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Timothy Syndrome Is Caused by Defective Calcium Channels

By Cheryl Simon Silver

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Heart Disease

Scientists have identified a genetic mutation that causes Timothy syndrome, a rare childhood disorder that leads to developmental problems involving many organs, including the heart. The mutation, which is the sole cause of the syndrome, occurs in a protein that controls the flow of calcium into and out of cells.

In addition to severe cardiac arrhythmia and cognitive and physical deficits, some children with Timothy Syndrome have autism, which led the researchers to hypothesize that problems with the calcium channel may contribute to the neurological disorder in some children.

Although the developmental problems associated with Timothy syndrome cannot be treated, the researchers believe that drugs known as calcium channel blockers may be able to treat the heart arrhythmia and other physiological problems.

In their effort to find the genetic cause of the syndrome, which was identified in 1989, Mark Keating of Children’s Hospital in Boston and his colleagues determined that the disorder is not inherited but rather caused by a mutation that occurs spontaneously. All of the children in the study shared a mutation in the same protein, called the CaV1.2 calcium channel.

“One of the interesting findings was that all of the cases had exactly the same mutation,” says Keating. The protein performs the important task of closing off the flow of calcium into the cells, and when it malfunctions too much calcium enters and overwhelms a cell.

Unchecked, the calcium causes a range of problems. The researchers found that the mutated gene was active not only in heart muscle, which had been known, but also in brain tissues, the gastrointestinal system, lungs, and immune systems. There are a number of kinds of calcium channels, but disturbing even one can cause a number of disorders because the proteins are important to proper function of organs.

And, the researchers note, problems with calcium signaling may contribute to at least some cases of autism.

“Our findings that individuals with Timothy Syndrome met the criteria for autism or had severe deficits of language and social development suggest that abnormal [calcium] signaling may contribute to these disorders,” the researchers write in Cell.

Splawski, I. et al. CaV1.2 Calcium Channel Dysfunction Causes a Multisystem Disorder Including Arrhythmia and Autism. Cell 119, 19-31 (October 1, 2004).

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