A Genetic Legacy
by Lauren Stancheck

When a Dutch orphan, Ariaantje Adriaanse, set sail for South Africa in 1688, chances are she offered more than her hand in marriage.

Now, more than 300 years and thousands of descendants later, scientists have uncovered her likely genetic legacy - a disease that has spread exponentially throughout the South African population.

In the 1950s a British doctor noticed South Africa's high incidence of a disease called variegate porphyria (poor-FEAR-ee-ah). Using family Bibles to trace lineages, he discovered its genetic nature. Since then scientists have found that variegate porphyria is the second most common inherited disease in South Africa.

Several kinds of porphyria have been found in humans, each with its own telltale combination of symptoms. For example, patients with variegate porphyria experience light sensitivity, easily broken skin, and occasional and unpredictable acute attacks involving intense abdominal pain. Various medications, chemicals and even sunlight can trigger these attacks.

Scientists like Peter Meissner at the University of Cape Town (UCT) study the disease and its symptoms to better understand how it affects the South African population. Researchers have learned that heme, the iron-rich molecule that transfers oxygen from the blood to cells, plays a key role in the disease.

Half a world away, Harry Dailey, a UGA professor of microbiology, biochemistry, and molecular biology and director of UGA's new Biomedical and Health Sciences Institute, is studying the body's assembly line-like production of heme.

Dailey drew the South Africans' attention with his research on PPO - which stands for protoporphyrinogen oxidase - one of the enzymes required to make heme. A defect in PPO is the key element in the onset of porphyria.

Producing heme requires eight different enzymes. When any one of these enzymes malfunctions, heme precursors, called porphyrins, build up in the blood. This increase in porphyrins results in porphyria.

The human body makes the heme molecules it needs like an assembly line - enzymes add each piece sequentially to create the finished product.

"So anything that affects one part of the assembly line will have an impact on the other part of the assembly line," Dailey said.

Science has yet to understand how the overproduction of porphyrins causes the skin sensitivity and abdominal pains.

"The actual symptoms are, as far as one can tell, really not directly related to the compound heme itself," Dailey said.

Porphyria is divided into seven types, depending on which enzyme is malfunctioning. For example, PPO functions at the sixth step in the heme assembly line. Defective PPO results in variegate porphyria, the type most common in South Africa.

Dailey's lab was the first to purify the PPO enzyme. For this reason, Meissner arranged to do post-doctoral studies in his lab, creating the foundation for a future partnership. Then UCT invited Dailey to South Africa to share laboratory techniques. Two years later, Meissner, now director of the internationally recognized Porphyria Research Unit at UCT and the leading researcher on porphyria in South Africa, again settled temporarily at the University of Georgia to work on another project - identifying the mutation responsible for variegate porphyria.

Together, Meissner and Dailey first found the normal PPO gene, or the chain of molecules within DNA that acts as a code to make PPO. They then sequenced the gene, or determined the order of the molecules in the gene, using the enzyme Dailey's lab had already copied.

"We had strong clues about what we were looking for and we had samples from patients," Meissner said. "My Cape Town lab was sequencing DNA from a patient named Lusinda and so was Harry's lab, because you can get sequence errors. So we both ran the sequences to compare results."

To determine the mutation - or change in the DNA sequence they compared the normal PPO sequence to that of a person with the disease. The researchers specifically compared the function of the normal and mutant PPO enzymes and found that the mutant PPO results in variegate porphyria.

In order to even begin this process, the researchers needed cells containing the mutation. Because variegate porphyria is a dominant inherited trait, an individual only needs one copy of the mutant gene to develop the disease.

Though symptoms do not usually appear until puberty, the severe condition of a 3-year-old South African girl named Lusinda led UCT researchers and Dailey to believe she had two copies of the mutation. This made her an ideal cell donor for the study.

In extreme cases like Lusinda's, people may have little or no sensation in their fingertips and are unable to feel a hot stove or use a conventional computer keyboard.

With Lusinda's cells and DNA, no matter which copy of the gene the scientists isolated, it would include the mutation responsible for her disease. They discovered two different mutations, one of which connected today's South African population to a previously insignificant piece of history - the marriage of Dutch orphan Ariaantje Adriaanse to fellow Dutchman Gerritt Jansz van Deventer at Cape Town in 1688.

"The whole thing is a quirk of history," Meissner said. "One of them carried a single, distinctive gene mutation that now constitutes 90 percent of the variegate porphyria cases in South Africa."

"If you look around the world you'll find that there are at least 50 mutations that have been identified that lead to variegate porphyria," Dailey said. "This is fairly common for many genetic diseases where the cause is not a single mutation but any one of a whole variety of mutations."

"It was a detective story that was sort of halfway done and we just added the molecular components to cap off the story," Dailey said.

Finding the mutation opened the door for UCT researchers to develop neonatal screening. Thanks to that research, South Africans with variegate porphyria can now avoid the medications and chemicals that aggravate their condition and can prevent painful, life-disrupting symptoms before they ever develop.

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Lauren Stanchek, a science writing intern in UGA's Research Communications Office, began her graduate studies in forensic science at Michigan State University in August.