Series: Sickle Cell Cells (Part 2)

NOTE: At the end of my introductory post on this topic, I said that I’d next cover patient symptoms (similar to what I did for the Henrietta Lacks/HPV series).  However, after further thought, I’ve decided that for this disease it makes the most sense to go from DNA problems, to protein problems, to cell problems, and finally patient symptoms.  

Also, it might be useful to re-familiarize yourself with the Central Dogma post and the Carbon Monoxide  post before reading this one.

My first post on this topic covered inherited disease.  I discussed how mutant genes are passed from parent to child.  Remember, a gene is a series of DNA bases that encode a particular protein (Central Dogma Post).  DNA is copied into RNA, which then goes to the ribosome where the RNA is translated.  Consecutive sets of three RNA bases encode for one amino acid.  The ribosome reads the sets of RNA bases, recruits the correct amino acid, and creates a protein chain. 

A mutant gene has a mistake in the DNA.  The mistake is simply an incorrect A, G, C or T.  Somewhere along the way, one base was switched for another.  When the RNA is copied from the DNA, the mutation is copied and the ribosome will translate exactly what the RNA says.  I will explain the implications of this very clearly in Figure 52.1.

 In the case of Sickle Cell Disease, one gene is mutated: the hemoglobin gene.  In my Carbon Monoxide post, I discussed a bit about this protein.  In summary, hemoglobin is a protein found in red blood cells and is responsible for carrying oxygen to all parts of our bodies.  It’s a special protein in that four individual molecules of hemoglobin come together in red blood cells to make oxygen delivery more efficient.

A normal, happy hemoglobin gene has the sequence shown on the top of Figure 52.1.  Underneath, I’ve shown how the ribosome reads the sets of three RNA bases and what amino acid each triplet encodes.  

On the bottom of Figure 52.1, I show you the hemoglobin gene found in Sickle Cell patients.  Look at it really carefully.  The difference is so small: A to T.

Unfortunately, the set of three RNA bases changes from GAG to GTG.  The ribosome reads GAG as one amino acid, but GTG is different amino acid.  Underneath the RNA sequence, I’ve shown what amino acids are encoded by this mutated gene.

This means that these hemoglobin molecules have an incorrect amino acid in them.  Sometimes this isn’t a big deal for proteins (good idea for a future post, I think), but in this case, it is a disaster.  

This one little amino acid change precludes the hemoglobin molecules from forming nice, discrete sets of four proteins in red blood cells.  Instead, many hemoglobin molecules come together at once and form long strands of protein.  Figure 52.2 shows you how this distorts a healthy red blood cell’s shape to form a more sickled (curved and pointy) shape both in cartoon format and by showing you actual red blood cells from a microscope image.

Remember from my first post, I told you that humans have two copies of each gene.  If you have two healthy copies of the hemoglobin gene, then all your hemoglobins are happy and your red blood cells look like the top of Figure 52.2.  If you have two bad copies of the hemoglobin gene, then the vast majority if your cells look like the bottom of Figure 52.2 and you have Sickle Cell Disease (also called Sickle Cell Anemia, which I’ll discuss in greater detail in my next post).  

One last option exists where you have one good hemoglobin gene and one mutated one.  Some of your cells will sickle, while some of your cells will not.  You are said to have Sickle Cell Trait in this circumstance since you show some sickled red blood cells, but not to the same extent as those with Sickle Cell Disease.  Interestingly, there a evolutionary advantage to having Sickle Cell Trait.

Sickled red blood cells can cause a variety of problems.  What those problems are and how it affects the health of the patient will be covered in the next post!

Note: The hemoglobin protein is much longer than the six amino acids I show you in Figure 52.1.  I just highlighted the area where the mutation lies for clarity.

REFERENCES

More info on the hemoglobin mutation: http://www.ornl.gov/sci/techresources/Human_Genome/posters/chromosome/hbb.shtml

Cell Images and more info from PubMed Health: http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001554/