the body. The abnormal skin limits movement and can lead to joint deformities called contractures that restrict the movement of certain joints. The signs and symptoms of stiff skin syndrome usually become apparent in infancy to mid-childhood.

Mutations in the FBN1 gene can cause another condition called MASS syndrome. This condition involves abnormalities in several parts of the body, including the mitral valve (one of the valves that controls blood flow through the heart), the aorta (a large blood vessel that distributes blood from the heart to the rest of the body), the skeleton, and the skin.

It is unknown why different mutations in the FBN1 gene cause such a variety of disorders.

Chromosomal Location

Cytogenetic Location: 15q21.1, which is the long (q) arm of chromosome 15 at position 21.1

Molecular Location: base pairs 48,408,313 to 48,645,709 on chromosome 15 (Homo sapiens Updated Annotation Release 109.20200522, GRCh38.p13) (NCBI)

The post FBN1 gene, fibrillin 1 appeared first on Medika Life.

Because connective tissue is found throughout the body, Marfan syndrome can affect many systems, often causing abnormalities in the heart, blood vessels, eyes, bones, and joints. The two primary features of Marfan syndrome are vision problems caused by a dislocated lens (ectopia lentis) in one or both eyes and defects in the large blood vessel that distributes blood from the heart to the rest of the body (the aorta).

The aorta can weaken and stretch, which may lead to a bulge in the blood vessel wall (an aneurysm). Stretching of the aorta may cause the aortic valve to leak, which can lead to a sudden tearing of the layers in the aorta wall (aortic dissection). Aortic aneurysm and dissection can be life threatening.

Many people with Marfan syndrome have additional heart problems including a leak in the valve that connects two of the four chambers of the heart (mitral valve prolapse) or the valve that regulates blood flow from the heart into the aorta (aortic valve regurgitation). Leaks in these valves can cause shortness of breath, fatigue, and an irregular heartbeat felt as skipped or extra beats (palpitations).

Individuals with Marfan syndrome are usually tall and slender, have elongated fingers and toes (arachnodactyly), loose joints, and have an arm span that exceeds their body height. Other common features include a long and narrow face, crowded teeth, an abnormal curvature of the spine (scoliosis or kyphosis), stretch marks (striae) not related to weight gain or loss, and either a sunken chest (pectus excavatum) or a protruding chest (pectus carinatum).

Some individuals develop an abnormal accumulation of air in the chest cavity that can result in the collapse of a lung (spontaneous pneumothorax). A membrane called the dura, which surrounds the brain and spinal cord, can be abnormally enlarged (dural ectasia) in people with Marfan syndrome. Dural ectasia can cause pain in the back, abdomen, legs, or head.

Most individuals with Marfan syndrome have some degree of nearsightedness (myopia). Clouding of the lens (cataract) may occur in mid-adulthood, and increased pressure within the eye (glaucoma) occurs more frequently in people with Marfan syndrome than in those without the condition.

The features of Marfan syndrome can become apparent anytime between infancy and adulthood. Depending on the onset and severity of signs and symptoms, Marfan syndrome can be fatal early in life; however, with proper treatment, many affected individuals have normal lifespans.

Causes of Marfan

The prevalence of Marfan Syndromw among the general public is approximately 1 in 5000 people.

Mutations in the FBN1 gene cause Marfan syndrome. The FBN1 gene provides instructions for making a protein called fibrillin-1. Fibrillin-1 attaches (binds) to other fibrillin-1 proteins and other molecules to form threadlike filaments called microfibrils. Microfibrils become part of the fibers that provide strength and flexibility to connective tissue. Additionally, microfibrils bind to molecules called growth factors and release them at various times to control the growth and repair of tissues and organs throughout the body.

A mutation in the FBN1 gene can reduce the amount of functional fibrillin-1 that is available to form microfibrils, which leads to decreased microfibril formation. As a result, microfibrils cannot bind to growth factors, so excess growth factors are available and elasticity in many tissues is decreased, leading to overgrowth and instability of tissues in Marfan syndrome.

Inheritance Pattern

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.

At least 25 percent of Marfan syndrome cases result from a new mutation in the FBN1 gene. These cases occur in people with no history of the disorder in their family.

The post Marfan Syndrome (MFS) appeared first on Medika Life.

