Focus
October 15, 2004
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Neurobiology:
Ion Channel Protein in Inner Ear Is Likely Long-sought Key to Hearing

Anesthesia:
Study Finds How Aspirin Dampens Inflammation

Genetics:
Broken Calcium Gate Leads to Heart Syndrome with Related Autism

State of the School
Martin Draws Picture of Tangible Progress at HMS

Biomedical Computing:
Faculty Receive Funding for Two National Biomedical Computing Centers

research briefs
Calcium Supplements During Pregnancy Linked to Healthy Blood Pressure in Children

Newly Found Cancer Gene Offers Model for Breast Tumor Development

Cell-Cell Interaction Not Needed for Normal Neuron Size in Retina

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Scholars Program Maintains Growth in Junior Faculty Awards

Former HMS Professor Wins 2004 Nobel Prize

HMS Revamps Program in Medical Education

NIH Pioneer Award Funds Developmental Biology Research

Modeling Disease: New Windows on a Hidden World

Grant Promotes Clinician-scientists in Eye Research

NIH Roadmap Supports Pilot for Vision Research Center

HMS Unveils New Web Pages

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Escape from the Stereotype Trap

Front Page

GENETICS

Broken Calcium Gate Leads to Heart Syndrome with Related Autism

Excessive Calcium Entry into Cells Disrupts Development

The babies were few and far between, but to clinical coordinator Katherine Timothy, they were hard to miss. Working to gather patients for genetic studies on abnormal heart function, Timothy was primarily interested in the infants' severely abnormal heartbeats. But their other features--webbed fingers or toes, extremely rounded faces, bald heads, and small teeth--stuck in her mind through the years. As treatment for the children improved and they began to survive beyond the first few years, she noticed 80 percent of the children showed autism or related cognitive problems. Over a span of 10 years, Timothy saw only 14 of these babies and children, but their common characteristics were so clear that she was able to define a syndrome that bears her name.

When Mark Keating (left) and Igor Splawski tracked down the genetic cause of Timothy syndrome, they discovered a widespread developmental role for the Cav1.2 calcium channel. (Photo by Graham Ramsay)


Now researchers at HMS and Children's Hospital Boston have discovered that the unusual constellation of physiological and developmental problems faced by children with Timothy syndrome are all caused by a mutation in a widely distributed calcium channel. The mutation leaves cells awash in calcium and perturbs the development and function of nearly every organ system, including the nervous system.

"This finding highlights in a profound way how important calcium signaling is for development and physiology."
"This channel is known as the cardiac calcium channel, but our work indicates its importance for the development and function of much more than the heart," said Mark Keating, HMS professor of cell biology and of pediatrics at Children's. Keating is the senior investigator on the project, reported in the Oct. 1 Cell.

The result immediately points to the use of calcium channel blockers as a new therapy for Timothy syndrome patients. "Given that this is a problem of inappropriate opening of calcium channels, the blockers could be a silver bullet for this disease," said Keating. And the suggestion that defective calcium signaling can result in one type of autism opens new avenues for research into a common disease whose causes and cure are still a mystery.

Genetic Basis of Arrhythmias

The Keating lab started looking for genetic causes of arrhythmias more than 15 years ago. They have focused on a particular abnormality called long QT syndrome, a killer of healthy young adults whose first symptom is often sudden cardiac death. So far, Keating and his colleagues have identified five genes that can cause inherited versions of long QT syndrome.

This illustration of the predicted topology of the Cav1.2 calcium channel sitting in the cell membrane shows the location of the single amino acid change (G406R) that causes Timothy syndrome. The alteration in just one of the 2,000-plus amino acids that make up the channel disrupts the molecule's shut-off mechanism and allows abnormal calcium entry into cells.


To identify the gene for Timothy syndrome, a subtype of long QT, Igor Splawski, an HMS instructor in pediatrics working in Keating's lab, sequenced the five known arrhythmia genes as well as more than a dozen other candidate genes in the DNA of 13 affected children. None of the genes, including Cav1.2, which codes for an L-type calcium channel thought to function mainly in the heart, revealed any alterations. Then Splawski, the first author on the Cell paper, checked a newly discovered variant of Cav1.2. To his amazement, 13 of 13 Timothy syndrome children carried an identical mutation in the variant form of Cav1.2.

In Timothy syndrome, a modest genetic change turns out to have a dramatic effect. Splawski found that a single nucleotide in one copy of the channel gene was changed, with a resulting substitution of the amino acid arginine for the original glycine. The mutation causes the channel, which normally opens and closes with each heartbeat, to stay open all the time, flooding cells with calcium.

Since calcium influx, particularly through Cav1.2, is known to trigger muscle contraction, it is easy to understand how persistent channel opening can lead to abnormal heartbeats. But a role for the calcium channel in development of many other body systems was not suspected before this work. When they checked in mice, Splawski, Keating, and their colleagues were not surprised to find the channel expressed in most tissues and organs, and in many areas of the brain.

The mutant channels can still be shut down with commonly available calcium channel blockers, medicines that are widely used to treat angina in adults. Early results from treating Timothy syndrome children look very promising for normalizing their heart rhythms, according to Keating. But, he says, it is too early to tell whether other conditions associated with the syndrome, like the autism or hypoglycemia and immune deficiencies, will be improved by this treatment.

Calcium-Autism Connection

The link between calcium and autism is an intriguing aspect of this discovery. Keating emphasized that there may be little similarity between the syndromic autism of the Timothy children and the common forms of autism that affect 200,000 to 400,000 children in the United States. But, he said, "We don't know anything about the common forms of autism at the molecular level, and our studies may point in a fruitful direction for that disease." One of the first things the researchers will do is examine patients with autism and related disorders for defects in the Cav1.2 gene.

Cav1.2 is the first calcium channel gene found to cause arrhythmia, and the first example in which the defect does not run in a family. Instead, the channel mutation occurs anew in each affected child. While this may explain the syndrome's rarity, the explanation for why the same mutation would show up in all the children independently is not entirely clear. The researchers speculate that the gene contains a mutation hot spot. The mutation that occurs there is unusual because it produces a gain of function in which more calcium is ushered into the cell than through a normal channel. "In general, it is much easier to break something than to make it work better," explained Splawski, and this may be why the spectrum of physiological and development problems of Timothy syndrome are only seen as a result of this unique mutation.

"This finding highlights in a profound way how important calcium signaling is for development and physiology," said Keating. "This is not novel--we've known calcium is important. But I'm not aware of another mutation in humans that illustrates it this well."

For Katherine Timothy, the second author of the Cell report, the best part of 12 years of gene hunting was this discovery. It is not every day that a finding in genetics translates into an immediately testable new treatment. And that is good news for her Timothy syndrome children.

--Pat McCaffrey