Stellenbosch scientists identifies the gene that causes inherited heart disease

(From left standing) Sr Althea Goosen (Stellenbosch University); Prof Olaf Pongs (University of Hamburg); Prof Paul Brink (Stellenbosch University); Dr Lou Hofmeyr (Stellenbosch University). (Front left sitting) Prof Eric Schulze-Bahr (University of Munster); Prof Valerie Corfield (Stellenbosch University).

After a scientific search of more than three decades, researchers in the Faculty of Health Sciences, Stellenbosch University - in collaboration with international partners - have pinpointed the rogue gene that causes the inherited heart disease, known as progressive familial heart block type I, in a group of South African families whose ancestors can all be traced to one immigrant who landed on these shores in 1696.

The disease was first described by Prof Andries Brink - a cardiac specialist and former dean of the Faculty - in 1977. In 1986, Brink's son, Prof Paul Brink, in collaboration with Prof Valerie Corfield - both of the Faculty of Health Sciences - embarked on the search for the genetic mutation that triggers the condition and causes a disruption of the electrical impulses that control heart contractions. They traced this to a small area on chromosome 19 which contained about 80 genes. This search recently came to an end when Brink and Corfield, in collaboration with scientists from Hamburg and Münster in Germany, managed to pinpoint the exact gene amongst this group.

The study, which represents years of research and at times involved teams of other scientists, clinicians, cardiac specialists and technologists of the Stellenbosch Faculty of Health Sciences, is due to be published in the September edition of the international Journal of Clinical Investigation. However, an online version of the article can be accessed ahead of print, on the Journal's website [http://www.jci.org/]

The study of progressive familial heartblock started at Stellenbosch University in the 1970's when Prof Andries Brink - then practicing as a cardiac specialist at the Tygerberg Hospital - treated a baby who was born with a very slow heart rate. The child's condition was so serious that she had to be fitted with an artificial cardiac pacemaker. She thus became the first baby in South Africa to be treated with a pacemaker. According to Prof Paul Brink, it was a big decision to make at the time because artificial pacemakers were at an early stage of development and they were almost the size of a brick. Today, the body of a pacemaker is less than four centimeters long, and it is implanted under the skin with electrodes regulating the beating of the heart.

While Brink was treating the baby, he became aware of another child who also needed a pacemaker. This child happened to be a close relative of the baby under his care. He then examined the mother and found evidence of a similar underlying disease - but not as advanced as that of the baby. This lead Brink to believe that he was dealing with a family problem and he called in the help of Dr Marie Torrington, an expert in the field of genealogical research, who soon traced the disease to other families - most of them living in the Eastern Cape. She found that the carrier of the defective gene came to South Africa from Madeira, Portugal in 1696. He married a woman of Dutch descent. Today, all South Africans affected by progressive familial heart block are descendants of this couple.

Roughly 50% of children born to an affected person will be carriers. Of these "about two thirds will need a pacemaker at one time or another," says Prof Valerie Corfield. "A very small percentage of them will show no evidence of the disease on an electrocardiogram, even though they carry the gene, while others will display an underlying electrical glitch."

According to Prof Paul Brink, progressive familial heart block is characterized by a slow heart rate which necessitates a pacemaker. "The disease can occur any time from birth until old age and in some cases it has been identified in utero. Today it can be managed with the timely implantation of a pacemaker, but before the advent of this device it often claimed the lives of patients affected by the condition."

He says the identification of the affected gene could not have taken place without the ongoing cooperation and interest of the families affected by the disease. At the same time, advances in molecular biology in the 1990's and the mapping of the human genome in particular, made it possible for himself and Corfield to use the information, gathered from large family studies, to pinpoint a particular place on one chromosome where the rogue gene was situated.

However, even with their access to the human genome, "it was like looking for a needle in a haystack. There were at least eighty genes in the area where we expected to find the rogue gene. Examining all of them was a costly and time-consuming process," says Corfield.
"It was during this search that Prof Olaf Pongs of a research team in Hamburg, Germany, contacted us serendipitously and told us that he was interested in a particular gene situated in our search area and that we should take a closer look at this gene. We thus teamed up with Pongs and another research team in Münster, Germany and through our joint efforts it was finally confirmed that the gene that interested Pongs, indeed showed a very small change that leads to the development of the disease. Through our research it soon became clear that the product of this gene was playing a role in the way heart cells handle sodium and potassium, which underlie the electrical signals of the heart."

The discovery of the rogue gene means that families in the affected population can now receive an accurate genetic diagnosis and learn at an early stage which members of a family is at risk of developing the disease - and should be followed up accordingly.

At the same time, it will give scientists and clinicians better insight and understanding of many conditions affecting the electrical system of the heart, such as non-genetic delays in the heart rate which is common in older people.

* Brink and Corfield are also involved in a wide range of studies of other genetic cardiac disorders, most of which also involve founder families of Afrikaner descent, i.e. a cardiac muscle disease known as hypertrophic cardiomyopathy that predisposes people – often young and seemingly healthy sportsmen and women - to sudden unexpected death, as well as a Long QT syndrome which causes dangerously irregular heart rhythms and another conduction disorder, known as progressive familial heart block, type II.