I wish the article had a clearer explanation of the mechanism of the condition. Most genetic disorders involve a missequenced protein. From what I gather, the defective protein is typically a thing the body intends to use as a tool at the cellular level, but now you have either a defective tool doing a lame job or a missing tool.
Anecdotally, cystic fibrosis also predisposes people to bloat, usually concentrated in the belly. CF involves a defect in a cell channel that handles trafficking of certain molecules into and out of the cell. There are a variety of different defects in this channel, depending on the alleles involved.
I have a diagnosis of atypical cystic fibrosis. I have chronic belly bloat. It used to be far worse and is also accompanied by fluid retention in the legs and lower body.
Consuming hot peppers in combination with walking a great deal has helped to reduce my fluid retention. I read up on capsaicin, the active ingredient, and also spoke with a man with a PhD in chemistry about it. Capsaicin opens a different cell channel and flushes fluid from the cell.
Lymph is circulated in part by the blood. It is basically the clear part of blood, minus blood cells. It is called interstitial fluid when it is out in the tissues. Muscle action causes it to be moved back to the blood system at much higher rates than the normal resting rate.
So it seems to me that if you are "leaking" lymph that has high levels of protein in it, something has gone wrong with the mechanism involved in returning lymph to the blood vessels. The protein probably does not come from nutrients consumed. It probably comes from the muscle tissue.
A diseased liver can cause damage to the portal vein. The liver filters the blood, removing toxic wastes. I imagine a disease that causes lymph to contain high levels of protein would put enormous stress on the liver. It would not be able to keep up with the filtering process.
The lungs filled with fluid because the body treats lungs and gut as interchangeable systems to some degree. When you are at altitude, you cannot breathe out wastes fast enough, so your body dumps them via urination. The lungs and gut both interact with the body via the blood.
I would really be interested in knowing if they have identified a particular cell channel or similar. To me, the explanation that this condition causes high pressure in the portal vein and this causes lymph backup makes no sense. It seems to me the high pressure in the portal vein would be a secondary or tertiary consequence of whatever mechanism is causing lymph to accumulate.
/thinking out loud in public after midnight, no doubt a terrible mistake
> Most genetic disorders involve a missequenced protein.
Most known do, but thats just due to identification bias. We do not even know how many genetic disorders there are. Nor how many people are affected. Nor can we identify most of those that are of complex origin or due to larger genomic alterations / structual variations.
Can you give some examples of genetic disorders that do not involve a missequenced protein? I can think of missing/duplicated chromosomes, but those should be easier to detect than smaller differences.
Lots more places things can go wrong not only before protein is synthesised, but also after too.
An example is anything that hits a regulatory region for a protein (i.e. outside protein coding region).
Chances are phenotype may not be as strong because you may end up with only partial transcriptional loss. I'm guessing it's super critical where you have developmental diseases, and you hit a TF binding site specific for development.
There are many things that can go wrong with a protein. The simplest is misregulation, like a regulatoy motif being disrupted, gene architecture (TAD) being changed, splicing changes (somehow linked to missequence proteins but only via changed ration of different splice isoforms) or mRNA being degraded faster or slower (UTR mutations), all leading to different protein concentrations (if its a protein being affected, might as well be some RNA molecule).
There is not that much known about these diseases so its hard to give typical examples. Here is an example of a tool that tries to predict such variants via ML, they curated a few hundered variants via literature search: https://www.ncbi.nlm.nih.gov/pubmed/27569544
I spent at least half an hour trying to figure out which gene it is. I have a sneaky feeling I have read this story before, and managed to track the gene down there, but not this time.
You'd think that if they were serious about tackling this, they would add a footnote with the name of the gene.
I wonder if the J97 after the author's name in the footer refers to the gene. But googling gene J97 gets me nothing that immediately and obviously says "yea, verily."
Odds are poor that merely naming the gene would clarify for me what the actual mechanism is. My mental model for CF is not in line with official dogma and most literature on it doesn't really talk in a detailed way about the malfunctioning CFTR channel, much less exactly how this malfunction leads to specific symptoms.
So, I am not really surprised the article doesn't make those connections for a newly identified disorder with a very small number of people who have it. They know some of the general symptoms and pathology. They know it is genetic. They have identified the gene. There is quite a lot of work still to do to connect the gene to the pathology.
Given that they plan to make sure the gene is not passed on, this step may never happen. There are at least tens of thousands of people with CF and it has been around a long time, yet they have done a poor job so far on connecting what the CFTR does at the cellular level to the broader pathology of CF at the system level in a logical and useful manner.
Anecdotally, cystic fibrosis also predisposes people to bloat, usually concentrated in the belly. CF involves a defect in a cell channel that handles trafficking of certain molecules into and out of the cell. There are a variety of different defects in this channel, depending on the alleles involved.
I have a diagnosis of atypical cystic fibrosis. I have chronic belly bloat. It used to be far worse and is also accompanied by fluid retention in the legs and lower body.
Consuming hot peppers in combination with walking a great deal has helped to reduce my fluid retention. I read up on capsaicin, the active ingredient, and also spoke with a man with a PhD in chemistry about it. Capsaicin opens a different cell channel and flushes fluid from the cell.
Lymph is circulated in part by the blood. It is basically the clear part of blood, minus blood cells. It is called interstitial fluid when it is out in the tissues. Muscle action causes it to be moved back to the blood system at much higher rates than the normal resting rate.
So it seems to me that if you are "leaking" lymph that has high levels of protein in it, something has gone wrong with the mechanism involved in returning lymph to the blood vessels. The protein probably does not come from nutrients consumed. It probably comes from the muscle tissue.
A diseased liver can cause damage to the portal vein. The liver filters the blood, removing toxic wastes. I imagine a disease that causes lymph to contain high levels of protein would put enormous stress on the liver. It would not be able to keep up with the filtering process.
The lungs filled with fluid because the body treats lungs and gut as interchangeable systems to some degree. When you are at altitude, you cannot breathe out wastes fast enough, so your body dumps them via urination. The lungs and gut both interact with the body via the blood.
I would really be interested in knowing if they have identified a particular cell channel or similar. To me, the explanation that this condition causes high pressure in the portal vein and this causes lymph backup makes no sense. It seems to me the high pressure in the portal vein would be a secondary or tertiary consequence of whatever mechanism is causing lymph to accumulate.
/thinking out loud in public after midnight, no doubt a terrible mistake