Q & A with Dr. Markus Bohn, expert for genetics of connective tissue disorders (main focus Tenascin X)


Welcome everyone to our first Q&A hosted by the bilingual EDS & CCI Website instabile-halswirbelsaeule.de. As our first expert we are happy to announce Dr. Markus-Frederik Bohn who contributes to EDS research in the field of Tenascin X, a now more common factor and potential cause in many EDS patients.

Dr. Bohn published many scientific articles and currently works at University of California San Francisco (UCSF). He is happy to answers question in either German or English language.

Some of his publications: 

http://www.ncbi.nlm.nih.gov/pubmed/25945571

http://www.ncbi.nlm.nih.gov/pubmed/25914058

After the Q&A we will create a blog post for the above mentioned website with your favorite questions and answers that will then be publicly available to read.

Instructions: 

Starting at 9 am PST you can begin to ask questions around the topic genetics of connective tissue disorders in the question section of this post or in my Facebook Event (https://www.facebook.com/events/1273688382642154).

To ask questions here you do not need to add an email address or name. You can also ask anonymously. But if you do enter your email address you will receive a notification if your question is answered. Only your Username will be shown. If you do not add one it will show “anonymous”

Our expert will then answer the questions as soon as possible.

We would be very happy about an active participation and hope this is only the first of a series of Q&A’s on this page.

Best

Karina

PS: There is no question that is too stupid to ask. Don’t worry, just ask 😉

Date: July 10 2016

Start Time 09 am PST

End Time: 3 pm PST

Disclaimer: 

This event exclusively serves the purpose of exchanging information and cannot be seen as medical advice. Neither the organizer (Karina Sturm) nor the expert (Dr. Bohn) are medical doctors and therefore no comment during the event can be seen as medical advice!

If you have medical questions about your condition please ask your doctor about it.

Furthermore, the organizer has no control over the questions asked by others during the event. These represent the opinion of the commentator and not necessarily the opinion of the organizer.

Any comment that violates German laws will be removed by the organizer.

This event is presented by www.instabile-halswirbelsaeule.de.

Imprint and privacy police as requested by German law:
http://www.instabile-halswirbelsaeule.de/imprint-privacy-statement/

Please keep in mind: This is a PUBLIC event that is accessible for everyone. This means your posts can be seen by friends, familiy and even strangers. Do not post what you do not feel comfortable to share.

 


If you provide an Email you will receive a message, once your Question is Answered.
  • Julie 10 July 2016
    Do you feel like a cure or better treatment options can come from these findings?

    Assuming you are talking about point mutations in TNXB that affect severity of an EDS phenotype, the answer is no. Finding the genetic basis for a disease does sadly not translate into curative approaches. Otherwise it would be very easy to deal with negative consequences of aneuploidies (e.g. trisomies). In the case of structural extracellular matrix proteins like Tenascin-X it's very hard to think about therapeutic/curative approaches since it's a protein that fulfills its function by being at the right time at the right place in the right amount. There is no enzyme that can be blocked by a small molecule or a receptor that needs to be activated, so it doesn't fall within what's currently possible with pharmaceutical intervention. Fixing a "broken" or supplementing "missing" Tenascin-X in the entire connective tissue is something for which no technology exists.
  • Julie 10 July 2016
    Do you think all cases of HEDS are genetic mutations vs. autoimmune?

    So far the working hypothesis is that there are direct genetic causes for the different EDS types. Also, there is no clear vs. in what you're asking. Quite a few autoimmune diseases can be linked to genetic mutations (e.g. there are epidemiological studies that give a 65% chance for inheritability of osteoarthritic hands), but those often imply polygenic inheritance.
  • Anonymous 10 July 2016
    How accurate/reliable is the gene test for vascular EDS?

    Currently >95% of pathogenic variants for vEDS can be detected by sequence analysis (and there are other genetic tests for some rare variants). But that's not 100% so there is always a chance for vEDS symptoms and no identifiable genetic cause. That's why clinical consequences > tissue phenotype > genetic variants. Also, there are overlapping EDS types that exhibit vascular-like symptoms on other genes than COL3A1. For example, a COL1A1 mutation leading to an overlap between classical and vEDS. De Paepe A, Malfait F. The Ehlers-Danlos Syndrome, a disorder with many faces. Clin Genet 2012; 82; 1-11.  
  • Angeline 10 July 2016
    My mother, both my daughter’s, and I are all diagnosed EDS Hypermobile Type. However, I recently learned that one of my daughters and I have the genetic variation associated with Stickler Syndrome (COL11A2) and are heterozygous for AMPD1 associated with myopathy (we were the only two family members to have genetic testing done). The geneticist said these findings were of “unknown clinical significance”. Since the specific gene responsible for EDS-HT has not yet been identified, I wonder if it’s possible multiple, fairly common variations such as these may be responsible in combination or with environmental factors. Are you aware of any research being done in this area?