There are five types of Loeys-Dietz syndrome, labelled types I through V, which are distinguished by their genetic cause. Regardless of the type, signs and symptoms of Loeys-Dietz syndrome can become apparent anytime from childhood through adulthood, and the severity is variable.

Loeys-Dietz syndrome is characterized by enlargement of the aorta, which is the large blood vessel that distributes blood from the heart to the rest of the body. The aorta can weaken and stretch, causing a bulge in the blood vessel wall (an aneurysm). Stretching of the aorta may also lead to a sudden tearing of the layers in the aorta wall (aortic dissection). People with Loeys-Dietz syndrome can also have aneurysms or dissections in arteries throughout the body and have arteries with abnormal twists and turns (arterial tortuosity).

Individuals with Loeys-Dietz syndrome often have skeletal problems including premature fusion of the skull bones (craniosynostosis), an abnormal side-to-side curvature of the spine (scoliosis), either a sunken chest (pectus excavatum) or a protruding chest (pectus carinatum), an inward- and upward-turning foot (clubfoot), flat feet (pes planus), or elongated limbs with joint deformities called contractures that restrict the movement of certain joints.

A membrane called the dura, which surrounds the brain and spinal cord, can be abnormally enlarged (dural ectasia). In individuals with Loeys-Dietz syndrome, dural ectasia typically does not cause health problems. Malformation or instability of the spinal bones (vertebrae) in the neck is a common feature of Loeys-Dietz syndrome and can lead to injuries to the spinal cord.

Some affected individuals have joint inflammation (osteoarthritis) that commonly affects the knees and the joints of the hands, wrists, and spine.

People with Loeys-Dietz syndrome may bruise easily and develop abnormal scars after wound healing. The skin is frequently described as translucent, often with stretch marks (striae) and visible underlying veins. Some individuals with Loeys-Dietz syndrome develop an abnormal accumulation of air in the chest cavity that can result in the collapse of a lung (spontaneous pneumothorax) or a protrusion of organs through gaps in muscles (hernias).

Other characteristic features include widely spaced eyes (hypertelorism), eyes that do not point in the same direction (strabismus), a split in the soft flap of tissue that hangs from the back of the mouth (bifid uvula), and an opening in the roof of the mouth (cleft palate).

Individuals with Loeys-Dietz syndrome frequently develop immune system-related problems such as food allergies, asthma, or inflammatory disorders such as eczema or inflammatory bowel disease. The prevalence of Loeys-Dietz syndrome is unknown. Loeys-Dietz syndrome types I and II appear to be the most common forms.

Causes

The five types of Loeys-Dietz syndrome are distinguished by their genetic cause: TGFBR1 gene mutations cause type I, TGFBR2 gene mutations cause type II, SMAD3 gene mutations cause type III, TGFB2 gene mutations cause type IV, and TGFB3 gene mutations cause type V.

These five genes play roles in a cell signaling pathway called the transforming growth factor beta (TGF-β) pathway, which directs the functions of the body’s cells during growth and development. This pathway also regulates the formation of the extracellular matrix, an intricate lattice of proteins and other molecules that forms in the spaces between cells and is important for tissue strength and repair.

Mutations in the TGFBR1, TGFBR2, SMAD3, TGFB2, or TGFB3 gene result in the production of a protein with reduced function. Even though the protein is less active, signaling within the TGF-β pathway occurs at an even greater intensity than normal in tissues throughout the body.

Researchers speculate that the activity of other proteins in this signaling pathway is increased to compensate for the protein whose function is reduced; however, the exact mechanism responsible for the increase in signaling is unclear. The overactive TGF-β pathway disrupts the development of the extracellular matrix and various body systems, leading to the signs and symptoms of Loeys-Dietz syndrome.

Inheritance Factors

Loeys-Dietz syndrome has an autosomal dominant pattern of inheritance, which means one copy of the altered gene in each cell is sufficient to cause the disorder.

In about 75 percent of cases, this disorder results from a new gene mutation and occurs in people with no history of the disorder in their family. In other cases, an affected person inherits the mutation from one affected parent.

The post Loeys-Dietz syndrome (LDS) appeared first on Medika Life.

You’ll often see this condition referred to as any one of the following, these names all indicate the same condition

• AAT
• AATD
• alpha-1 protease inhibitor deficiency
• alpha-1 related emphysema
• genetic emphysema
• hereditary pulmonary emphysema
• inherited emphysema

Alpha-1 antitrypsin deficiency is an inherited disorder that may cause lung disease and liver disease. The signs and symptoms of the condition and the age at which they appear vary among individuals.

