What is the Defect in our DNA?

[Updated 2009 Post] 

A few years ago, I asked one of the doctors on the KDA's Scientific Review Board to describe the defect in our DNA and what it means to those of us living with Kenndy's Disease. His explanation follows:

"The androgen receptor is important for our body's response to male hormones, such as testosterone and dihyodrotesteoserone. The receptor is like a baseball glove, and normally catches ("binds") androgens and then moves them to the nucleus, which is the main control center for the cell. There it helps control the things that make us men (like the genes for watching TV while lounging in our favorite chairs). In Kennedy disease, it is as if the lacing has come out of our baseball glove, and the androgen receptor is not working right. The glove does not have the right shape (it is misfolded), and that makes it hard to catch the baseball well. The androgen receptor can still move to the nucleus, but because it is misfolded, this causes problems. The cell does not work right and eventually might die. And, since this androgen receptor is made by both motor nerve cells and muscle cells, this causes us big problems with moving our arms and legs, and swallowing."

Now for a more scientific explanation, a college professor on the board provided the following:

"In Kennedy's Disease, the defective gene is in the "X" chromosome. The symptoms of Kennedy's Disease are due to a mutation in the gene that produces the androgen receptor (AR) protein. The AR protein acts to mediate all the effects of androgens (testosterone and dihydrotestosterone - male hormones) in cells and in our bodies. Those individuals with Kennedy's Disease produce an altered form of the AR protein, a form that, while it still works well enough mediating the effects of androgens (and so males are still male), produces an additional effect of causing certain spinal cord and brain cells to die. The affected nerve cells are primarily those that control the activation of muscle cells. When the nerve cells die, the muscle fibers that they control shrink and become inactive causing the muscle weakness characteristic of Kennedy's Disease."

Research suggests that the altered form of the AR has problems being recycled (cleaned of all garbage) in the presence of androgens and instead of being completely removed; mutant proteins (the garbage) are only partially digested in the affected cells. This partial digestion of the AR results in the production of AR fragments that, through an unknown mechanism, are toxic to cells. Since this effect is dependent on relatively high levels of androgens, severe muscle weakening is generally not seen in women who carry the mutant form of the AR gene.



Okay, now that I have read both explanations, I feel a little more comfortable. However, I still do not believe I have accomplished what I set out to do today and that was to simplify the explanation. So, I asked "Joe, the Plumber" and he explained the defect like this. “The thingamajig is broken and that causes the whatchamacallits not to work properly.” Now that helps. 😛