Q: What got you interested in working on McCune Albright Syndrome?
A: After I earned my PhD I worked as a fellow in the lab of Andy Shenker, then at Children’s Memorial in Chicago. The deal we had was I’d do some biochemistry/cell biology work for him on a sex-reversal gene project and I could try to model precocious puberty in a yeast cell model. I didn’t start out to study MAS, but its mutation turns out to be a lot easier to look at in the yeast model than the ones I began with. I learned about MAS from Andy. He was treating a few of the patients. Now he’s in industry at Bristol-Myers-Squibb. I think he’s working on prostate hyperplasia & cancer.So basically, I had an organism that I wanted to use to study a human disease. Eventually MAS fit the model better than the other things I was trying!
Q: Is there any connection between MAS and maternal/paternal age?
A: No. MAS isn’t a due to an extra chromosome or being “short” one chromosome which is the cause of most things you thing of with older parents – Downs syndrome, etc.
Q: What makes a missense mutation happen?
A: They happen all the time. When our cells get ready to divide, they make a new copy of all the DNA in their nucleus. 6 billion “letters”. And some of the letters get copied incorrectly.
Q: What does the information on alleles and imprinting for MAS mean?
A: Basically, the allele information means that there’s more than one “misspelling” in the DNA that can cause MAS. All of the misspellings occur at the same spot, though. Here’s an analogy: if you misspelled the word “dog”, you could end up with “log” or “iog” (or 24 other things). But nothing else means “dog”.
The imprinting information means that the effects of misspelling the MAS gene depend on which chromosome carries the misspelling – mom’s or dad’s. Now, I need to point out that the actual misspelling occurred in your son’s cells, not in the sperm/egg that started him off. His misspelling happened while he was developing as a fetus. So, back to imprinting. I forget which parent’s chromosome is actually used for making the G-protein, but if the mutation is on the other parent’s chromosome, then the effects of the mutation will not be seen. Honestly, the imprinting thing is interesting to geneticists but pretty irrelevant to patients and their physicians.
Q: Do you think there will ever be a treatment for MAS?
A: Maybe. Right now there’s just symptom-directed treatments. I’m hoping that the work I’m doing will give some talented drug chemists the information they need to design exactly the right drug – one that would turn off your son’s MAS-mutated G-protein and leave all his normal proteins alone. It would probably be even better if someone else beat me to the finish line. Over 50% of my job is teaching undergraduate students, so the research progress isn’t as fast as it would be if I was running a lab at a big university. So there’s not a known biological reason why we couldn’t develop a good drug for MAS, but we don’t know enough to do it yet. And when we know enough, economics will come into play – will there be a drug company willing to take on the project? I don’t know.
Q: How does gain of function G Protein affect histamine? What are the mechanics of MAS histamine excess? Where is the extra histamine and how does it get there?
A: I have to consult my physiology reference books to answer this question. I’ll get back to you within the next week on this.
Q: What other things (in addition to bone, endocrine, histamine . . .) could be considered G Protein related such that the gain of function mutation could bring about an unexpected/unusual result?
A: I’ll get back to you on this one too. The list is long. The G-protein Gs controls a ton of physiological pathways, including cardiac pathways (adrenaline), brain pathways, etc.
Q: Do you think severity of MAS is based on timing of mutation? I've read an article by Lee Weinstein "Mutations in FD and MAS" (Journal of Bone and Mineral Research, Supplement 2, 2006) and also an article by Riminucci (et al) "FD as a Stem Cell Disease" (same supplement) -- they seem to have contradictory conclusions on the timing of mutations causing FD/MAS. The Weinstein article concludes: "Mutations that occur in early development produce a widespread distribution with multiple manifestations (MAS), whereas mutations that occur later in development affect a single locus (e.g., isolated endocrine tumor, monostotic FD)." While the Riminucci article says: "Different severity, numbers, and distributions of organ lesions, therefore, do not indicate, and are not explained by, different times of mutation. It is only the embryological origin of the different organs involved, not their number that validates deductions on the timing of mutation. If the embryologic origin of the involved organs is considered, mutation must arise before gastrulation in all cases of MAS and in most cases of FD, regardless of disease extent or severity."
A: I haven’t read either article recently, but I think I’d side with Weinstein.
Q: Do you see an increasing awareness of MAS/FD/G Proteins in the scientific community?
A: G-proteins are huge. Most of the prescription drugs we take, other than antibiotics, are directed against G-proteins or the processes they’re involved in. In terms of MAS/FD, you’d be better to ask Drs. Collins or Feuillan that question. They’re more active in the broader community than I am.
* Edited to Add First Question on Sept. 21.
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