A rare mutation offers wide possibilities

As they flow through veins and arteries, most red blood cells are plump with water. Channels lining the membrane of each red blood cell help ensure that it has the right balance of salts and liquids, keeping the cells elastic and healthy. It’s a process vital to human biology, but also one that’s been hard for researchers to fully explain. A team including scientists at the School of Medicine has now uncovered a protein that is key to how blood cells maintain their hydration, and which could have implications for treating sickle cell anemia, the most common inherited blood disorder in the United States.

The discovery came out of a quest to understand a much rarer inherited blood disorder called xerocytosis. In this disease, the equilibrium of red blood cells is off: extra potassium and water seep out of cells as they careen against the sides of blood vessels, leaving the cells fragile and causing anemia, a shortage of red blood cells. Sickle-cell anemia, which affects some 70,000 Americans, is characterized by misshapen red blood cells, and a common complication, apart from the clumping of the misshapen cells, is cell dehydration. “Some of the mechanisms that cause the dehydration are known, but we’ve never uncovered what is that channel at the top of the mountain that starts the avalanche going,” says Patrick G. Gallagher, M.D., professor of pediatrics, genetics, and pathology.

Gallagher and a team of collaborators thought that if they could understand dehydration in hereditary xerocytosis, it might help explain the similar phenomenon they see in sickle cell patients. So, in a study supported by the Doris Duke Foundation and conducted in collaboration with a team from the University of Manitoba, they analyzed the genomes of two large, multi-generational families affected by xerocytosis. As reported in the August 30, 2012, issue of Blood, in both families they identified mutations in the gene for a protein called PIEZO1.

Fortuitously, the PIEZO1 protein had been characterized for the first time in late 2010 as a channel that senses mechanical force or pressure on a cell’s outer membrane—such as the change in pressure that could be caused by swelling or shrinkage of the cell. “This is the first example of a human disease connected to the protein,” says Jesse Rinehart, Ph.D., assistant professor of cellular and molecular physiology, who joined Gallagher to study the protein’s role in xerocytosis.

Rinehart showed that PIEZO1 is indeed found in the membrane of red blood cells and went on to analyze its structure. He hasn’t yet uncovered the effect of the xerocytosis-linked mutations on PIEZO1’s function, but that’s a next step. “The first take away from this is that here is what causes xerocytosis,” says Gallagher, director of the Yale Center for Blood Disorders. “But the second is that it looks like PIEZO1 is a very good candidate to be what initiates dehydration in sickle cell.”

The cause of sickle cell anemia—a mutation in the oxygen-carrying protein hemoglobin—has been known for decades. Though scientists haven’t established what causes the cellular dehydration seen in the disease, many suspect that another protein initiates the dehydration process. If PIEZO1 is that long sought-after protein, says Gallagher, drugs targeting PIEZO1 could treat some of sickle cell’s symptoms as well as those of hereditary xerocytosis.

At an international meeting on red blood cells at Yale this winter, investigators from around the world will be sharing their data on PIEZO1 to help complete the story. “Already, this really validates the idea that studying the rarest diseases can help us understand biology more broadly,” says Rinehart.