This web page was produced as an assignment for Genetics 677, an undergraduate course at UW-Madison.
Ankyrins Away: The Mutations of Hereditary Spherocytosis
It’s entirely possible to live normally with anemia. However, being plagued with symptoms such as fatigue, headaches, and shortness of breath will often cause inconveniences in life. The most common cause of cases of hemolytic anemia in those of Northern European descent is caused by Hereditary Spherocytosis (HS) - a genetic disease that causes red blood cells to be the wrong shape. Since HS is responsible for so many cases of anemia, it is important to understand what kind of genetic mutations are causing symptoms and how parents are passing them on to their children. Stefan Eber and his collaborators recognized this importance and studied the genes of 46 individuals with HS and found a wide array of mutations in one common gene: ankyrin-1.
Ankyrin-1 acts as a linker protein in red blood cells. As a rough analogy, if blood cells were compared to a human, ankyrin would act as the muscles and tendons that hold the bones to the skin. When red blood cells have malformed copies of this protein or are missing them all together, it can’t form the characteristic donut-like shape we normally think of and instead forms tiny fragile spheres. This becomes a problem when the body is trying to filter the blood- it’s like trying to fit balloons through a path meant for Frisbees, and often the balloons pop. When fragile blood cells are popping like balloons, this causes a shortage of red blood cells in the body that doctors call hemolytic anemia.
The researchers managed to characterize a wide range of mutations, but the more interesting and useful information came from the patterns they found. When mutations occurred that caused the protein to be unusable by the cell, the patient had severe anemia and often one of the patient’s parents also had HS. In cases where the patient had milder symptoms of HS, the cells could still use the incorrect protein or there was a smaller amount of ankyrin-1.In these cases there were often other mutations found that affected related proteins that ankyrin binds to. With this knowledge, researchers are now closer to understanding how HS develops and how to better treat its symptoms.
Ankyrin-1 acts as a linker protein in red blood cells. As a rough analogy, if blood cells were compared to a human, ankyrin would act as the muscles and tendons that hold the bones to the skin. When red blood cells have malformed copies of this protein or are missing them all together, it can’t form the characteristic donut-like shape we normally think of and instead forms tiny fragile spheres. This becomes a problem when the body is trying to filter the blood- it’s like trying to fit balloons through a path meant for Frisbees, and often the balloons pop. When fragile blood cells are popping like balloons, this causes a shortage of red blood cells in the body that doctors call hemolytic anemia.
The researchers managed to characterize a wide range of mutations, but the more interesting and useful information came from the patterns they found. When mutations occurred that caused the protein to be unusable by the cell, the patient had severe anemia and often one of the patient’s parents also had HS. In cases where the patient had milder symptoms of HS, the cells could still use the incorrect protein or there was a smaller amount of ankyrin-1.In these cases there were often other mutations found that affected related proteins that ankyrin binds to. With this knowledge, researchers are now closer to understanding how HS develops and how to better treat its symptoms.
Reference
Eber, S.W., Gonzalez, J.M., Lux, M.L., Scarpa, A.L., Tse, W.T., Dornwell, M., Herbers, J., Kugler, W., Ozcan, R., Pekrun, A., Gallagher, P.G., Shroter, W., Forget, B.G., Lux, S.E. 1996. Ankyrin-1 mutations are a major cause of dominant and recessive hereditary spherocytosis. Nature Genetics 13, 214 – 218 doi:10.1038/ng0696-214
Cover Image: http://pedsinreview.aappublications.org/content/suppl/2001/06/27/22.7.219.DC1/020-003aHereditary_Spherocytosis_smear.jpg
Cover Image: http://pedsinreview.aappublications.org/content/suppl/2001/06/27/22.7.219.DC1/020-003aHereditary_Spherocytosis_smear.jpg