Published April 26, 2013
University at Buffalo researchers have identified a genetic mutation leading to a hereditary anemia—marking the first time defects in a mechanosensitive ion channel have been implicated as the cause of a disease.
Their findings have been published in a paper in the Proceedings of the National Academy of Sciences.
Researchers have found that familial xerocytosis, a
mild-to-moderate form of anemia, is caused by alterations in the
kinetics of an ion channel in red blood cells.
Ion channels are tiny conduits that help control the flow of important substances, such as calcium, into cells.
“Mutations in the gene that codes for the ion channel PIEZO1 cause the channel to stay open too long, causing an ion leak in red cells,” explains Frederick Sachs, PhD, SUNY Distinguished Professor of physiology and biophysics, who led the research team.
“Calcium and sodium enter, and potassium leaves, affecting the ability of the red cell to regulate its volume."
"As a result, the cells become dehydrated and can break open,
releasing their hemoglobin into the blood,” he
This causes symptoms, such as the shortness of breath seen in anemic patients.
The ion channel PIEZO1 is normally about 10 nanometers across,
but significantly increases in size upon opening; that change in
dimensions is responsible for its mechanical sensitivity.
Sachs discovered in the 1980s that some ion channels are mechanosensitive, that is, they convert mechanical stress into electrical or biochemical signals.
Because all cells are mechanically sensitive, mechanosensitive ion channels are likely to play a role in many diseases.
Sachs and his team have worked on activation of mechanosensitive ion channels in Duchenne muscular dystrophy, caused by errors in a gene coding for a fibrous protein that reinforces the cell membrane.
The loss of reinforcement leads to increased stress, causing the channels to open and leak calcium, which is likely what causes the muscles to atrophy, Sachs explains.
Sachs and his colleagues also have discovered a peptide in a
tarantula venom that inhibits the PIEZO1 and other channels,
suggesting a possible therapy.
Sachs helped found the biotech company Tonus Therapeutics to create a therapy for muscular dystrophy based on this peptide.
Now synthesized chemically, the peptide has received orphan drug designation from the FDA for muscular dystrophy.
The peptide’s channel-inhibiting ability could make it a
potential therapy for blood diseases where there are defects in the
ways red blood cells regulate cell volume, Sachs notes.
He postulates that mechanosensitive ion channels function as a cell’s emergency valve, “so the only time they open is when cells are under extreme stress,” he explains.
“Consequently, our peptide only affects unhealthy, mechanically stressed cells; it doesn’t bother healthy cells, so it’s nontoxic.”
Co-authors on the study are all part of UB’s Department of
Physiology and Biophysics: Philip A. Gottlieb, PhD, research
associate professor; postdoctoral fellows Chilman Bae, PhD, first
author, and Radhakrishnan Gnanasambandam, PhD; and
programmer/analyst Christopher L. Nicolai.
The research was supported by the National Institutes of Health, the U.S. Department of Defense and the Children’s Guild of Buffalo.