Pump failure implicated in a form of dystonia

July 21, 2004

Tiny genetic flaws in a protein that pumps sodium and potassium across the membranes of neurons have been implicated in a rare but devastating form of dystonia. Patricia de Carvalho Aguiar and her colleagues have pinpointed for the first time genetic mutations that underlie the disorder known as rapid-onset dystonia parkinsonism.

The disorder usually strikes adolescents or young adults, suddenly and without warning. After a fever, heat exposure, prolonged exercise, childbirth, or emotional stress, people with the disorder begin to suffer tremors and loss of muscle control over mere hours or days. Once they occur, the symptoms are permanent.

Aguiar and her colleagues began by analyzing numerous candidate genes in the cells of seven families with the disorder. The genes lay within the chromosomal region known to be linked to inheritance of the disease. The researchers pinpointed mutations in one particular gene, called ATP1A3, as common in all the families. This gene is the blueprint for a protein that is a key catalytic subunit in a larger enzyme that pumps sodium and potassium across the membranes of neurons, using the energy of ATP to do so. Such transport is critical to maintaining the gradients of those substances that are necessary for the neurons to fire properly, activating muscle cells.

The scientists' analyses of the mutations revealed them to be six different "missense" mutations in the gene, each of which caused the incorporation of an incorrect amino acid unit into the protein during synthesis. The incorrect amino acid, while different in the six mutations, had in common that all appeared to either jam the pump's molecular machinery, cause unstable misfolding in the protein, or both.

The researchers tested the effects of the mutations by incorporating them into cultured cells. They found that each of the six mutations tended to kill the cultured cells. The researchers determined that the death of the cultured cells was due, not just to the malfunctioning of the mutant protein, but to its lower production in the cells.

Thus, the researchers theorized, people with the mutations may abruptly suffer symptoms after stressful events when the nerves controlling their muscle cells are unable to keep up with the higher demand for the transport of sodium and potassium.
Patricia de Carvalho Aguiar, Kathleen J. Sweadner, John T. Penniston, Jacek Zaremba, Liu Liu, Marsha Caton, Gurutz Linazasoro, Michel Borg, Marina A.J. Tijssen, Susan B. Bressman, William B. Dobyns, Allison Brashear, and Laurie J. Ozelius: "Mutations in the Na+/K+-ATPase a3 Gene ATP1A3 Are Associated with Rapid Onset Dystonia Parkinsonism"

Published in Neuron, Volume 43, Number 2, July 22, 2004, pages 169-175.

Cell Press

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