Protein mutations are at the center of an investigation into the deaths of four children who seen their mother, Kathleen Folbigg, convicted of murder and manslaughter. So what is calmodulin and what can a mutation in the gene that encodes it do to the heart? Paul Biegler explains in this updated March 2021 story.
A group of leading Australian and international experts have called on the Governor of NSW to pardon serial child killer Kathleen Folbigg.
The petition, whose signatories include Nobel laureates Elizabeth Blackburn and Peter Doherty, cites new DNA evidence suggesting that all four of Folbigg’s children, whom she was convicted of murdering in 2003, may have died of natural causes.
It comes as Folbigg awaits judgment on an appeal by the NSW Supreme Court, which she launched to overturn the findings of a 2019 inquest which upheld her guilt. (Later in March 2021, the court upheld the findings of the 2019 inquest, which kept Folbigg in jail.)
So what exactly is the scientific argument put forward in the petition?
Among the evidence examined by the 2019 inquest was ‘molecular autopsies’ on the two female Folbigg children – one of whom died at 10 months and the other at 18 months – which revealed they had genetic mutations that predispose to sudden cardiac death.
Despite these findings, the investigation did not exonerate Folbigg. On the contrary, Commissioner Reginald Blanch QC concluded that the evidence “makes his guilt of these offenses even more certain”.
This conclusion is disputed in the current petition which claims that the investigation did not have access to critical data. While both children had genetic mutations, there was no “functional validation” or hard data at the time to show the variants were likely to have caused a fatal cardiac event.
These data are, according to the petitioners, now at their fingertips.
An international study commissioned by the 2019 survey, led by Peter Schwartz of the Center for Genetic Cardiac Arrhythmias in Milan, Italy, published in November 2020, found a genetic variant known as CALM2 G114R had “probably precipitated the natural deaths of both girls”.
What is the CALM2 mutation, what does it do and how could it have caused the deaths of two Folbigg children?
CALM2 G114R is a variation of the gene CALM2 which codes for a protein called calmodulin (read our genetics explanation) which, in turn, regulates the movement of calcium into heart muscle cells. Calcium is essential for what is called excitation-contraction coupling in the heart.
Each of your approximately 70 heartbeats per minute begins in a nucleus of cells at the top of the heart called the sinoatrial (SA) node. The SA node has a property called “automaticity”, which means that it can generate an electric spark, called an action potential, on its own.
The spark travels to another stage called the atrioventricular node before triggering a succession of contractions in heart muscle cells or ‘myocytes’. It all happens like a Mexican wave, and the end result is your heart squeezing blood into the large arteries that supply the rest of your body.
CALM2 G114R is a variation of the gene CALM2 which codes for a protein called calmodulin which, in turn, regulates the movement of calcium into heart muscle cells. Calcium is essential for what is called excitation-contraction coupling in the heart.
So where does calcium come from? Each myocyte must have its own action potential fired in a coordinated fashion, which is caused by changes in electrical charge across the cell wall called “depolarization”. These finely tuned charge changes are triggered by ion channels that open and close to admit and release all-important sodium, potassium, and calcium ions in rapid succession.
If there is a hiccup in the flow of any of these ions, coordination is lost and your Mexican wave is interrupted. Depending on which ion is the culprit, a hierarchy of effects occurs, some of which fatally alter the heart rate. This is where calcium comes into play.
Calmodulin closes the ion channels through which calcium enters and leaves heart muscle cells. But if you have the CALM2 G114R variant, calmodulin has trouble closing the channel – it stays open and calcium can come and go as it pleases. The result? This nice connection between the “excitement” of the SA node and the “contraction” of the cardiac muscles is lost.
So what happens to people with this variant? Schwartz assembled an earlier team to find out. The researchers looked at 74 people with mutations in the calmodulin gene suite known as CALM1, CALM2 and CALM3, conditions known as calmodulinopathies. Their report, published in the european journal of the heart in 2019, makes disturbing reading.
Twenty-seven percent of people with calmodulinopathy had sudden cardiac death. Their average age was just under six years old. The genetic variants were linked to irregular heartbeats called ventricular fibrillation, which are usually fatal, and a condition called long QT syndrome, which shows up on the resting heart trace or “ECG” and can cause chaotic and fatal heartbeats. .
One arrhythmia particularly stood out
“Catecholaminergic polymorphic ventricular tachycardia” (CPVT) is a very rapid beating of the lower chambers of the heart, triggered by an increase in “catecholamine” hormones such as adrenaline, often due to exercise or intense emotion. In the latest study, Schwartz’s team had this arrhythmia in their sights.
First, they performed genetic sequencing on samples from the four children and from Kathleen Folbigg herself. They found the CALM2 The G114R variant was present in the mother and the two daughters – Sarah and Laura, referred to as Child 3 and Child 4 in the study. Then they did a series of experiments in the lab. These showed CALM2 G114R interfered with the ability of calmodulin to regulate two pivotal calcium channels. The discovery led the authors to a crucial conclusion. The variant, they write, makes carriers “prone to cardiac arrhythmias…which could cause cardiac arrest during sleep.”
But two other aspects of the girl’s death were also telling. Four days before her death, Sarah (Child 3) was diagnosed with a croupy cough and put on antibiotics by the GP. “Severe infections could have caused an elevated catecholamine state,” the authors state, plausibly triggering an arrhythmia such as CPVT.
Laura (child 4) also had a respiratory infection two days before her death, which was treated with a drug containing pseudoephedrine, an adrenaline-like drug. In addition, she had myocarditis, an inflammation of the heart, at the autopsy. “Combinations of these factors may have triggered the fatal events,” the authors write.
Of course, neither of these explanations is relevant for the two male children (Child 1 and Child 2 in the article), who did not have the CALM2 G114R variant. The new 2020 study, however, found that both boys had a rare genetic mutation linked to fatal epilepsy in mice.
In sum, the studies provide evidence for the “functional validation” missing in the 2019 survey, potentially linking the genetic variant to life-threatening arrhythmias in Folbigg girls.
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