Monday, February 10, 2014

A little story into genetic investigation leads me to CPRIT and Alfred Gilman.

2 days ago a man I am following  for basic medical problem and follow-up, called my clinic.
One of his daughter who is obese and diabetic was having significant leg pains.  She had developed a cellulitis from an infected wound.  The cellulitis/purulent wound had failed Bactrim and Mupirocin provided by a local Ambulatory clinic.

2 months prior to this incident, the same man had called me for another daughter who is also obese but was found with Breast Cancer Metastatic to the bone.  The lady was on Letrozole.

I knew right away there is a genetic basis for these syndromes given the age of the patients and family congregation.  As a curious mind I tried to think about this in a categorical/objective way.  My current patient who is now in a local Hospital getting Infectious Disease specialist attention had a infected wound.  It is clear that not all diabetics develop such a complication, but those with a Vasculitis do.  So I let my self look up vasculitis...and of course I found that bio-markers of Vasculitis include ANCA, ESR, c-Reactive Protein, leucocytosis and sometime Eosinophilia.

But as I look further, I fell on the Sturge-Weber Syndrome a prominent Vasculitis.   Well, this landed me on the GNAQ gene.  The same gene that is incriminated in the Uveal Melanoma, mind you!
This is a  Guanine nucleotide-binding protein.  The same proteins that gave Alfred Gilman the Nobel Price back in the days.  This same Gilman who was recently embroiled in the CPRIT debacle!  Bless his soul!
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"G proteins were discovered when Alfred G. Gilman and Martin Rodbell investigated stimulation of cells by adrenaline. They found that, when adrenaline binds to a receptor, the receptor does not stimulate enzymes directly. Instead, the receptor stimulates a G protein, which stimulates an enzyme. An example is adenylate cyclase, which produces the second messenger cyclic AMP.[4] For this discovery, they won the 1994 Nobel Prize in Physiology or Medicine.[5]"  wikipedia

G proteins are important signal transducing molecules in cells. "Malfunction of GPCR [G Protein-Coupled Receptor] signaling pathways are involved in many diseases, such as diabetes, blindness, allergies, depression, cardiovascular defects, and certain forms of cancer. It is estimated that about 30% of the modern drugs' cellular targets are GPCRs." [6]
The human genome encodes roughly 800 [7] G protein-coupled receptors, which detect photons (light), hormones, growth factors, drugs, and other endogenous ligands. Approximately 150 of the GPCRs found in the human genome have unknown functions."wikipedia
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This man did great work!  I am appreciating even more his work today as I am facing this family where I suspect abnormality of the G proteins must be involved in their ordeal!  But with current standard I can't test this !  Nobody will pay for it!   It could be that Ibrutinb or medication such as this, derivative of Pertusis or cholera toxin could help but with our current knowledge and boundaries, targeting therapy is out of bound!
Or may be minimal dose of Cytoxan and prednisone for God sake!  More clinical trials are needed!

3 important gene findings though

1.As you start ramaging into the genes involved
you soon encounter the PTPN11---PLCG2----BTK (Bruton), but also Lyn, SHC1 to block Apoptosis, and GAB2 that binds Grb2 the begining of trouble ("wild gene").

2.The Breast Cancer inference comes when you bring in C1QBP---PKC zeta---YWHAC which interacts with BCAR1, and you know BRCAs are not far!

3.For 1 of the daughter to be positive for Estrogen Receptor, you must assume that her receptor stays on because of imbalance G protein. (look into the RIC8 which I assume to be decrease! leading to increase of GB gamma  and of course because of the Phosducin -like Protein PHLP1).  Folks I can't test any further, got to wait 10-20 years at the pace of our progress!

Or else call me to help 915-307-3354!
The CRBCM, at work always...

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