    I am not working in diagnostics, but as far as I understand "clinical significance" can only be granted if that precise mutation has been reported to be correlated with a disease phenotype in the literature. It is very hard to impossible to predict what the phenotype of individual mutations is going to be. Several groups are working hard to find genetic variations that are linked to EDS so the number of mutations with "clinical significance" should keep going up. Regarding combinations of common/insignificant variants: small changes to different parts of complex networks can indeed add up or have synergistic effects (leading to a "perfect storm") and cell/tissue functions form an extraordinary difficult network. So research mostly starts with the low hanging fruit looks for clear 1 genetic variant - 1 defect relations and if that doesn't work we move up. At the very end people stop looking for specific variants and start comparing all variants. A current example would be search for the genetic basis of schizophrenia, which turns out to be very difficult and where groups started looking genome-wide at correlations between single nucleotide variants. That kind of approach would indeed discover if combinations of common variants correlate with a clinical phenotype. I don't think this is being done with EDS (yet). Environmental factors: Without a clean cut cause-effect relationship it's hard to get applicable insight, but it does appear that in some cases of EDS there are hormonal or immunological circumstances that might influence disease onset or progression. So I would count that as environmental factors, but I'm not aware of anything actionable that could be used for diagnostics (yet).
  • Anonymous 8 July 2016
    If I remember right, some genetic diseases can be diagnosed by metabolic markers in blood and urine (for example hypophosphatasia, in which some values are too low and others too high because there is a metabolic blockage). Would it be possible to conclude from abnormal blood or urine tests in which area there might be a metabolic blockage, even if the location of a potential mutation isn’t known yet? Would it be feasible to systematically look into the different metabolic regulatory circuits which might be responsible for abnormal lab results, and conclude in which genetic areas there might be a mutation? Is this a path research is taking? Is there any way in which low alkaline phosphatasia might be related to EDS (hypermobile, mutation unknown)?

    There is a lot of exciting research going on in the area of linking metabolic markers with the genetic underpinnings of a disease. As an example, there is a spectacular technology in which during surgery tissue is vaporized right on the surgeons "blade" and analyzed for metabolic markers of a tumor type in real time while the surgeon is removing it (so he knows where the healthy tissue starts and the tumor ends). This data (specific metabolic tumor markers) is combined with deep sequencing data (mRNA levels for every gene) and across patients to look for new connections or entire networks of interdependent factors that might be involved in disease outcome. So yes, there is strong research into that 🙂 Regarding the alkaline phosphatase in EDS: As far as I know there is no clear connection between low enzyme levels and EDS. But the individual role enzymes that are broadly involved in metabolic functions are hard to be pinned down in a multifaceted syndrome.
  • Karina 4 July 2016
    How meaningful / precise are genetests and which method is the best?

    Exome Sequencing has the potential to detect defects in the protein-encoding region but not in the regulatory region for example promotor or intron splicing sites. Whole Genome Sequencing examines the whole DNA with all regulatory elements. Both are limited by a high error rate if one is looking for a single nucleotide differences. It is easier to find larger deletions. Many mutations are silent mutations that have no impact. Panel diagnostics and single gene tests are more precise but rely on a predetermined group of markers.
  • Karina 4 July 2016
    How does a genetic predisposition lead to a phenotype?

    The Cysteine is replaced by a Tryptophan. The replacement of Cysteine with a Tryptophan leads to  breakage of a disulfide bond disrupting the folding of secondary structure. This again leads to failure in organizing fibrillin fibers in tissue and to the EDS tissue phenotype.
  • karina 4 July 2016
    What are the different TNX EDS types?

    1. TNX deficiency: No TNX detectable in serum (homozygous) 2. TNX haploinsufficiency: Half the amount of TNX in serum compared to unaffected people 3. CAH-X: TNX haploinsufficiency + CAH 4. TNXB mutations we don’t know what they are doing at the moment (functional impairment?): Full amount TNX in serum. Produce a protein with altered characteristics.
  • Karina 4 July 2016
    What is a protein and how does a mutation affect the protein?

    Genes encode for proteins that have a function. A gene is only information whereas the protein is the functional entity. Mutations can lead to different amounts of protein if they are in a non-coding region or they can affect the function of the protein.
  • Karina 4 July 2016
    What is the difference between a scientist and a medical doctor?

    The job of medical doctors is to apply recent knowledge and insights. Scientists have to generate broadly applicable knowledge and insights which then are again applicable by practicing medical doctors.
  • Karina 4 July 2016
    Can you give us a few insights into your new TNXB paper?

    CAH-X patients suffer from TNX haploinsufficiency because one of the two allels is non-functional. Despite this, the EDS phenotype exhibited high variability. We hypothesized that point mutations on the remaining TNXB allel lead to the different EDS phenotypes.
  • Karina 4 July 2016
    What are the benefits of biomedical research?

    We don’t just see association between a special genotype with a phenotype but we are in a position to find causative relationships and develop new option for diagnostics and treatments.