By David N. Leff

If a new car turns out to be a lemon, there are so-called "lemon laws" to ensure it gets repaired free, or replaced.

Presumably, such defective automobiles result from lapses by workers on the assembly line. Comparable Oops! factors can account for congenitally defective hearts — in people, mice and fruit flies. In such inborn cardiac flaws, the assembly-line workers are genes that build the prenatal hearts of fetuses during embryogenesis.

When a middle-aged individual slumps lifeless to the sidewalk, his or her heart attack is often blamed on coronary artery disease, perhaps brought on by too much rich food and too little exercise. But when a young athlete suddenly drops dead in the heat of the game, that death bespeaks congenital heart disease, inherited before birth.

By the middle of the third week into the gestation of a human embryo, the four-chambered embryonic heart begins to take shape.

"That's when you start to see an already-beating heart tube form," recounted human molecular geneticist Jon Seidman, at Harvard Medical School, in Boston. "Then there's a very complicated process," he went on, "whereby this two-chambered tube loops and folds on itself so the two atria and the two ventricles can form. Septal formation begins during the fifth week, and the primitive atrium is divided into right and left atria. By the end of that week, the architecture of the heart is essentially complete.

"Normally, Seidman continued, "we were all born with a hole in the septum — the thin membrane that separates the left and right atrial chambers. This hole shunts the fetal blood away from its still-undeveloped lungs. It usually closes very shortly after birth, within the first week or so of a human baby's life. If not, heart surgery in early childhood can repair the hole, which is about the size of a finger's width."

Heart-Breaking Gene Mutations Tracked Down

That's if the gene responsible for building that part of the heart is doing its job right. But once in every 1,500 live births in the U.S., it screws up, and that hole in the septum never closes.

"Anatomically," Seidman went on, "in people who have such a hole, blood passes from the left side of the atrium to the right side. The problem is that normally blood returning from the lungs is collected in the left atrium and then passed to the left ventricle.

"In an individual who has a hole, when the left atrium contracts, instead of the blood being forced into the left ventricle, it gets forced into the right atrium. Such patients don't get enough blood in their left ventricle, so when that chamber squeezes, it doesn't squeeze enough blood into the circulation to provide adequate oxygenated blood to the rest of body.

"These children become cyanotic. That is, their skin turns bluish-purple. Their particular congenital heart disease is called atrial septal defect — ASD."

Seidman has just announced discovery of gene mutations responsible for that cardiac lemon. The July 3, 1998, issue of Science carries his report under the title "Congenital heart disease caused by mutations in the transcription factor NKX2-5 [gene]."

The heart-building NKX2-5 gene fulfills cardiac construction contracts not only with Homo sapiens (human) and Mus musculus (mouse), but with Drosophila melanogaster (fruit fly), as well as with higher forms of life in general.

To track his new gene down to the long arm of human chromosome 5, Seidman first consulted the fruit fly genome. "It had been shown," he recalled, "that in D. melanogaster, a gene called tinman was required for the fly's cardiac development. It didn't dawn on me for a year and a half," he revealed, "that the fruit fly people had named that gene tinman because the Tin Man in "The Wizard of Oz" had no heart — reflecting a fruit fly embryo with two mutated tinman alleles [parental gene variants]."

By the same heartless token, he added, "A mouse minus both NKX2-5 alleles dies in utero, because of failure to form the appropriate cardiac structures."

To scope the gene mutations' role in atrial septal defect, and determine the disorder's inheritance pattern, Seidman analyzed the DNA of a five-generation extended congenital heart disease family numbering 32 members, 17 still living.

"The members of this family who harbor this NKX2-5 mutation," he recounted, "have a septal defect. In recent years, the technology for determining if there is a septal defect has improved very dramatically with echo cardiography, so it's possible to look at the wall of the septum and ask: 'Where's the hole?'

"In these individuals, at familial risk of inheriting ASD, the hole is right in the same region of septum as in some people where there's no evidence yet of genetic etiology."

But there's more to ASD than a vestigial aperture.

Family In Study Provides Unusual Twist

"Individuals with a surgically repaired septum usually do quite well," Seidman said." In other circumstances, they have electrical conductance defects, and require a pacemaker to maintain a strong, steady heartbeat.

"In this extended family," he went on, "every living member required a pacemaker. The surprising thing is that many of them had the devices installed before they went on to have surgery to repair the hole."

Explaining the surprise element, Seidman observed, "It had been hypothesized previously that it was the surgical repair itself that led to the destruction of the electrical conductance system, which thus required a pacemaker. That may be true in many instances," he allowed, "but in this family it appears not to be. There are individuals here who had a conduction defect well before they showed any signs of a septal defect."

Of the three NKX2-5 gene mutations he detected in the DNA of these family members, two caused truncation of their expressed proteins, essentially knocking them out. The third, a missense mutation, he suspects, was also inactivated.

Among various clinical payoffs one might envisage from this gene discovery, Seidman suggested one diagnostic prospect.

"Because not all individuals with septal defects have conduction disease, certainly one could imagine screening the NKX2-5 gene of patients with septal defects to see if they have gene mutations, and therefore will develop conduction disease." But he added, "I just don't know if the low number of cases will make it worthwhile."

Farther down the road, he foresees that "the potential for doing gene therapy — or something like gene therapy — in individuals with septal defects becomes real if you can identify the proteins in the septum that are not being made adequately. "You could imagine eventually turning those genes on, and thereby stimulating septal formation, thus providing a treatment for people with this condition. Of course," he concluded, "that's sort of a pipe dream right now." *