A question concerning CAG repeats

I recently received the following question this week:

“Do you know of any understandable explanation of CAG Count and its importance and implications to SBMA sufferers? Everything I have found is pretty unintelligible to me (and I thought I was a pretty intelligent kind of a person!!). From what I can gather the count length - whatever that is (& I have no idea of mine) is important to diagnosing the condition but is of no particular relevance in assessing the outcome. Is that correct?”


So I consulted our biology professor and asked for help. Ed provided the following explanation of the DNA mutation and Kennedy’s Disease. I definitely learned something from his explanation. Thanks, Ed.

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Kennedy’s Disease (aka SBMA) is a genetic disease.  Aside from the fact that this means one inherits the disease from one's parents, this fact has other implications.   The fact that it is genetic also means that there is a change in a gene - a gene being an inheritable factor that influences some trait.  Genes are made of a type of biomolecule called DNA.  DNA, in turn, is composed of long chains of small subunit molecules called nucleotides.  Different genes are linked together to form larger DNA structures called chromosomes.  Humans have 23 pairs of chromosomes (for a total number of 46) and each chromosome can have over a thousand different genes.  Nonetheless, each chromosome in every person should contain the same genes in the same order.  Now since genes are made up of DNA, and genes make up chromosomes, chromosomes contain DNA.  So essentially, the genetic material has a hierarchical structure:  Chromosomes:Genes:Nucleotides.  A simple, similar analogy might be Building:Walls:Bricks.

Now one might wonder what makes each gene different.  As was stated, each gene is made of DNA which is in turn made of nucleotides.  DNA employs 4 different nucleotides: adenine, guanine, cytosine and thymine.  Scientists, being efficient (or maybe lazy) abbreviate these with single letters - A, G, C and T.   Each gene has a specific, unique sequence of nucleotides much like words have a specific, unique sequence of letters.  The primary difference is that each gene's sequence is very long, often in excess of a thousand nucleotides.   The sequence of nucleotides in a gene tells the cell how to make a specific protein, thus each gene codes for the production of a specific protein.  If the nucleotide sequence of a gene is altered (this alteration is known as a mutation), the resulting protein is altered and it may not work normally (and often does not work at all).  The result of such a change may results in changes in the way the cells work and if this occurs, we would say that this would be a genetic disease.  Thus Kennedy’s Disease is due to a mutation in a specific gene that alters the function and structure of a specific protein.

The gene mutated in Kennedy’s Disease is the gene that codes for the protein known as the androgen receptor (AR).  The type of change in the nucleotide sequence in the gene for AR that causes KD is quite unusual.  Usually, mutations are due to nucleotide substitutions or deletions or insertions - but this is not true for Kennedy’s Disease.

Kennedy’s Disease is due to the repeat of a three nucleotide sequence - a repeat of the sequence that is cytosine-adenine-guanine or CAG in the scientific shorthand.   This CAG (pronounces see-a-gee, NOT pronounced so it rhymes with hag) repeat actually occurs in the AR gene in all humans where its repeat number is quite variable.  The repeat only causes Kennedy’s Disease when the repeat number exceeds 40 (CAG repeated 40 times).  Individuals with repeat numbers less than 40 do not have Kennedy’s Disease.  At this time, it is not clear why this causes Kennedy’s Disease (scientists are trying to find out) but it does!