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A Fatal Flaw in the Hearts of Children
Scientists identify a gene involved in the sudden cardiac deaths of healthy children
Edward R. Winstead

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Every child in Italy who plays competitive sports must first pass an exercise stress test and have a normal cardiogram. The goal is to identify kids who may develop a rare but potentially fatal heart condition, one of several stress-induced arrhythmia disorders. The stress test can reveal an underlying susceptibility. If running on a treadmill causes an irregular heartbeat in a 12-year-old athlete, then playing a game of soccer might trigger the arrhythmia and lead to cardiac arrest. For many victims, cardiac arrest is the first symptom of the disease.

Detail from figure representing evidence of CPVT in three individuals with hRyR2 mutations. View full

An Italian cardiologist and her collaborators have identified a gene involved in an arrhythmia disorder first described in the 1970s, catecholaminergic polymorphic ventricular tachycardia (CPVT). Silvia G. Priori, of the University of Pavia, Italy, and colleagues identified four families with disease-related mutations in the cardiac ryanodine receptor gene, or hRyR2. The gene encodes a calcium release channel protein.

‘This is all part of a very primitive response the body has evolved over millions of years.’

"The findings demonstrate the existence of another genetically mediated arrhythmia that should be treated as a new disease," says Silvia Priori. The status of the disorder has until recently been unclear, and few doctors know about it. The study was published online in December in Circulation. Since then, the Italian group has identified four other families that have mutations in the same gene that are associated with the arrhythmia. Priori's laboratory offers genetic screening for mutations in hRyR2 at no cost for patients worldwide with a clinical diagnosis of CPTV.

"The identification and follow-up of these families is critical to improving our knowledge about this disease," says Priori. "Now that we have a critical mass of cases we can begin to define the prevalence of the disease in the population."

This type of arrhythmia can be triggered by either physical or emotional activity, the researchers found. In one family, two teenage sisters died of sudden cardiac death, one at age 16 while climbing stairs and the other at age 14 while taking exams at school. Because of her family history, a third sister received a heart implant to deliver therapeutic shocks in response to an irregular heartbeat. The device successfully terminated two episodes in the patient, then age 30. Both instances involved emotional stress: The first episode occurred while her boss was firing her; the second while she was acting in a play.

Detail from schematic of a calcium release channel.
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Autopsies and clinical examinations have shown that the hearts of CPVT patients are structurally sound. Cardiac arrest in these patients may be due to an electrical problem involving calcium release channels—the proteins that regulate the amount of calcium inside cardiac cells. "The calcium ion is very important, and its concentration should be carefully controlled so that the heart contracts without developing arrhythmias," explains Priori.

The electrical problem may have its origin in the genome. Priori's group hypothesizes that mutations in the hRyR2 gene make calcium release channels sensitive to activation under the stress of emotional or physical activity. "Emotion and exercise increase the release of calcium inside the heart, and we think this generates the arrhythmia," summarizes Priori. If a channel releases too much calcium from its stores in the cell, the cell can experience calcium overload, a condition associated with arrhythmias that can degenerate into cardiac arrest.

‘The usefulness of universal screening is a matter of debate in Italy.’

The role of excitement as a trigger in the process makes evolutionary sense. Heart cells naturally release more calcium during the body's fight-or-flight response, says Andrew R. Marks, of Columbia University College of Physicians and Surgeons in New York. "This is all part of a very primitive response the body has evolved over millions of years to increase the pumping of the heart to escape predators."

Marks has studied calcium release channels for 15 years, and Priori's findings support his hypothesis that some stress-induced arrhythmia disorders are due to defects in the operation of calcium release channels. "We have proposed that defective regulation of these channels can cause sudden cardiac death, so we were thrilled to see mutations in the ryanodine receptor gene," he says.

The Columbia researchers have introduced the mutations identified by Priori into synthetic cell membranes to try to understand how channel defects may lead to arrhythmias. "What's clear is that the heart beats too rapidly in these disorders," says Marks. "What isn't clear is the molecular mechanism that leads to this."

Mutations in hRyR2 were found only in a third of the families in Priori's study. Mutations may be present in the other families, she says, but finding them could prove difficult because hRyR2 is so large (the biggest ion channel gene yet reported, according to Marks). A second difficulty is that hRyR2 probably is not the only gene involved in CPVT. Priori expects the genetics of CPVT to be analogous to those of long QT syndrome, another stress-induced arrhythmia disorder. "At least five genes have been implicated in long QT syndrome," she says.

Indeed, most cases of CPVT are likely to be complex in origin, involving as yet unknown combinations of unidentified genetic and environmental risk factors, the researchers say. Risk factors that modify the effects of a single-gene defect appear to be important in determining the severity of disease in a patient.

The complexity of CPVT is suggested by the variable age of onset. Although a stress-induced arrhythmia usually manifests around age 8, there are cases of individuals developing the disease much later in life, and some carriers of the genetic defect never develop symptoms their entire lives.

Models of the channels certainly are not simple. In Marks' model, the calcium release channel is a 'signaling complex' whose operation is governed by the interactions of multiple proteins.

‘Hopefully we will be able to help reduce the frequency of this tragedy in little kids.’

Priori's conclusion that the calcium release channel gene plays a role in the disorder is based on several lines of evidence. First, the hRyR2 gene resides in a region of chromosome one that has been linked to the disorder. Second, the mutations identified in the study occur in regions of hRyR2 that are likely to influence gene function. And third, defects in the calcium release channel protein are associated with calcium overload, which is presumed to be a factor in CPVT.

Screening every child in Italy for relatively rare exercise-induced arrhythmia disorders is expensive. "The usefulness of universal screening is a matter of debate in Italy," says Priori. But she points out that early identification is essential for managing the disease and patients can often be treated effectively with medications such as b-blockers. Until it becomes feasible to screen for mutations associated with the disorders in the general population, the treadmill test is a reliable way to identify individuals at risk.

As news about the hRyR2 study has spread, physicians around the world have referred possible cases of CPTV to Priori. She recently learned of a 7-year-old girl who developed an arrhythmia on Christmas Day. The girl had never shown symptoms of a heart condition, and it was the level of excitement that apparently triggered the disease.

"She was jumping around and playing with her cousin," says Priori. "Suddenly she dropped to the floor, and her arms were shaking in seizure-like activity. She was brought to the Emergency Room, and when they finally successfully interrupted the incessant arrhythmias, she was brain dead. Her story is very touching. Hopefully we will be able to help reduce the frequency of this tragedy in little kids."

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Priori, S.G. et al. Mutations in the Cardiac Ryanodine Receptor Gene (hRyR2) Underlie Catecholaminergic Polymorphic Ventricular Tachycardia. Circulation 103,196-200 (published online on December 11, 2000).

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