People with alpha-1 antitrypsin deficiency usually develop the first signs and symptoms of lung disease between ages 20 and 50. The earliest symptoms are shortness of breath following mild activity, reduced ability to exercise, and wheezing. Other signs and symptoms can include unintentional weight loss, recurring respiratory infections, fatigue, and rapid heartbeat upon standing.

Affected individuals often develop emphysema, which is a lung disease caused by damage to the small air sacs in the lungs (alveoli). Characteristic features of emphysema include difficulty breathing, a hacking cough, and a barrel-shaped chest. Smoking or exposure to tobacco smoke accelerates the appearance of emphysema symptoms and damage to the lungs.

About 10 percent of infants with alpha-1 antitrypsin deficiency develop liver disease, which often causes yellowing of the skin and whites of the eyes (jaundice). Approximately 15 percent of adults with alpha-1 antitrypsin deficiency develop liver damage (cirrhosis) due to the formation of scar tissue in the liver. Signs of cirrhosis include a swollen abdomen, swollen feet or legs, and jaundice. Individuals with alpha-1 antitrypsin deficiency are also at risk of developing a type of liver cancer called hepatocellular carcinoma.

In rare cases, people with alpha-1 antitrypsin deficiency develop a skin condition called panniculitis, which is characterized by hardened skin with painful lumps or patches. Panniculitis varies in severity and can occur at any age.

Prevalence and Distribution

Alpha-1 antitrypsin deficiency occurs worldwide, but its prevalence varies by population. This disorder affects about 1 in 1,500 to 3,500 individuals with European ancestry. It is uncommon in people of Asian descent. Many individuals with alpha-1 antitrypsin deficiency are likely undiagnosed, particularly people with a lung condition called chronic obstructive pulmonary disease (COPD).

COPD can be caused by alpha-1 antitrypsin deficiency; however, the alpha-1 antitrypsin deficiency is often never diagnosed. Some people with alpha-1 antitrypsin deficiency are misdiagnosed with asthma.

Causes

Mutations in the SERPINA1 gene cause alpha-1 antitrypsin deficiency. This gene provides instructions for making a protein called alpha-1 antitrypsin, which protects the body from a powerful enzyme called neutrophil elastase. Neutrophil elastase is released from white blood cells to fight infection, but it can attack normal tissues (especially the lungs) if not tightly controlled by alpha-1 antitrypsin.

Mutations in the SERPINA1 gene can lead to a shortage (deficiency) of alpha-1 antitrypsin or an abnormal form of the protein that cannot control neutrophil elastase. Without enough functional alpha-1 antitrypsin, neutrophil elastase destroys alveoli and causes lung disease. Abnormal alpha-1 antitrypsin can also accumulate in the liver and damage this organ.

Environmental factors, such as exposure to tobacco smoke, chemicals, and dust, likely impact the severity of alpha-1 antitrypsin deficiency.

Inheritance Pattern

This condition is inherited in an autosomal codominant pattern. Codominance means that two different versions of the gene may be active (expressed), and both versions contribute to the genetic trait.

The most common version (allele) of the SERPINA1 gene, called M, produces normal levels of alpha-1 antitrypsin. Most people in the general population have two copies of the M allele (MM) in each cell. Other versions of the SERPINA1 gene lead to reduced levels of alpha-1 antitrypsin.

For example, the S allele produces moderately low levels of this protein, and the Z allele produces very little alpha-1 antitrypsin. Individuals with two copies of the Z allele (ZZ) in each cell are likely to have alpha-1 antitrypsin deficiency. Those with the SZ combination have an increased risk of developing lung diseases (such as emphysema), particularly if they smoke.

Worldwide, it is estimated that 161 million people have one copy of the S or Z allele and one copy of the M allele in each cell (MS or MZ). Individuals with an MS (or SS) combination usually produce enough alpha-1 antitrypsin to protect the lungs. People with MZ alleles, however, have a slightly increased risk of impaired lung or liver function.

Diagnosing AAT Deficiency

If you suffer from any of the symptoms or conditions described above consider discussing with your doctor the possibility of testing for this condition. There are various biochemical and molecular genetic tests available.

The post AAT Deficiency, Inherited Emphysema appeared first on Medika Life.